tag:theconversation.com,2011:/us/topics/genetic-mutation-5511/articlesGenetic mutation – The Conversation2023-02-22T12:54:03Ztag:theconversation.com,2011:article/2002102023-02-22T12:54:03Z2023-02-22T12:54:03ZHow frontotemporal dementia, the syndrome affecting Wendy Williams, changes the brain – research is untangling its genetic causes<figure><img src="https://images.theconversation.com/files/511473/original/file-20230221-16-3xvr3l.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some of the same genetic mutations can lead to FTD, ALS or symptoms of both.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/brain-lp-pr-royalty-free-illustration/1164761753">antoniokhr/iStock via Getty Images Plus</a></span></figcaption></figure><p>Around <a href="https://www.who.int/news-room/fact-sheets/detail/dementia">55 million people worldwide</a> suffer from dementia such as Alzheimer’s disease. On Feb. 22, 2024, it was revealed that former talk show host <a href="https://www.npr.org/2024/02/22/1233172648/wendy-williams-aphasia-frontotemporal-dementia-diagnosis">Wendy Williams</a> had been diagnosed with <a href="https://www.theaftd.org/what-is-ftd/disease-overview/">frontotemporal dementia, or FTD</a>, a rare type of dementia that typically affects people <a href="https://www.alzheimers.gov/alzheimers-dementias/frontotemporal-dementia">ages 45 to 64</a>. <a href="https://apnews.com/article/what-is-frontotemporal-dementia-bruce-willis-fbfdbfca4793bb65ef3f38f31e31bd68">Bruce Willis</a> is another celebrity who was diagnosed with the syndrome, according to his family. In contrast to Alzheimer’s, in which the major initial symptom is memory loss, FTD typically involves changes in behavior.</p>
<p>The <a href="https://www.nia.nih.gov/health/what-are-frontotemporal-disorders">initial symptoms of FTD</a> may include changes in personality, behavior and language production. For instance, some FTD patients exhibit inappropriate social behavior, impulsivity and loss of empathy. Others struggle to find words and to express themselves. This insidious disease can be especially hard for families and loved ones to deal with. There is no cure for FTD, and there are no effective treatments.</p>
<p><a href="https://www.theaftd.org/genetics-of-ftd/">Up to 40% of FTD cases</a> have some family history, which means a genetic cause may run in the family. Since researchers identified the first genetic mutations that cause FTD in 1998, <a href="https://doi.org/10.15252%2Fembj.201797568">more than a dozen genes</a> have been linked to the disease. These discoveries provide an entry point to determine the mechanisms that underlie the dysfunction of neurons and neural circuits in the brain and to use that knowledge to explore potential approaches to treatment.</p>
<p><a href="https://profiles.umassmed.edu/display/130139">I am a researcher</a> who studies the development of FTD and related disorders, including the motor neuron disease <a href="https://www.als.org">amyotrophic lateral sclerosis, or ALS</a>. ALS, also known as Lou Gehrig’s disease, results in progressive muscle weakness and death. Uncovering the similarities in pathology and genetics between FTD and ALS could lead to new ways to treat both diseases.</p>
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<figcaption><span class="caption">Wendy Williams’ care team announced her diagnosis of frontotemporal dementia on Feb. 22, 2024.</span></figcaption>
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<h2>Genetic causes of FTD</h2>
<p>Genes contain the instructions cells use to make the proteins that carry out functions essential to life. Mutated genes can result in mutated proteins that lose their normal function or become toxic. </p>
<p>How mutated proteins contribute to FTD has been under intense investigation for decades. For instance, one of the key proteins in FTD, called <a href="https://doi.org/10.1016%2Fj.neuron.2011.04.009">tau</a>, helps stabilize certain structures in neurons and can form clumps in diseased brains. Another key protein, <a href="https://doi.org/10.1038%2Fnrn.2017.36">progranulin</a>, regulates cell growth and a part of the cell called the lysosome that breaks down cellular waste products.</p>
<p>Remarkably, the most common genetic mutation in FTD – in a gene called C9orf72 – <a href="https://doi.org/10.15252%2Fembj.201797568">also causes ALS</a>. In fact, apart from the mutations in genes that encode for tau and progranulin, most genetic mutations that cause FTD <a href="https://doi.org/10.15252%2Fembj.201797568">also cause ALS</a>. Another protein, <a href="https://doi.org/10.15252/embj.201797568">TDP-43</a>, forms clumps in the brains of over 95% of ALS cases and almost half of FTD cases. Thus, these disorders share close links in genetics and pathology.</p>
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<figcaption><span class="caption">Frontotemporal dementia typically affects people under 60.</span></figcaption>
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<h2>Modifier genes</h2>
<p>The same genetic mutation can cause FTD in one patient, ALS in another or symptoms of both FTD and ALS at the same time. Remarkably, some people who carry these genetic mutations may have no obvious symptoms for decades.</p>
<p>One reason the same mutation can cause both FTD and ALS is that, in addition to <a href="https://theconversation.com/als-is-only-50-genetic-identifying-dna-regions-affected-by-lifestyle-and-environmental-risk-factors-could-help-pinpoint-avenues-for-treatment-179169">lifestyle and environmental factors</a>, other genes may also influence whether mutated genes lead to disease. Identifying these <a href="https://doi.org/10.1016%2Fj.neuron.2020.08.022">modifier genes</a> in FTD, ALS and other neurodegenerative diseases could lead to new treatment approaches by boosting the activity of those that protect against disease or suppressing the activity of those that promote disease. </p>
<p>Modifier genes have long been a focus of research in <a href="https://www.umassmed.edu/fen-biaogaolab/">my laboratory</a> at the University of Massachusetts Chan Medical School. When my laboratory was still in San Francisco, we collaborated with neurologist <a href="https://profiles.ucsf.edu/bruce.miller">Bruce Miller</a> and generated the first stem cell lines from FTD patients with mutations in <a href="https://doi.org/10.1016%2Fj.celrep.2012.09.007">progranulin</a> and <a href="https://doi.org/10.1007%2Fs00401-013-1149-y">C9orf72</a>. These stem cells can be turned into neurons for researchers to study in a petri dish. My team also uses fruit flies to identify modifier genes and then test how they influence disease in neurons from patients with FTD or ALS.</p>
<p>For instance, in close collaboration with cell biologist <a href="https://www.stjude.org/directory/t/j-paul-taylor.html">J. Paul Taylor</a>, my laboratory was among the first to discover a small <a href="https://doi.org/10.1038%2Fnature14974">subset of modifier genes</a> that help transport molecules into or out of the nucleus of a neuron. We also <a href="https://doi.org/10.1016%2Fj.neuron.2016.09.015">discovered</a> <a href="https://doi.org/10.1073%2Fpnas.1901313116">modifier genes</a> that encode for some proteins that help repair damaged DNA. Targeting these modifier genes using <a href="https://doi.org/10.1089%2Fnat.2018.0725">gene-silencing techniques</a> developed by Nobel laureate <a href="https://www.nobelprize.org/prizes/medicine/2006/mello/facts/">Craig Mello</a> and other researchers at UMass Chan could offer potential treatments.</p>
<h2>Treating behavioral changes in FTD</h2>
<p>Because the brain is an extremely complex organ, it can be very difficult to understand what causes personality and behavioral changes in FTD patients. </p>
<p>Over the years, my team has used mice to study the causes of these changes. For instance, we found that the reduced social interaction we observed in mice engineered to have FTD is linked to <a href="https://doi.org/10.1038%2Fnm.3717">two different</a> <a href="https://doi.org/10.1038%2Fs41593-019-0397-0">disease proteins</a> in the same part of the brain, suggesting that this symptom may be caused by defects in the same neural circuit. These deficits could be reversed by injecting a molecule called <a href="https://doi.org/10.1038%2Fnm.3717">microRNA-124</a> into the prefrontal cortex, the part of the brain that controls social behaviors.</p>
<p>Moreover, with my longtime collaborator neuroscientist <a href="https://www.upstate.edu/psych/faculty.php?empID=yaow">Wei-Dong Yao</a>, our labs found that mice with FTD have <a href="https://doi.org/10.1038%2Fnm.3717">defects at</a> <a href="https://doi.org/10.1038%2Fs41593-019-0397-0">the synapses</a> in this part of the brain. Synapses are areas where neurons are in contact with each other and play an important role in transporting information in the nervous system. Recently, he found that <a href="https://doi.org/10.1016/j.neuron.2022.12.027">lack of empathy</a> in another mouse model of FTD could be reversed by increasing activity in the prefrontal cortex. </p>
<p>Further research to understand the molecular mechanisms and brain circuitry behind FTD offer hope that its devastating symptoms, including behavioral and personality changes, will be treatable in the future.</p>
<p><em>This is an updated version of an article originally published on Feb. 22, 2023.</em></p><img src="https://counter.theconversation.com/content/200210/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Fen-Biao Gao receives and has previously received funding from the NIH, The Muscular Dystrophy Association, The Association for FTD, Target ALS Foundation, The ALS Association, The Tau Consortium, The Consortium for Frontotemporal Dementia Research, The Ricico Fund, The Cellucci Fund, Merck, and Stealth BioTherapeutics.
He works for the NIH as a member of its CMND study section, for The Muscular Dystrophy Association as a member of its Research Advisory Council and for The Association for FTD as a member of its Scientific Review Panel. </span></em></p>FTD leads to changes in personality and behavior. Understanding its genetic and molecular causes could lead to new ways to treat neurodegenerative diseases.Fen-Biao Gao, Professor of RNA Therapeutics, Governor Paul Cellucci Chair in Neuroscience Research, Founding Director of Frontotempral Dementia Research Center, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1936132022-11-14T18:23:13Z2022-11-14T18:23:13ZWhy South Asians are at increased risk for diabetes: A complex interplay of genetics, diet and history<figure><img src="https://images.theconversation.com/files/493649/original/file-20221105-25-6t92cl.jpg?ixlib=rb-1.1.0&rect=2%2C2%2C1524%2C1020&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Person having their blood glucose level measured with a glucometer.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><iframe style="width: 100%; height: 100px; border: none; position: relative; z-index: 1;" allowtransparency="" allow="clipboard-read; clipboard-write" src="https://narrations.ad-auris.com/widget/the-conversation-canada/why-south-asians-are-at-increased-risk-for-diabetes--a-complex-interplay-of-genetics--diet-and-history" width="100%" height="400"></iframe>
<p>In 2021, there were <a href="https://www.diabetesatlas.org">537 million adults living with diabetes</a>, of which approximately 90 per cent had Type 2 diabetes. When someone has Type 2 diabetes, specialized cells within the pancreas known as “beta cells” produce insufficient amounts of insulin.</p>
<p><a href="https://doi.org/10.1038%2Fs41591-021-01418-2">Insulin is a hormone</a> that travels through the bloodstream and tells other cells to take excess sugar out of the blood and use this sugar as energy, making sure the body keeps doing everything it needs to. </p>
<p>Individuals with Type 2 diabetes are “insulin resistant,” meaning cells do not adequately recognize insulin. These individuals require more insulin than normal to regulate blood sugar levels. When beta cells fail to compensate for the increased insulin demand, blood sugar levels rise, adversely affecting organ function.</p>
<p>Globally, the South Asian community is composed of over two billion individuals. In Canada, <a href="https://www.diabetes.ca/DiabetesCanadaWebsite/media/Advocacy-and-Policy/Backgrounder/2022_Backgrounder_Canada_English_1.pdf">14.4 per cent of South Asians have Type 2 diabetes</a>, the highest prevalence of any other ethnic group in the country.</p>
<p>As a member of the South Asian community, it is incredibly common for me (Lahari Basu) to learn that someone I know has been diagnosed with Type 2 diabetes. When I joined <a href="http://www.bruinlab.com/">Dr. Jenny Bruin’s lab</a> at Carleton University to study diabetes for my PhD, I was intrigued by this question: Why are South Asians disproportionately impacted by Type 2 diabetes?</p>
<p>That answer lies in a web of genetic, behavioural and cultural factors.</p>
<h2>Genetic variants</h2>
<p>In 2013, researchers confirmed that South Asians are particularly insulin resistant. Compared to Caucasians, <a href="https://doi.org/10.1016/j.metabol.2013.10.008">South Asians had higher insulin concentrations in their blood after ingesting sugar</a>. This means that South Asian individuals require more insulin to regulate their blood sugar levels, a characteristic of Type 2 diabetes.</p>
<p>There are numerous possible explanations for this, but genetic variants could be one culprit. Variation, or mutations, in genes can alter cell function. In the case of beta cells, genetic variants can lead to inappropriate levels of insulin secretion and insulin resistance.</p>
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<img alt="Cropped image of a young man in a plaid shirt holding an insulin pen" src="https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/494899/original/file-20221111-2672-d6vtg1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Individuals with Type 2 diabetes are insulin resistant, meaning cells do not adequately recognize insulin. Some people with Type 2 diabetes inject insulin with an insulin pen.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
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<p>It turns out that South Asians have <a href="https://doi.org/10.1038/s42003-022-03248-5">acquired mutations in various genes required for proper beta cell function</a>. They also have a higher prevalence of mutations in a <a href="https://doi.org/10.1038%2Fng.921">gene called GRB14</a>, resulting in increased insulin resistance.</p>
<p>Although not all South Asians have these mutations, a significant proportion do. There are also likely other gene variants that have yet to be uncovered in this population. These gene variants begin to paint an interesting picture of how genetic predisposition increases their risk of developing diabetes.</p>
<h2>Physiological adaptations</h2>
<p>Genetic variants only explain a small part of the increased insulin resistance in South Asian individuals. This observed insulin resistance may also have historical context.</p>
<p>South Asians have faced multiple famines throughout history. The recurrence of depleted food sources and malnutrition led to the development of a <a href="https://doi.org/10.2337%2Fdc11-0442">starvation adaptation</a>. This adaptation allowed them to efficiently process food and store fat during times of abundance, providing an advantage during famine.</p>
<p>Now, with urbanization and migration, this trait can be detrimental to South Asians. The adaptation does not bode well in a world with increased access to high-fat foods. Combined with modern-day diets, this adaptation can result in <a href="https://doi.org/10.1007/s00125-022-05803-5">increased fat storage and abdominal obesity in South Asian individuals</a>, leading to greater risk of insulin resistance and diabetes.</p>
<h2>Cultural differences</h2>
<p>Food plays an important social role in South Asian culture. For as long as I can remember, big family dinners were integral to my lifestyle and cultural identity. For us, food is a way to communicate, to honour ancestors and to celebrate.</p>
<p>The staples of South Asian cuisine include white rice, flatbreads and potatoes, with most cooking being done in clarified butter. This diet is influenced from a time before refrigerators and food abundance, focusing on shelf-stable, self-preserving foods. Diets high in carbohydrates and fat have been <a href="https://doi.org/10.1017/s0007114508073649">linked to increased insulin resistance and decreased metabolism</a> (the process of converting food into energy).</p>
<h2>Culture-centred treatment</h2>
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<img alt="A woman in a green shirt listening to a man in a white coat with his back to the camera" src="https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1131&fit=crop&dpr=1 754w, https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1131&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/494900/original/file-20221111-11-bzc8rr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1131&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Implementing treatment programs that focus on the culture of the patients can help approach diabetes management in a new light.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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</figure>
<p>There is clearly a complex relationship between South Asian ethnicity and diabetes risk. The interplay of culture and genetics presents a unique challenge for this community. For many, <a href="https://doi.org/10.1002/pdi.619">unfamiliarity with diabetes</a> may prevent them from getting the care they need.</p>
<p>Implementing <a href="https://doi.org/10.1186/s12992-019-0451-4">treatment programs that focus on the culture of the patients</a> can help approach diabetes management in a new light. Healthier versions of traditional foods, familiar languages and being cognizant of cultural barriers can help South Asians with diabetes understand the seriousness of the condition, their predisposition to it, and how to manage their symptoms.</p>
<h2>A call for South Asian-centric research</h2>
<p>As a South Asian woman studying diabetes, learning about this phenomenon opened my eyes to how little we know about ethnicity-specific diabetes risk. <a href="https://doi.org/10.1136%2Fbmjopen-2016-014889">South Asians are severely underrepresented in clinical research</a>. To truly understand the complex relationship between Type 2 diabetes and South Asians, it is vital to conduct clinical studies that specifically target this ethnic group.</p>
<p>A better scientific understanding of the link between South Asians and increased Type 2 diabetes and implementing culture-centred management programs can help alleviate the mystery and stigma behind this phenomenon.</p><img src="https://counter.theconversation.com/content/193613/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jennifer Bruin receives funding from the Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), and JDRF. </span></em></p><p class="fine-print"><em><span>Lahari Basu does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>In Canada, 14.4 per cent of South Asians have Type 2 diabetes, the highest prevalence of any other ethnic group in the country. Why is this population so disproportionately affected by diabetes?Lahari Basu, PhD Candidate, Department of Biology and Institute of Biochemistry, Carleton UniversityJennifer Bruin, Associate professor, Department of Biology and Institute of Biochemistry, Carleton UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1942342022-11-10T19:01:30Z2022-11-10T19:01:30ZHow cancer cells can become immortal – research finds a mutated gene that helps melanoma defeat the normal limits on repeated replication<figure><img src="https://images.theconversation.com/files/494498/original/file-20221109-2908-x151bw.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3295%2C2608&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Melanoma is a particularly aggressive form of skin cancer.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/melanoma-cancer-cell-royalty-free-image/177233874">Dlumen/iStock via Getty Images Plus</a></span></figcaption></figure><p>A defining characteristic of cancer cells is their <a href="https://doi.org/10.1016/S0092-8674(00)81683-9">immortality</a>. Usually, normal cells are limited in the number of times they can divide before they stop growing. Cancer cells, however, can overcome this limitation to form tumors and bypass “mortality” by continuing to replicate. </p>
<p><a href="https://doi.org/10.1038/345458a0">Telomeres</a> play an essential role in determining how many times a cell can divide. These repetitive sequences of DNA are located at the ends of chromosomes, structures that contain genetic information. In normal cells, continued rounds of replication shorten telomeres until they become so short that they eventually trigger the cell to stop replicating. In contrast, tumor cells can maintain the lengths of their telomeres by activating an enzyme called <a href="https://doi.org/10.1186/s12929-018-0422-8">telomerase</a> that rebuilds telomeres during each replication.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of chromosome with red telomeres at the ends" src="https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=655&fit=crop&dpr=1 600w, https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=655&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=655&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=823&fit=crop&dpr=1 754w, https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=823&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/494502/original/file-20221109-16-a949gi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=823&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Telomeres are protective caps at the ends of chromosomes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/telomere-is-the-end-of-a-chromosome-royalty-free-illustration/916486974">FancyTapis/iStock via Getty Images Plus</a></span>
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</figure>
<p>Telomerase is encoded by a gene called <a href="https://www.ncbi.nlm.nih.gov/gene/7015">TERT</a>, one of the most frequently mutated genes in cancer. TERT mutations cause cells to <a href="https://doi.org/10.1126/science.279.5349.349">make a little too much telomerase</a> and are thought to help cancer cells keep their telomeres long even though they replicate at high rates. <a href="https://www.cancer.org/cancer/melanoma-skin-cancer/about/what-is-melanoma.html">Melanoma</a>, an aggressive form of skin cancer, is highly dependent on telomerase to grow, and <a href="https://doi.org/10.1126/science.1230062">three-quarters</a> <a href="https://doi.org/10.1126/science.1229259">of all melanomas</a> acquire mutations in telomerase. These same TERT mutations also occur across <a href="https://doi.org/10.1158/1541-7786.MCR-16-0003">other cancer types</a>.</p>
<p>Unexpectedly, researchers found that TERT mutations could <a href="https://doi.org/10.1126/science.aao0535">only partially explain</a> the longevity of telomeres in melanoma. While TERT mutations did indeed extend the life span of cells, they did not make them immortal. That meant there must be something else that helps telomerase allow cells to grow uncontrollably. But what that “second hit” might be has been unclear.</p>
<p>We are researchers who study the role telomeres play in <a href="https://scholar.google.com/citations?user=ViGpANMAAAAJ&hl=en">human health and diseases</a> like <a href="https://scholar.google.com/citations?user=lUDPKTEAAAAJ&hl=en">cancer</a> in the Alder Lab at the University of Pittsburgh. While investigating the ways that tumors maintain their telomeres, we and our colleagues found another piece to the puzzle: <a href="https://www.science.org/doi/10.1126/science.abq0607">another telomere-associated gene</a> in melanoma.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/QVCjdNxJreE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cancer is a result of uncontrollable cell growth.</span></figcaption>
</figure>
<h2>Cell immortality gets a boost</h2>
<p>Our team focused on melanoma because this type of cancer is linked to people with <a href="https://doi.org/10.1172/jci120851">long telomeres</a>. We examined DNA sequencing data from hundreds of melanomas, looking for mutations in genes related to telomere length. </p>
<p>We identified a cluster of mutations in a gene called <a href="https://medlineplus.gov/genetics/gene/tpp1/">TPP1</a>. This gene codes for one of the six proteins that form a molecular complex called <a href="https://doi.org/10.1101/gad.1346005">shelterin</a> that coats and protects telomeres. Even more interesting is the fact that TPP1 is known to <a href="https://doi.org/10.1038/nature05454">activate telomerase</a>. Identifying the TPP1 gene’s connection to cancer telomeres was, in a way, obvious. After all, it was <a href="https://doi.org/10.1038/nature05454">more than a decade ago</a> that researchers showed that TPP1 would increase telomerase activity.</p>
<p>We tested whether having an excess of TPP1 could make cells immortal. When we introduced just TPP1 proteins into cells, there was no change in cell mortality or telomere length. But when we introduced TERT and TPP1 proteins at the same time, we found that they worked synergistically to cause significant telomere lengthening. </p>
<p>To confirm our hypothesis, we then inserted TPP1 mutations into melanoma cells using CRISPR-Cas9 genome editing. We saw an increase in the amount of TPP1 protein the cells made, and a subsequent increase in telomerase activity. Finally, we returned to the DNA sequencing data and found that 5% of all melanomas have a mutation in both TERT and TPP1. While this is still a significant proportion of melanomas, there are likely other factors that contribute to telomere maintenance in this cancer.</p>
<p><a href="https://www.science.org/doi/10.1126/science.abq0607">Our findings</a> imply that TPP1 is likely one of the missing puzzle pieces that boost telomerase’s capacity to maintain telomeres and support tumor growth and immortality.</p>
<h2>Making cancer mortal</h2>
<p>Knowing that cancer use these genes in their replication and growth means that researchers could also block them and potentially stop telomeres from lengthening and make cancer cells mortal. This discovery not only gives scientists another potential avenue for cancer treatment, but also draws attention to an underappreciated class of mutations outside the traditional boundaries of genes that can play a role in cancer diagnostics.</p><img src="https://counter.theconversation.com/content/194234/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jonathan Alder receives funding from the National Heart, Lung, and Blood Institute to support this work. </span></em></p><p class="fine-print"><em><span>Pattra Chun-On does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>One enzyme plays a key role in how tumor cells replicate and divide indefinitely. Identifying the genes that give these cells their immortality could provide new drug targets to treat cancer.Pattra Chun-On, Ph.D. Candidate in Environmental and Occupational Health, University of PittsburghJonathan Alder, Assistant Professor of Medicine, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1538122021-01-27T17:44:15Z2021-01-27T17:44:15ZCoronavirus: a single ‘escape mutant’ shouldn’t render a vaccine useless<figure><img src="https://images.theconversation.com/files/380831/original/file-20210127-21-n0wbkl.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3055%2C2390&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/w/index.php?curid=92612457">NIAID-RML/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Several coronavirus variants have emerged in recent weeks that have got scientists worried. The variants, which were first identified in the UK (B117), South Africa (B1351) and Brazil (P1 and P2), have several mutations in the <a href="https://theconversation.com/new-coronavirus-variant-what-is-the-spike-protein-and-why-are-mutations-on-it-important-152463">spike protein</a> – the little projections on the surface of the virus that help it latch onto human cells. This protein is the target for all the COVID vaccines currently being rolled out. So will the vaccines protect us from these new variants? </p>
<p>Viruses are often not very good at making identical copies of themselves. This means that each time they replicate, changes or “mutations” in their genetic sequence can occur. Most of these mutations are harmless and have no effect on the virus. However, a small minority may allow the virus to avoid being recognised by components of our immune system. Such mutations are known as “escape mutants”.</p>
<p>For months, <a href="https://www.scientificamerican.com/article/the-u-k-coronavirus-mutation-is-worrying-but-not-terrifying/">scientists have predicted</a> that mutations in the spike protein of SARS-CoV-2 could emerge that stop antibodies being effective. Until recently, this was mostly studied for drugs called monoclonal antibodies. These are artificial antibody treatments, such as REGN-COV2, developed by Regeneron. A spike protein monoclonal antibody only recognises a single part of the spike. This means that a single mutation could, in theory, stop the antibody from binding and neutralising the virus.</p>
<h2>A multifaceted response</h2>
<p>However, our own antibody response to the spike protein, from either infection or vaccination, is made up of many different antibodies – we make a “polyclonal” response. This means that many different B cells (white blood cells that make antibodies) are activated – and all make different antibodies. So it is highly unlikely that a new virus variant will suddenly appear that cannot be recognised by any of our vaccine-induced antibodies. </p>
<p>But what if there is a partial decrease in antibody efficacy in the face of new virus variants? Several teams of scientists around the globe have been working relentlessly to test whether antibodies from vaccinated people are less able to recognise the new virus variants. </p>
<p><a href="https://www.medrxiv.org/content/10.1101/2021.01.19.21249840v1">Scientists at the University of Cambridge</a> studied a small group of vaccinated people and identified some reduction in the ability of their antibodies to neutralise the variant identified in the UK (B117). Similarly, a slight reduction in neutralisation of the variant found in South Africa has been <a href="https://www.biorxiv.org/content/10.1101/2021.01.25.427948v1.full.pdf">reported from the US</a> (B1351). But what do these lab results actually mean for vaccinated people?</p>
<p>At the moment, it is very difficult to examine lab data and predict what will happen in humans. First, we don’t know the minimum number or “titre” of effective antibodies needed to protect someone from the virus. If vaccine-induced antibodies are “excellent” against the original virus but only “good” against the variant, is this good enough? The answer is not yet known for certain, but the mRNA vaccine manufacturer <a href="https://www.statnews.com/2021/01/25/moderna-vaccine-less-effective-variant/">Moderna</a> is confident the answer will be yes.</p>
<p>Second, the lab tests performed on these variants only measure antibodies. Despite this, we know that <a href="https://theconversation.com/coronavirus-how-t-cells-are-involved-and-what-it-might-mean-for-vaccine-development-140374">T cells are important</a> in protective immune responses against SARS-CoV-2. At present, it is unknown what effect the virus variants will have on T cells. Although, as mechanisms of virus recognition by antibodies and T cells are very different, it is reasonable to assume that escape mutants will be responded to differently. So even if a virus variant can avoid certain antibodies, there should still be some effective T cell activity.</p>
<p>On a more reassuring note, scientists widely agree that it is very unlikely a few virus mutations will render the current COVID vaccines useless. However, mutations may make these vaccines less effective overall. One solution is to <a href="https://theconversation.com/covid-vaccines-focus-on-the-spike-protein-but-heres-another-target-150315">include additional viral proteins within vaccines</a>, so a more diverse immune response is induced. Another solution is to update the genetic sequence of the spike protein in vaccines at regular intervals, a strategy already being explored by <a href="https://www.ft.com/content/c0c8f72c-e58e-4319-80c4-0db153ad85db">Moderna</a>. </p>
<p>Either way, future vaccines in development will need to be effective against an evolving virus, and ongoing monitoring of vaccinated populations will be essential.</p><img src="https://counter.theconversation.com/content/153812/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sarah L Caddy does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Neutralising antibodies aren’t the only game in town.Sarah L Caddy, Clinical Research Fellow in Viral Immunology and Veterinary Surgeon, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1208522019-08-12T14:28:11Z2019-08-12T14:28:11ZCryptic genetic variation: the hidden changes in your DNA that could produce new diseases<figure><img src="https://images.theconversation.com/files/287692/original/file-20190812-71909-4hg9hg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-dna-sanger-sequencing-magnifying-796117591?src=u-EYgs0kxs-KDCLMgtNxPQ-1-89">ktsdesign/Shutterstock</a></span></figcaption></figure><p>Rarely has our environment changed so quickly. On top of climate change, we’re exposing ourselves to air pollutants, <a href="https://theconversation.com/youre-eating-microplastics-in-ways-you-dont-even-realise-97649">microplastics</a> and unprecedented levels of fat, salt and sugar in our food.</p>
<p>Environmental change is one of the things that can produce big, serious mutations in our DNA that can quickly lead to disease, such as cancer caused by radiation. But our DNA also contains many tiny hidden mutations. While they initially have no effect on us thanks to a box of genetic tricks our bodies use to protect us, these “cryptic” variations can build up over many generations and then be brought to life by big environmental changes.</p>
<p>Recent research has shown just how important these cryptic variations are to evolution. There’s a chance they could be <a href="https://pearson.com.au/products/Gibson-Greg/It-Takes-a-Genome-How-a-Clash-Between-Our-Genes-and-Modern-Life-Is-Making-Us-Sick/9780134770246?R=9780134770246">behind the growing risk</a> of problems such as diabetes, cancer and heart disease, and could even produce new diseases. But these mutations could also be hidden gifts from our ancestors that enable us to adapt more quickly to the issues we face, from medical conditions to climate change. </p>
<p>Changes to DNA combined with the process of natural selection are what allow species to evolve. Some genetic variations provide a selective advantage and the individuals who have them are more likely to survive and pass on their genes, gradually spreading them throughout the species. Any changes that are a disadvantage reduce the survival or reproductive chances for an individual and are less likely to be passed to future generations.</p>
<h2>Buffer against change</h2>
<p>Cryptic genetic variation gives us a third alternative. Some changes in DNA have little or no effect, giving neither an advantage or disadvantage but slowly building up over generations. These variations hide in various ways. For example, simple organisms are able to reduce the impact of changes in the environment on their biological functions using a process known as <a href="https://www.ncbi.nlm.nih.gov/pubmed/16250465">canalisation</a>. This means minor changes to their DNA don’t cause visible differences.</p>
<p>Sometimes, genes are even duplicated in different parts of the DNA, so that there is <a href="https://www.nature.com/articles/hdy200881?proof=true&draft=collection">redundancy in the system</a>. Any changes in one gene can then be hidden by the others.</p>
<p>In complex lifeforms, many new variations also go unseen because we have two versions of most of our genes (one from mum and one from dad), and <a href="https://learn.genetics.utah.edu/content/basics/patterns/">one of the versions is dominant</a> over the other. Cryptic genetic variations are recessive (not dominant) in this relationship and so under normal conditions do not show.</p>
<p>There are also some very minor changes that <a href="https://www.khanacademy.org/test-prep/mcat/biomolecules/genetic-mutations/v/the-different-types-of-mutations">don’t cause any real change</a> to the biochemistry of the organism. They perhaps swap one component in a protein for something very similar.</p>
<p>All these things act as a buffer against physical changes, allowing a build-up of variation in the DNA that only becomes visible when there is a significant change in the environment. Many researchers in the field of evolutionary genetics believe that this cryptic genetic variation may answer the problem of how species have been able to rapidly adapt to new challenges in the past. The <a href="https://www.theguardian.com/science/2018/jul/30/origin-of-the-species-where-did-darwins-finches-come-from">finches of the Galapagos islands</a> helped Darwin to develop his theory of evolution, and the rapid creation of the different types of finches he saw is very likely to be an example of cryptic variation at work.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/287693/original/file-20190812-71926-1uti3t5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Illuminating experiment: fluorescent green <em>E. coli</em> bacteria.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/plate-green-fluorescent-normal-escherichia-coli-1151406107?src=5C-Svt4lIhhmy-aYyHv6VQ-1-2">KPWangkanont/Shutterstock</a></span>
</figcaption>
</figure>
<p>Observing this change in animals or in the wild is impossible, given the multi-generational timescales involved. But <a href="https://science.sciencemag.org/content/365/6451/347">researchers at the University of Zürich</a> recently used <em>E. coli</em> bacteria to prove the importance of this variation in evolution and adaptation to new environments.</p>
<p>In their experiments, they created an artificial environment in which bacteria that could produce green fluorescence had an advantage over those that produced yellow. The researchers showed that bacterial colonies containing higher levels of cryptic variation were able to switch more rapidly to fluorescing green.</p>
<p>This was a tiny, insignificant change for the bacteria, but a very clear proof of the concept that cryptic variation can help a species adapt more quickly to environmental change. This may be very important in understanding the importance of cryptic variation in more critical systems affecting disease resistance and susceptibility.</p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383966/">Researchers at the University of Würzburg</a> have shown that the level of cryptic genetic variation in <em>Neisseria meningitidis</em>, a bacterium that can cause meningitis, contributes to how harmful the resulting disease is. This higher level of variation is only a factor when the bacteria enter the bloodstream, but has no impact in their normal environment of the human throat.</p>
<p>A better understanding of how these bacteria change when they’re in the blood may help us to combat diseases such as meningitis. We will have a better understanding of how the symptoms occur and, crucially, could be able to tackle any antibiotic resistance <a href="https://www.reactgroup.org/toolbox/understand/antibiotic-resistance/mutation-and-selection/">hidden away in the bacteria’s DNA</a>. </p>
<h2>Hidden potential</h2>
<p>Our own DNA also harbours <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1000027">high levels of cryptic variation</a>. The potential for cryptic genetic variants hidden away in our DNA suddenly becoming not so cryptic thanks to changes in the environment is a serious concern.</p>
<p>Though we still don’t understand the exact effects of cryptic variation, several changes in our DNA, silently inherited from our ancestors, have already been linked to increased risk of diseases such as <a href="https://www.nature.com/articles/s41370-019-0136-3">asthma</a> or <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535288/">cancer</a>. For people with these changes, exposure to car exhaust fumes, is more likely to have an effect.</p>
<p>However, there may also be solutions as well as problems hidden in DNA. As the world warms as a result of climate change, could cryptic genetic variation give us and other species a much-needed lifeline? The increased ability to evolve quickly and adapt, may be all that stands between a species surviving global warming and extinction.</p><img src="https://counter.theconversation.com/content/120852/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Michael Porter does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Changes in our environment can reveal previously hidden mutations in our DNA with potentially good and bad consequences.Michael Porter, Lecturer in Molecular Genetics, University of Central LancashireLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1056832018-11-14T11:59:17Z2018-11-14T11:59:17ZHuman evolution is still happening – possibly faster than ever<figure><img src="https://images.theconversation.com/files/245368/original/file-20181113-194516-oggasm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Yes, we're still evolving.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/molecule-body-concept-human-dna-eps10-719729686?src=pwyQ2BkKUmKj0JDOpwKYgQ-1-1">watchara/Shutterstock</a></span></figcaption></figure><p>Modern medicine’s ability to keep us alive makes it tempting to think human evolution may have stopped. Better healthcare disrupts a key driving force of evolution by keeping some people alive longer, making them more likely to pass on their genes. But if we look at the rate of our DNA’s evolution, we can see that human evolution hasn’t stopped – it may even be happening faster than before.</p>
<p><a href="https://www.bbc.com/bitesize/guides/zt4f8mn/revision/3">Evolution</a> is a gradual change to the DNA of a species over many generations. It can occur by <a href="https://evolution.berkeley.edu/evolibrary/article/evo_25">natural selection</a>, when certain traits created by genetic mutations help an organism survive or reproduce. Such mutations are thus more likely to be passed on to the next generation, so they increase in frequency in a population. Gradually, these mutations and their associated traits become more common among the whole group. </p>
<p>By looking at global studies of our DNA, we can see evidence that natural selection has recently made changes and continues to do so. Though modern healthcare frees us from many causes of death, in countries without access to good healthcare, populations are continuing to evolve. Survivors of infectious disease outbreaks drive natural selection by giving their genetic resistance to offspring. Our DNA shows evidence for recent selection for resistance of killer diseases like <a href="https://www.nature.com/scitable/content/Genome-wide-detection-and-characterization-of-positive-26459">Lassa fever</a> and <a href="http://science.sciencemag.org/content/312/5780/1614">malaria</a>. Selection in response to malaria is <a href="http://www.pnas.org/content/112/22/7051.full">still ongoing</a> in regions where the disease remains common. </p>
<p>Humans are also adapting to their environment. Mutations allowing humans to <a href="https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1001116">live at high altitudes</a> have become more common in populations in <a href="http://science.sciencemag.org/content/329/5987/75">Tibet</a>, <a href="https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003110">Ethiopia</a>, and the <a href="https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1001116">Andes</a>. The spread of genetic mutations in Tibet is possibly the fastest evolutionary change in humans, occurring over the last 3,000 years. This rapid surge in frequency of a <a href="http://science.sciencemag.org/content/329/5987/75">mutated gene</a> that increases blood oxygen content gives locals a survival advantage in higher altitudes, resulting in more surviving children.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=402&fit=crop&dpr=1 600w, https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=402&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=402&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=505&fit=crop&dpr=1 754w, https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=505&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/245318/original/file-20181113-194519-1xrqsvq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=505&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Evolution explains why we can still drink milk.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/milk-pouring-384945307?src=emAMfxIei9F_pAydoz-plQ-1-75">Valerii__Dex/Shutterstock</a></span>
</figcaption>
</figure>
<p>Diet is another source for adaptations. Evidence from <a href="http://science.sciencemag.org/content/349/6254/1343">Inuit DNA</a> shows a recent adaptation that allows them to thrive on their fat-rich diet of Arctic mammals. <a href="https://www.nature.com/articles/ng1946">Studies also show</a> that natural selection favouring a mutation allowing adults to produce lactase – the enzyme that breaks down milk sugars – is why some groups of people can <a href="https://www.sciencedirect.com/science/article/pii/S0002929707628389">digest milk after weaning</a>. Over 80% of north-west Europeans can, but in parts of East Asia, where milk is much less commonly drunk, an inability to digest lactose <a href="https://www.sciencedirect.com/science/article/pii/S0002929707628389">is the norm</a>. Like high altitude adaptation, selection to digest milk has evolved <a href="https://www.nature.com/scitable/content/Convergent-adaptation-of-human-lactase-persistence-in-26486">more than once in humans</a> and may be the strongest kind of recent selection.</p>
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Read more:
<a href="https://theconversation.com/paleo-diet-science-has-moved-on-since-the-stone-age-43571">Paleo diet? Science has moved on since the stone age</a>
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<p>We may well be adapting to unhealthy diets too. <a href="http://www.pnas.org/content/107/suppl_1/1787">One study</a> of family genetic changes in the US during the 20th century found selection for reduced blood pressure and cholesterol levels, both of which can be lethally raised by modern diets. </p>
<p>Yet, despite these changes, natural selection only affects about <a href="https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004525">8% of our genome</a>. According to the <a href="https://www.nature.com/scitable/topicpage/neutral-theory-the-null-hypothesis-of-molecular-839">neutral evolution theory</a>, mutations in the rest of the genome may freely change frequency in populations by chance. If natural selection is weakened, mutations it would normally purge aren’t removed as efficiently, which could increase their frequency and so increase the rate of evolution.</p>
<p>But neutral evolution can’t explain why some genes are evolving much faster than others. We measure the speed of gene evolution by comparing human DNA with that of other species, which also allows us to determine which genes are fast-evolving in humans alone. One fast-evolving gene is <a href="https://www.nature.com/articles/nature05113">human accelerated region 1 (HAR1)</a>, which is needed during brain development. A random section of human DNA is on average more than 98% identical to the chimp comparator, but HAR1 is so fast evolving that it’s only around 85% similar. </p>
<p>Though scientists can see these changes are happening – and how quickly – we still don’t fully understand why fast evolution happens to some genes but not others. Originally thought to be the result of natural selection exclusively, we now know this <a href="https://www.sciencedirect.com/science/article/pii/S0168952507001138">isn’t always true</a>.</p>
<p>Recently attention has focused on the process of <a href="https://www.sciencedirect.com/science/article/pii/S0168952507001138#bib19">biased gene conversion</a>, which occurs when our DNA is passed on via our sperm and eggs. Making these sex cells involves breaking DNA molecules, recombining them, then repairing the break. However, molecular repairs tend to happen in a biased manner.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=420&fit=crop&dpr=1 600w, https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=420&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=420&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=528&fit=crop&dpr=1 754w, https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=528&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/245319/original/file-20181113-194506-1v4axue.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=528&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Biased DNA repairs can cause fast evolution of genes.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/dna-helix-on-colored-background-3d-551281720?src=dALRpK45ij8Z7I22xf0uhw-1-50">Ravil Sayfullin/Shutterstock</a></span>
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<p>DNA molecules are made with <a href="https://www.genome.gov/25520880/deoxyribonucleic-acid-dna-fact-sheet/">four different chemical bases</a> known as C, G, A and T. The repair process prefers to make fixes using C and G bases rather than A or T. While unclear why this bias exists, it tends to cause G and C to become more common.</p>
<p>Increases in G and C at DNA’s regular repair sites causes ultrafast evolution of parts of our genome, a process easily mistaken for natural selection, since both cause rapid DNA change at highly localised sites. About a fifth of our <a href="https://academic.oup.com/mbe/article/29/3/1047/1008844">fastest evolving genes</a>, including HAR1, have been affected by this process. If the GC changes are harmful, natural selection would normally oppose them. But with selection weakened, this process could largely go unchecked and could even help speed up our DNA’s evolution.</p>
<p>The human mutation rate itself may also be changing. The main source of mutations in human DNA is the cell division process that creates <a href="https://www.nature.com/articles/nature24018">sperm cells</a>. The older males get, the more mutations occur in their sperm. So if their contribution to the gene pool changes – for example, if men delay having children – the mutation rate will change too. This sets the rate of <a href="https://www.nature.com/scitable/topicpage/neutral-theory-the-null-hypothesis-of-molecular-839">neutral evolution</a>.</p>
<p>Realising evolution doesn’t only happen by natural selection makes it clear the process isn’t likely to ever stop. Freeing our genomes from the pressures of natural selection only opens them up to other evolutionary processes – making it even harder to predict what future humans will be like. However, it’s quite possible that with modern medicine’s protections, there will be more genetic problems in store for future generations.</p><img src="https://counter.theconversation.com/content/105683/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Laurence D. Hurst receives funding from European Research Council. </span></em></p>Natural selection isn’t the only factor deciding human evolution.Laurence D. Hurst, Professor of Evolutionary Genetics at The Milner Centre for Evolution, University of BathLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1045582018-10-14T19:06:40Z2018-10-14T19:06:40ZBoyer Lectures: gene therapy is still in its infancy but the future looks promising<figure><img src="https://images.theconversation.com/files/240370/original/file-20181012-119132-1l8k67h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Determining the structure of the DNA was the beginning of the gene therapy journey.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p><em>This year marks the 60th anniversary of the ABC’s Boyer Lectures. Delivered by Professor John Rasko, the 2018 <a href="http://about.abc.net.au/press-releases/life-re-engineered-abc-boyer-lectures-explore-how-gene-therapy-will-change-what-it-means-to-be-human/">Life Engineered</a> lectures explore ethical and other issues around gene therapy and related technologies, and their potential to cure disease, prolong life and change the course of human evolution.</em> </p>
<p><em>The first lecture will be broadcast on RN’s <a href="http://www.abc.net.au/radionational/programs/bigideas/">Big Ideas</a> at 8pm tonight. In light of this, we’ve asked Merlin Crossley to explain what gene therapy actually is and how we got to where we are with it.</em></p>
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<p>Over the last few centuries, infectious diseases have been understood and tackled, through advances in sanitation, anti-microbial medications and vaccination. One day we may also be able to tackle genetic diseases – lifelong conditions arising from mutations that we inherit from our ancestors or that occur during our development.</p>
<p>We’re over the foothills but we still have mountains to climb in treating genetic diseases.</p>
<h2>Step 1 – understanding genetic disease</h2>
<p>The key step to tackling infectious diseases was to truly define the nature of the microorganisms that caused them. Similarly, with genetic diseases the first step was to understand and define the nature of a gene. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=424&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=424&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=424&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=533&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=533&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240360/original/file-20181012-154583-158hjmi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=533&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Our red blood cells carry oxygen with the help of the protein haemoglobin.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>Scientists, including Watson, Crick and Franklin, <a href="https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin">determined the structure of DNA</a> in 1953. Gradually it became clear that a gene was a stretch of DNA that encoded a functional product, such as the oxygen-carrying protein haemoglobin. </p>
<p>Around the same time in 1949, US chemist <a href="https://www.britannica.com/biography/Linus-Pauling">Linus Pauling demonstrated</a> that the disease sickle cell anaemia was caused by a chemical change in haemoglobin. He called this the first “molecular disease”. With the advent of DNA sequencing in the 1970s, the <a href="https://ghr.nlm.nih.gov/gene/HBB">actual mutation</a> in the globin gene was identified. </p>
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Read more:
<a href="https://theconversation.com/explainer-one-day-science-may-cure-sickle-cell-anaemia-28153">Explainer: one day science may cure sickle cell anaemia</a>
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<p>Rapidly after this, the genetic lesions responsible for other inherited diseases – such as haemophilia, cystic fibrosis and muscular dystrophy – were identified. From this moment on, the idea of replacing defective genes or correcting them captured people’s imaginations, and this is the basis of what we now call “gene therapy”.</p>
<h2>Step 2 – replacing defective genes</h2>
<p>Patients suffering from genetic diseases either have a defective gene or may altogether lack a key gene. In the early stages of gene therapy there was no way of correcting genes, so researchers focused on supplementing the body with a replacement gene. </p>
<p>In the 1980s, recombinant DNA technology (where chosen DNA molecules are transferred between individual organisms) was developed by harnessing the miniature machinery bacteria and viruses use to move DNA around. This allowed researchers to isolate individual human genes and encapsulate them in harmless viruses to deliver them into human cells.</p>
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<span class="caption">In somatic gene therapy, the therapeutic genes can be put inside a virus and transported into the body.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>It was possible to get the genes into certain blood cells and other accessible tissues. This process was termed somatic gene therapy (from “soma” meaning, “the body”) and was distinct from <a href="https://www.genome.gov/10004764/germline-gene-transfer/">germline gene therapy</a> where eggs or sperm, or early embryos, would be modified and whole people and their offspring changed forever. </p>
<p>Human germline gene therapy is widely outlawed and there is no evidence it has ever been seriously attempted.</p>
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<p>
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<strong>
Read more:
<a href="https://theconversation.com/human-genome-editing-report-strikes-the-right-balance-between-risks-and-benefits-72951">Human genome editing report strikes the right balance between risks and benefits</a>
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<p>But <a href="https://www.ncbi.nlm.nih.gov/pubmed/8976157">somatic gene therapy</a> has been attempted and, in some cases, has been successful. Viruses really can be made harmless and filled with human DNA, which they deliver into the patient’s cells. </p>
<p>A handful of people have now been successfully treated in this way for <a href="https://presse.inserm.fr/en/new-gene-therapy-success-in-beta-thalassemia-22-patients-treated-in-france-united-states-thailand-and-australia/31149/">haemoglobin deficiencies</a>, <a href="https://www.haemophilia.org.au/publications/national-haemophilia/2018/no-201-march-2018/gene-therapy">haemophilia</a>, and for immune disorders, such as so-called <a href="https://www.webmd.com/baby/news/20171209/gene-therapy-may-be-cure-for-bubble-boy-disease#1">“bubble boy” disease </a> (where victims are particularly vulnerable to infectious diseases).</p>
<h2>Step 3 – improving replacement gene therapy</h2>
<p>Attempts at these forms of gene replacement therapy began in the 1990s but <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681190/">early results</a> were disappointing. It proved difficult to get the genes into enough human cells, and when the genes did get in they were often <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC289175/">turned off</a> after a few weeks.</p>
<p>More worryingly, it was not possible to determine where in the chromosome the replacement gene would land. Often it integrated harmlessly in an unimportant part of the genome, but sometimes it landed near to, and activated, growth control genes called “oncogenes” that drive cellular proliferation and cancer. </p>
<p>Some of the <a href="https://www.newscientist.com/article/dn2878-miracle-gene-therapy-trial-halted/">first children treated</a> for “bubble boy” disease developed leukemias. These leukemias were treatable, but the complications, together with immune reactions, such as led to the death of <a href="https://en.wikipedia.org/wiki/Jesse_Gelsinger">Jesse Gelsinger</a> in an early gene therapy trial in 2000, led to caution.</p>
<p>Over the years, researchers have developed better viruses, systematically improved the gene delivery protocols and found control switches that aren’t turned off by our body’s anti-viral response. In recent gene therapy trials for <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1708538">haemophilia</a>, <a href="http://www.bloodjournal.org/content/130/Suppl_1/355?sso-checked=true">haemoglobin</a> disorders, and also for specific inherited forms of <a href="https://mashable.com/2018/03/24/gene-therapy-blindness-treatment/">blindness</a>, many of the patients treated have benefited.</p>
<h2>Step 4 – gene correction</h2>
<p>The advent of new techniques, most notably CRISPR-mediated gene editing, has led to the idea of correcting a mutant gene rather than adding a replacement. CRISPR is a system that bacteria use to identify and cut invading viral DNA. It has now been used by researchers to direct DNA modification machines to chosen human genes. </p>
<p><iframe id="tc-infographic-229" class="tc-infographic" height="580px" src="https://cdn.theconversation.com/infographics/229/1e1ccd9abbd9a92604e144561050c08a9c49d8b3/site/index.html" width="100%" style="border: none" frameborder="0"></iframe></p>
<p>We can now develop miniature chemical tools to convert harmful mutations back into normal sequences. News that this technology was being used on <a href="https://link.springer.com/article/10.1007%2Fs13238-015-0153-5">human embryos in China</a> created a storm of controversy but so far those experiments have only involved embryos that were known to be non-viable and the research has been purely experimental.</p>
<p>Elsewhere researchers aren’t exploring modifications of whole embryos. Instead the somatic gene therapy approach is being followed, for example, to see if genes can be corrected in a high proportion of <a href="https://www.sciencedirect.com/science/article/pii/S1525001616453323">blood stem cells</a> and whether these cells can then be transplanted back into the patient to cure their disease.</p>
<h2>Step 5 – The future</h2>
<p>We will soon see an increasing number of patients helped by both gene replacement therapy and by CRISPR-mediated gene correction. But the work is likely to be focused on a few specific diseases rather than there being a broad advance across all genetic diseases. </p>
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<a href="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=629&fit=crop&dpr=1 600w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=629&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=629&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=791&fit=crop&dpr=1 754w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=791&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/240385/original/file-20181012-119114-19u0x3q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=791&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">An increasing number of patients will soon be helped by CRISPR-mediated gene correction.</span>
<span class="attribution"><span class="source">shutterstock.com</span></span>
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<p>The diseases treated first will share some key characteristics: the genetic defects would be well-understood; they must affect a tissue we can get at easily (blood will be easier than brains and bones); the conditions would be serious and have no other effective treatments. </p>
<p>And they must be so costly in terms of human suffering and economic burdens that a complex and expensive treatment such as gene therapy becomes a viable option. </p>
<p>This means common blood and immune disorders are likely to feature in the first generation trials. Cancer is also a genetic disease, but one typically caused by mutations that accumulate in our cells over time rather than by inherited mutations, and somatic gene therapy, in the form of immunotherapy, involving enhancing the capacity of our immune systems to fight cancer may also become common. </p>
<p>A Nobel Prize was <a href="https://www.nytimes.com/2018/10/01/health/nobel-prize-medicine.html">just awarded</a> for anti-cancer immunotherapy, and it is likely that the genetic modification of the immune system will increasingly be used to treat cancers.</p>
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<p>
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<strong>
Read more:
<a href="https://theconversation.com/how-two-1990s-discoveries-have-led-to-some-cured-cancers-and-a-nobel-prize-104221">How two 1990s discoveries have led to (some) cured cancers, and a Nobel Prize</a>
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<p>The age of gene therapy is arriving but it will be gradual, not sudden. But incrementally, more people will benefit from these treatments. </p>
<p>In the long term, as we all become aware of mutations we carry in our own genomes that may affect our offspring, there may be pressure to correct more and more genetic lesions. This will remain too risky and expensive for many years so gene therapy will likely remain a niche and specialist treatment for the foreseeable future.</p><img src="https://counter.theconversation.com/content/104558/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for UNSW and receives funding from the Australian Research Council and National Health and Medical Research Council, and serves on the Trust of the Australian Museum, the Australian Science Media Centre, UNSW Press, UNSW Global, and is on the Editorial Board of The Conversation and of he journal Bioessays. </span></em></p>Once genetic lesions for diseases such as cystic fibrosis and haemophilia were identified, the idea of replacing or correcting defective genes grew into what we now call “gene therapy”.Merlin Crossley, Deputy Vice-Chancellor Academic and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/955722018-04-26T10:38:41Z2018-04-26T10:38:41ZMother’s milk holds the key to unlocking an evolutionary mystery from the last ice age<figure><img src="https://images.theconversation.com/files/216345/original/file-20180425-175050-1rnqanl.jpg?ixlib=rb-1.1.0&rect=550%2C202%2C3315%2C2231&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Sunrise at noon in the Arctic. Little exposure to sun was a piece of the genetic puzzle.</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Winter_Solstice_noon_sunrise_on_the_Bering_Sea_(8433692952).jpg">Bering Land Bridge National Preserve</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>As biologists explore the variation across the genomes of living people, they’ve found evidence of evolution at work. Particular variants of genes increase or decrease in populations through time. Sometimes this happens by chance. Other times these changes in frequency result from the gene’s helping or hindering individuals’ survival, a <a href="https://www.amnh.org/exhibitions/darwin/evolution-today/how-does-natural-selection-work">phenomenon known as selection</a>. If a gene conferred a survival advantage, people with the mutation would have more offspring and the mutation would become more common in subsequent generations.</p>
<p>Most of those past <a href="https://evolution.berkeley.edu/evolibrary/article/evo_25">episodes of selection</a> make sense, as they worked on genes involved with things like <a href="https://www.nature.com/scitable/topicpage/natural-selection-uncovering-mechanisms-of-evolutionary-adaptation-34539">resisting disease</a>, <a href="https://news.nationalgeographic.com/news/2004/02/0224_040225_evolution.html">blood oxygen levels at high altitudes</a>, and having <a href="https://www.nature.com/scitable/topicpage/evolutionary-adaptation-in-the-human-lineage-12397">paler skin at northern latitudes</a>.</p>
<p>However, researchers have also identified an episode of strong selection that doesn’t have such an obvious logic. It’s a mutation on a gene involved with the development of a suite of traits that don’t seem very similar at first glance: hair, teeth, sweat glands and breasts. This one was a mystery — what could have been the adaptive value of this mutation that led to it being common in northeastern Asia but nowhere else?</p>
<p><a href="https://scholar.google.com/citations?user=2B6GhHoAAAAJ&hl=en&oi=ao">My research</a> usually focuses on teeth, specifically genetic influences on their development. I came to this particular evolution puzzle when my colleagues and I gathered in Boston at the AAAS meeting last year to discuss the latest evidence of how people first migrated into the Western Hemisphere. We put together the clues about this episode of selection on human genetic variation – and found an example of <a href="https://doi.org/10.1073/pnas.1711788115">adaptation to life at high latitude during the last ice age</a>.</p>
<h2>Natural selection … of what?</h2>
<p>We were trying to understand selection for a mutation in the gene called EDAR – it encodes the ectodysplasin A receptor that plays a role in how tightly cells adhere to each other during the development of hair, teeth, sweat glands and breasts. All of these anatomical structures form via a very similar developmental process that happens while you’re still in your mother’s womb. Slight changes to the developmental mechanism results in the final differences between hair and teeth and sweat and mammary glands. But there is a fundamental similarity that, among other things, includes the activity of EDAR. </p>
<p>This shared development is especially obvious when things go wrong. For example, 1 in 10,000 newborns have a disorder called <a href="https://www.nfed.org/learn/">ectodermal dysplasia</a>, which causes disruption to the development of their hair, teeth, skin, sweat glands and breasts.</p>
<p>The V370A mutation that we focused on, the one that experienced strong selection, doesn’t disrupt development of these structures; rather, it augments them. People with V370A have thicker and straighter hair shafts, and their incisors have extra buttressing on the tongue side – a feature biologists call “shoveling.”</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=428&fit=crop&dpr=1 600w, https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=428&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=428&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=538&fit=crop&dpr=1 754w, https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=538&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/216342/original/file-20180425-175035-1jkd39w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=538&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Human upper incisors with significant ‘shoveling’ on the tongue side.</span>
<span class="attribution"><span class="source">Christy G. Turner, II, courtesy G. Richard Scott</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>So why did this mutation provide such an advantage to people who carried it? Mice that have been experimentally induced to have the V370A mutation have thicker fur shafts and increased density of sweat glands. A previous study of modern human genomic variation <a href="https://doi.org/10.1016/j.cell.2013.01.016">interpreted the selection</a> to have occurred in northern China during the last ice age and focused on the sweat glands. The researchers suggested that the selection was for improved sweating that could help with regulating body temperature. But to my colleagues and me, that just didn’t feel like a convincing adaptive scenario given that this took place during the (cold) ice age. </p>
<p>Instead of the sweat glands, our attention was drawn to another trait. Mice with the V370A mutation also have an increase in the branching of their mammary ducts – the tiny tubes that intertwine with breast tissue and extract nutrients to make milk. Maybe it was this change in the breast tissue that was so valuable to people with this mutation?</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=429&fit=crop&dpr=1 600w, https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=429&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=429&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=539&fit=crop&dpr=1 754w, https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=539&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/216356/original/file-20180425-175058-ebxo40.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=539&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Christy G. Turner II, shown working in 1975, and his students assessed variation in incisor shoveling in over 30,000 people around the world. The current study relied on a subset of these data collected by co-author G. Richard Scott.</span>
<span class="attribution"><span class="source">G. Richard Scott and Joshua P. Carlson</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>Rather than trying to sample DNA from thousands of ancient people’s remains to see if they carried the mutation, we took advantage of the effect V370A has on human incisors. Relying on data collected over many years by my colleague <a href="https://scholar.google.com/citations?user=vtkFh8kAAAAJ&hl=en&oi=ao">G. Richard Scott</a> from the University of Nevada, Reno, our group looked at the dental variation of over 5,000 skeletons from archaeological sites in Europe, Asia and the Americas to get a sense of how this mutation varied through time.</p>
<p><a href="https://doi.org/10.1073/pnas.1711788115">We found that</a> all of the indigenous people living in the Western Hemisphere prior to European colonization had shovel-shaped incisors, which means they all likely had the V370A mutation. In contrast, only about 40 percent of the people in Asia had shovel-shaped incisors, and essentially no one in Europe did.</p>
<p>This pattern suggests that a population ancestral to Native Americans experienced the strong selection for V370A, an interpretation that differed from what my colleagues found when they only looked at genomic variation in living people. Using these ancient teeth, we were able to figure out when and where the selection happened. The next question we needed to address was why this selection occurred. What was going on to make this mutation so helpful and thus so much more prevalent?</p>
<h2>An ice age advantage</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=448&fit=crop&dpr=1 600w, https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=448&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=448&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=564&fit=crop&dpr=1 754w, https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=564&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/216339/original/file-20180425-175047-1aqtxmn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=564&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Beringia outlined over today’s Siberia and Alaska.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:BeringiaMap-NPSgov.jpg">U.S. National Park Service</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p><a href="https://doi.org/10.1371/journal.pone.0000829">Previous genetic work</a> found that Native Americans descend from a common ancestral population that lived in Beringia, the region that links Siberia and Alaska. During the dramatic climate change associated with the last ice age 28,000 to 18,000 years ago, plants and animals that had previously lived in Siberia took refuge in a circumscribed area called the Beringian Refugium. For about 5,000 years, they were genetically isolated from other populations because of a vast dry tundra to the west and a lot of ice to the east. <a href="https://doi.org/10.1002/evan.21478">The people who found haven there too</a> are referred to as the Beringian Standstill population.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=363&fit=crop&dpr=1 600w, https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=363&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=363&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=457&fit=crop&dpr=1 754w, https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=457&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/216343/original/file-20180425-175050-1gs4hbz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=457&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Modern-day mesic shrub tundra near the northwestern Alaskan town of Kotzebue is similar to what the environment would have been like in Beringia during the ice age.</span>
<span class="attribution"><span class="source">Scott Elias</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>It’s not easy to live that far north. Sure, it’s cold. But more importantly, at high latitudes the sun is lower in the sky so sunlight must travel through more atmosphere to reach Earth’s surface. This journey through the atmosphere mostly filters out the Sun’s ultraviolet radiation. Most life forms need sun exposure to be healthy, in large part <a href="https://doi.org/10.1016/j.pbiomolbio.2006.02.016">because UV exposure induces</a> the <a href="https://www.mayoclinic.org/drugs-supplements-vitamin-d/art-20363792">body to make vitamin D</a>.</p>
<p><a href="https://doi.org/10.1073/pnas.0914628107">Lighter skin tones let in more UV</a> and have been selected for multiple times in human history. But once you get to the Arctic, skin depigmentation alone won’t suffice. In order to live with so little UV, people have culturally innovated, <a href="http://scienceline.org/2007/06/ask-dricoll-inuiteskimos/">eating diets rich in vitamin D</a>, such as oily fish. But nursing infants don’t eat these foods. Babies get their nutrients through their mother’s milk.</p>
<p>This is where our EDAR gene comes back into the picture. The V370A mutation in mice increases the branching density of the mammary ducts, and very likely does the same exact thing in human breasts. Scientists know that vitamin D deficient conditions <a href="https://doi.org/10.1016/j.jsbmb.2015.09.035">induce more ductal branching</a> during the breast development that happens with pregnancy. All of the evidence suggests that the increased ductal branching associated with V370A helped transfer nutrients from mother to infant through breast milk in a population that was extremely vitamin D deficient. </p>
<p>So the selection wasn’t for thicker hair or shovel-shaped incisors – instead, it was much more likely to have been on mammary ducts. The thicker hair and tooth variation just went along for the ride because they are created by the same basic developmental pathway. Selection on genetic variation in EDAR is probably related to health consequences for nursing infants rather than its effects on hair, teeth or sweat glands.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/216350/original/file-20180425-175061-1dkjjzs.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Excavation of a site occupied in Beringia 32,000 years ago.</span>
<span class="attribution"><span class="source">V. V. Pitul'ko & E. Yu. Pavlova</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Still traceable genetic inheritance</h2>
<p>Once the Earth started warming up at the end of the last ice age, those ice sheets started to melt, sea level rose and global climate became more humid. The people living in Beringia needed to move again. Some went east, populating the Western Hemisphere rapidly and extensively. Some went west, merging back into populations that were living in northern and eastern Asia. Scientists see traces of this migration today. The occurrence of incisor shoveling <a href="https://doi.org/10.1002/ajpa.1330740316">decreases as you move away from the Arctic</a>, there is <a href="https://doi.org/10.1371/journal.pone.0091722">evidence of a long-lost language</a>, and some of those Beringian Standstill mitochondrial DNA mutations <a href="https://doi.org/10.1371/journal.pone.0000829">can be found in Asian populations</a>.</p>
<p>Today, everyone with shovel-shaped incisors carries a little remnant of this ephemeral population with them and a reminder of the importance of the maternal-infant bond to human survival.</p>
<p>But they also have the other effects of the V370A mutation. The increase in mammary ductal branching seems likely to influence the transfer of nutrients from breast tissue into milk. It may also play a role in susceptibility to breast cancer, given that <a href="https://doi.org/10.2214/AJR.06.0619">breast density differs</a> between Asian and non-Asian women as does the <a href="https://doi.org/10.1093/jnci/djv048">occurrence of breast cancer</a>, a relationship that matches the distribution of V370A around the world today.</p>
<p>These ideas present exciting hypotheses to test in future studies. For now, our research shows that the bones of our ancestors can provide evidence of human adaptation, evidence that shifts our understanding of how genes work.</p><img src="https://counter.theconversation.com/content/95572/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Leslea Hlusko does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Why was one gene mutation that affects hair, teeth, sweat glands and breasts ubiquitous among ice age Arctic people? New research points to the advantage it provided for ancestors of Native Americans.Leslea Hlusko, Associate Professor of Integrative Biology, University of California, BerkeleyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/935172018-03-28T12:57:42Z2018-03-28T12:57:42ZWould standing on the first butterfly really change the history of evolution?<figure><img src="https://images.theconversation.com/files/212431/original/file-20180328-109207-12h38q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/textured-grunge-old-paper-background-boots-274803299?src=I6RQSRvM1gPTgmuOvH6rIA-1-31">Shutterstock</a></span></figcaption></figure><blockquote>
<p><strong>Martha Jones:</strong> It’s like in those films: if you step on a butterfly, you change the future of the human race.</p>
<p><strong>The Doctor:</strong> Then don’t step on any butterflies. What have butterflies ever done to you? </p>
</blockquote>
<p>Science fiction writers can’t seem to agree on the rules of time travel. Sometimes, as in Doctor Who (above), characters can travel in time and affect small events without appearing to alter the grand course of history. In other stories, such as Back To The Future, even the tiniest of the time travellers’ actions in the past produce major ripples that unpredictably change the future.</p>
<p>Evolutionary biologists have been holding a similar debate about how evolution works for decades. In 1989 (the year of Back To The Future Part II), the American palaeontologist Stephen Jay Gould published his timeless book Wonderful Life, named after <a href="http://www.imdb.com/title/tt0038650/">the classic movie</a> that also involves time travel of sorts. In it, he proposed a thought experiment: what would happen if you could replay life’s tape, rewinding the history of evolution and running it again? Would you still see the same movie with all the evolutionary events playing out as before? Or would it be more like a reboot, with species evolving in different ways?</p>
<p>Gould’s answer was the latter. In his view, unpredictable events played a major role in natural history. If you were to travel back in time and step on the first butterfly (reminiscent of the 1952 short story <a href="http://web1.nbed.nb.ca/sites/ASD-S/1820/J%20Johnston/short%20stories/A%20Sound%20of%20Thunder%20with%20questions%20--Ray%20Bradbury.pdf">A Sound of Thunder</a> by Ray Bradbury), then butterflies wouldn’t evolve ever again.</p>
<p>This is supposedly because the variation we see in nature - the many different physical features and forms of behaviour that lifeforms can have – is caused by random genetic events, such as genetic mutations <a href="https://www.nature.com/scitable/topicpage/genetic-recombination-514">and recombination</a>. Natural selection filters this variation, preserving and spreading the features that give organisms the best reproductive advantage. In Gould’s view, because the series of mutations that led to the first butterfly were random, they would be unlikely to occur a second time.</p>
<h2>Convergent evolution</h2>
<p>But not everyone agrees with this picture. <a href="https://www.templetonpress.org/books/runes-evolution">Some scientists</a> defend the idea of “convergent evolution”. This is when organisms that aren’t related to each other independently evolve similar features in response to their environment. For example, bats and whales are very different animals, but both have evolved the ability to “see” by listening to how sound echoes around them (<a href="http://www.sciencemag.org/news/2013/09/bats-and-dolphins-evolved-echolocation-same-way">echolocation</a>). Both pandas and humans have evolved <a href="https://daily.jstor.org/why-do-pandas-have-thumbs/">opposable thumbs</a>. Powered flying has evolved <a href="https://academic.oup.com/icb/article/56/5/1044/2420642">at least four times</a>, in birds, bats, pterosaurs, and insects like butterflies. And eyes have independently evolved <a href="https://www.annualreviews.org/doi/abs/10.1146/annurev.ne.15.030192.000245">at least 50 times</a> in animal history.</p>
<p>Even intelligence has evolved multiple times. The famous palaeontologist Simon Conway-Morris was once asked if dinosaurs would have become intelligent if they were still here. <a href="http://www.bbc.co.uk/news/science-environment-28488044">His answer</a> was that “the experiment has been done and we call them crows”, referring to the fact that birds, including the <a href="https://theconversation.com/clever-crows-can-plan-for-the-future-like-humans-do-80627">very intelligent crow species</a>, evolved <a href="https://theconversation.com/how-did-dinosaurs-evolve-beaks-and-become-birds-scientists-think-they-have-the-answer-84633">from a group of dinosaurs</a>.</p>
<p>Convergent evolution suggests that there are a few optimal ways in which species can adapt to their environment, which means that (if you have enough information) you could predict how a species is likely to evolve over a long time. If you were to step on the first butterfly, another butterfly-like insect will eventually evolve because other mutations will eventually produce the same features that will be favoured by natural selection.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/212433/original/file-20180328-109199-u1mzs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Gold stick spider.</span>
<span class="attribution"><span class="source">George Roderick</span></span>
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<p>A <a href="http://www.cell.com/current-biology/fulltext/S0960-9822(18)30149-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0960982218301490%3Fshowall%3Dtrue">recent study</a> in the journal Current Biology seems to tip the scale in favour of convergent evolution. This study investigates how stick spiders have evolved in the Hawaiian Islands and provides evidence for different, isolated groups of animals evolving the same features independently.</p>
<p>Islands are often referred to as natural laboratories because they are effectively closed environments. Every time a species colonises a new island, a new independent experiment on adaptation takes place. An iconic example is the finches that have adapted to the various food sources on each island of the Galapagos, a fact that helped Charles Darwin develop his theory of natural selection. Some of these populations have even been caught in the act of becoming new <a href="http://www.bbc.co.uk/news/science-environment-42103058">species of finch</a>.</p>
<p>Most of the stick spiders on the Hawaiian Islands have gold, dark or white body colouring as camouflage to hide from predators, such as birds. The scientists used the DNA of the various spider species to reconstruct the history of how they evolved. They showed that the dark spiders and the white spiders have repeatedly evolved from ancestral gold spiders, six times in the case of the dark spiders and twice in the case of the white ones.</p>
<h2>Chance or necessity?</h2>
<p>This study is a remarkable example of convergent evolution taking place in the same geographical area. It’s reminiscent of the classic studies on <a href="http://www.cell.com/current-biology/abstract/S0960-9822(09)00722-2">Anolis lizards</a> by evolutionary ecologist Jonathan Losos, who noticed lizards on different Caribbean islands had independently evolved the <a href="http://www.sciencemag.org/news/1998/03/lizards-take-convergent-evolution-extreme">same adaptations multiple times</a>. All this suggests that lifeforms living in a specific environment over a long enough time period are likely to evolve certain features. </p>
<p>But the evidence for convergent evolution doesn’t rule out the role of chance. There is no doubt that mutations and the biological variations they create are random. Organisms are a mosaic of multiple traits, each with different evolutionary histories. And that means whatever evolved in the butterfly’s place might well not look exactly the same. </p>
<p>The evidence isn’t conclusive either way, but maybe both chance and necessity play a role in evolution. If we were to run the tape of life again, I think we would end up with the same types of organisms we have today. There would probably be primary producers extracting nutrients from the soil and energy from the sun, and other organisms that move around and eat the primary producers. Many of these would have eyes, some would fly, and some would be intelligent. But they might look quite different from the plants and animals we know today. There might not even be any intelligent two-legged mammals.</p>
<p>So just in case you ever find yourself travelling back in time, don’t step on any butterflies.</p><img src="https://counter.theconversation.com/content/93517/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jordi Paps receives funding from the University of Essex, the Royal Society, and the Wellcome Trust.</span></em></p>More and more evidence shows evolution isn’t as random as often thought.Jordi Paps, Lecturer, School of Biological Sciences, University of EssexLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/905392018-01-30T23:30:15Z2018-01-30T23:30:15ZIt’s 2030, and precision medicine has changed health care – this is what it looks like<figure><img src="https://images.theconversation.com/files/203929/original/file-20180130-170419-1eah061.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">In 2030, some diseases are defined more specifically than in the past with a focus on their molecular makeup. This is known as precision medicine.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p><em>This article is part of a <a href="https://theconversation.com/au/topics/precision-medicine-series-49226">package on precision medicine</a>, where we explore genomic sequencing and what it means for better diagnosis and treatment of many conditions including cancer and rare diseases.</em></p>
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<p>Imagine it is 2030. Ten-year-old Amy is wheeled into a children’s hospital clinic by her mother and, across town, 45-year-old Anh is visiting his oncologist one week after leaving hospital for his lung cancer operation. </p>
<p>Amy is slowly losing her ability to walk due to a muscle disorder that has only recently been given a name. Many diseases of muscle in children such as muscular dystrophy are caused by gene mutations (muscle disorders in adults are less likely to have a genetic mutation basis). In 2018, <a href="https://www.ncbi.nlm.nih.gov/pubmed/25380242">only around 40%</a> of these mutations were known. </p>
<p>In 2030, we know 99% of mutations causing inherited muscle diseases worldwide. Because the costs of genetic sequencing are so much lower, more people have had their genomes scanned. Researchers have spent the last 20 years gathering information about various genetic markers and mutations into massive biobanks. This data is now globally accessible, which has led to international collaboration and better understanding of diseases.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/personalised-medicine-has-obvious-benefits-but-has-anyone-thought-about-the-issues-59158">Personalised medicine has obvious benefits but has anyone thought about the issues?</a>
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</em>
</p>
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<p>So, 2030 is seeing a boom in precision medicine – where some diseases are defined more specifically than in the past with a focus on their molecular makeup. That is, the genes related to the DNA of the disease and other molecular elements. Precision medicine has vastly improved the ability to diagnose rare inherited diseases; to diagnose and treat cancers; and to aid in diagnosis and management of infectious diseases, dementia, heart disease and diabetes, among many others.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=798&fit=crop&dpr=1 600w, https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=798&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=798&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1003&fit=crop&dpr=1 754w, https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1003&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/203743/original/file-20180129-100915-eipqys.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1003&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Scientists have been able to pinpoint exactly which gene mutation caused Amy’s disease.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<h2>Amy’s story</h2>
<p>At Amy’s fifth gene test during her life, performed using the seventh version of specialist software for mutation detection associated with muscle disease, she was finally told which mutation led to her disability.</p>
<p>Some rare neuromuscular diseases are limited to very few families in the world. When only one family member is affected, and particularly if they are the first in the family, the responsible defect in the gene can be extremely difficult to determine among all the normal variations in the human genome.</p>
<p>Through access to global repositories of genomic data, Amy’s specialist has been able to download all known cases of this disease in the world. She has summarised information on the likely health outcomes of other patients and available treatment options or trials. </p>
<p>Amy’s disease is so newly diagnosed that there has been no funded research in this specific area. But there are similarities with other better known muscle disorders. Using international databases, the specialist finds a potential trial applicable to Amy. The trial has shown promise in preventing continued decline of muscle function. </p>
<p>Amy’s mother is relieved she finally has an answer to the cause of her daughter’s disability. Putting a name to it and knowing there are others with this disease comforts her. Of course, knowing potential trials might help stabilise her daughter’s condition leaves her with some hope that continued decline in Amy’s muscle strength is not inevitable.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/203741/original/file-20180129-100912-1axgper.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Amy’s mother is relieved doctors know what has caused her daughter’s disease.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>That night, after putting Amy to bed, Amy’s mother contemplates trying for a second child. There has been a public debate in Australia about preconception screening, which would allow a mother to abort her fetus if it’s known to be carrying a gene mutation that causes a severe debilitating disease. The debate has concluded that preconception screening is allowed under certain circumstances. </p>
<p>Now that Amy’s mutation is known, preconception screening is an option. Amy’s mother will discuss this with her husband in the morning. </p>
<hr>
<p><strong><em>Read more:</em></strong></p>
<ul>
<li><p><strong><em><a href="https://theconversation.com/explainer-what-is-pre-pregnancy-carrier-screening-and-should-potential-parents-consider-it-79184">What is pre-pregnancy carrier screening and should potential parents consider it?</a></em></strong></p></li>
<li><p><strong><em><a href="https://theconversation.com/what-prospective-parents-need-to-know-about-gene-tests-such-as-prepair-87083">What prospective parents need to know about gene tests such as ‘prepair’</a></em></strong></p></li>
</ul>
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<h2>Anh’s story</h2>
<p>Anh, a 45-year-old web designer, wants to know more about the prognosis and management of his cancer now that he has had the operation to remove it. </p>
<p>Before the operation, he was examined with the latest nuclear-medicine-based imaging technologies. This includes imaging at the molecular level with state-of-the-art scans that have been subsidised through Medicare. Specialist radiologists examined the results using high-resolution smart sensing imaging software to look for any spread of tumour (the software can sense known tumour markers).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/203740/original/file-20180129-100899-j2zghk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Ahn’s cancer has been completely removed and the doctors are confident it hasn’t spread anywhere else.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>Anh had also had his blood examined by molecular pathologists who looked for any tiny bits of tumour DNA circulating in his blood. In 2018, this technology (known as a liquid biopsy) was only just starting out and used in very few places as it required specialist molecular knowledge. It was purely a research tool, unfunded by Medicare and not approved for use in a diagnostic laboratory setting.</p>
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Read more:
<a href="https://theconversation.com/a-new-blood-test-can-detect-eight-different-cancers-in-their-early-stages-90221">A new blood test can detect eight different cancers in their early stages</a>
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<p>Anh’s treating team used a combination of information to feel reasonably confident there was no evidence of any tumour spread prior to his operation. Unfortunately, the sensitivity of these tests is still not yet at 100%, so ongoing follow-up will be required.</p>
<p>At the time of the operation, specialist hospital pathologists examined part of Ahn’s lung affected by the tumour. They performed tests that looked at the entire makeup of the tumour, which yielded lots of information to compare with the world literature and international database for the same tumour, including its specific markers. </p>
<p>Tumour markers are the unique aspects of DNA and proteins that make the tumour “signature”. Drugs can then target and block some of these specific markers to prevent the tumour from progressing, or even to destroy the tumour. </p>
<p>Mutation of the tumour over time and changes in the molecular markers remain a problem. This has been an ongoing area of research, central to government funding policy, for the past ten years. It takes many years and a large amount of expertise and money from the time of finding a target to developing and trialling drugs. </p>
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<a href="https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/203932/original/file-20180130-170410-17809mh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Anh had a number of state-of-the-art scans that his team used to make more precise decisions on his condition.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>In 2018 only 10-15% of patients with lung cancer had a <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1713137">tumour molecular target</a> that had an available drug that could work on it. In 2030, that rate is much higher.</p>
<p>Anh asks his oncologist what he expects will happen to him in the future. The doctor explains each individual needs to be seen in his own right despite the collective world of data about his tumour. He says the presence of this new gene marker will be fed into a research and trials database to find what is happening in the world in relation to drugs targeting this novel marker.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-cancer-doctors-use-personalised-medicine-to-target-variations-unique-to-each-tumour-47349">How cancer doctors use personalised medicine to target variations unique to each tumour</a>
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</em>
</p>
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<p>For now, Anh has a good outlook. The results of the analysis of his lung tumour in the pathology department – which looked at key issues like the tumour type and size and whether it has been removed completely or entered small vessels – and the examination of the molecular signature of the tumour are all entered into the diagnostic algorithm based on global data. It has suggested the chances of Anh’s tumour coming back within five years are around 5-10%. Pretty low.</p>
<p>The oncologist tells Anh he is free to go back to work. He will monitor him with regular blood checks aimed at markers for his specific tumour. Now that these are known, the specific test can be individualised to Anh’s tumour. The hand-held screening gadget can send the information straight to the specialist’s office, so he will be notified automatically in the event of change. </p>
<p>Precision medicine has truly made a difference in the lives of millions of people around the world. While there are still many issues to be fixed, including adequate funding for further research continuing on from the new information provided, appropriate drug trial funding and ethical issues, the future is looking brighter.</p>
<hr>
<p><strong><em>Read the other articles in our <a href="https://theconversation.com/au/topics/precision-medicine-series-49226">precision medicine package here</a>.</em></strong></p><img src="https://counter.theconversation.com/content/90539/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Catriona McLean does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>In 2030, there is a boom in precision medicine, where diseases – from cancer to dementia – are defined and targeted more specifically with a focus on their molecular makeup.Catriona McLean, Professor, Central Clinical School, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/836212017-09-12T02:17:58Z2017-09-12T02:17:58ZEvolutionary geneticists spot natural selection happening now in people<figure><img src="https://images.theconversation.com/files/185567/original/file-20170911-20832-ofi678.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">As genes are favored or phased out, human evolution continues.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/3d-illustration-method-dna-sequencing-430949605">ktsdesign/Shutterstock.com</a></span></figcaption></figure><p>Human evolution can seem like a phenomenon of the distant past which applies only to our ancestors living millions of years ago. But human evolution is ongoing. To evolve simply means that mutations – the accidental changes to genes that happen normally in the process of copying DNA – are becoming more or less common in the population over time.</p>
<p>These changes can happen by chance, because the individuals who reproduced happened to carry a particular mutation somewhat more often than individuals who didn’t have children. They can also happen because of natural selection, when carriers of a specific mutation are better able to survive, reproduce or tend to their family members – and therefore leave more descendants. Every biological adaptation, from the ability of humans to walk upright on two feet to flight in birds, ultimately traces back to natural selection acting on these minute changes, generation after generation.</p>
<p>So humans are definitely still evolving. The question is whether we are still adapting: Are individuals who carry harmful mutations living less long, reproducing less – ultimately leaving fewer descendants? For instance, terrible eyesight may have been a major survival disadvantage living on the savanna, but with glasses and laser surgery, it’s unlikely to prevent people from living a long life today. How commonly then are mutations under selection in contemporary humans?</p>
<h2>Long time scale makes evolution hard to study</h2>
<p>Because adaptations involve tiny changes in the frequencies of mutations from generation to generation and their fortune plays out over tens to hundreds of thousands of years, they are incredibly hard to study directly – at least in long-lived organisms such as people.</p>
<p>So while there is overwhelming evidence for human evolution and unequivocal footprints of adaptation in the genome, rarely have scientists been able to directly observe natural selection operating in people. As a result, biologists still understand very little about the workings of natural selection in humans.</p>
<p>Indeed, one of the clearest footprints of a past adaptation in the human genome involves a mutation that permits milk to be digested in adulthood. This mutation in the lactase gene rapidly rose in frequency with the rise of dairy farming thousands of years ago, independently in multiple populations. It’s the reason some people can drink milk as adults, whereas most remain lactose intolerant.</p>
<p>But <a href="https://www.ncbi.nlm.nih.gov/pubmed/28426286">even in this well-studied case</a>, let alone for the rest of the genome, researchers don’t know whether the mutation was beneficial for survival or for reproduction; whether the benefits were the same for both sexes, or across all ages; or whether the benefit depended on the environment (for instance, availability of other food sources). As <a href="https://academic.oup.com/ije/article-lookup/doi/10.1093/ije/dyw189">pointed out</a> by evolutionary biologist Richard Lewontin in the 1960s, to learn these properties of natural selection would require a massive study, in which genetic and genealogical information is obtained for hundreds of thousands of people. </p>
<p>Fifty years later, our group realized that this thought experiment is starting to become feasible. We sought large biomedical data sets that would let us learn about mutations that affect survival.</p>
<h2>Looking at gene frequency across age groups</h2>
<p>Our basic idea was that mutations that lower the chance of survival should be present at lower frequency in older individuals. For example, if a mutation becomes harmful at the age of 60 years, people who carry it have a lower chance to survive past 60 – and the mutation should be less common among those who live longer than that.</p>
<p>We therefore looked for mutations that change in frequency with age among around 60,000 individuals from California (part of the <a href="http://www.genetics.org/keyword/gera-cohort">GERA cohort</a>) and around 150,000 from the <a href="http://www.ukbiobank.ac.uk/">U.K. Biobank</a>. To avoid the complication that people whose ancestors lived in different places carry a somewhat different set of mutations, we focused on the largest group with shared ancestry within each study.</p>
<p>Across the genome, <a href="https://doi.org/10.1371/journal.pbio.2002458">we found two variants that endanger survival</a>. The first is a variant of the APOE gene, which is a well-known risk factor for Alzheimer’s disease. It drops in frequency beyond age 70. The second harmful variant we found is a mutation in the CHRNA3 gene. Associated with heavy smoking, this inherited mutation starts to decrease in frequency at middle age in men, because carriers of this mutation are less likely to survive longer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=517&fit=crop&dpr=1 600w, https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=517&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=517&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=649&fit=crop&dpr=1 754w, https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=649&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/185560/original/file-20170911-9863-6sfa95.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=649&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">People who carry a variant of the APOE gene die at a higher rate and are less common among the old age categories.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1371/journal.pbio.2002458">Mostafavi et al, PLOS Biology</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Both deleterious variants only had an effect long after the typical ages of reproduction for both females and males. Biologists usually consider such mutations to not be under selection. After all, by late middle age, most people have already passed their genes on to whatever offspring they’ll have, so it seems like it might not matter how long they live beyond that point.</p>
<p>Why then would we only find two, when our study was large enough to detect any such variant, if common in the population? One possibility is that mutations that only imperil survival so late in life almost never arise. While that is possible, the genome is a large place, so that seems unlikely.</p>
<p>The other intriguing possibility is that natural selection prevents even late-acting variants from becoming common in the population by natural selection, if they have large enough effects. Why might that be? For one, men can father children in old age. Even if only a tiny fraction of them do so, it may be enough of an evolutionary fitness cost for selection to act on. Survival beyond the age of reproduction could also be beneficial for the survival of related individuals who carry the same mutations, most directly children. In other words, surviving past typical reproductive ages may be beneficial for humans after all. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/185541/original/file-20170911-28358-1krdw8u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Smokers who carry a mutation in the CHRNA3 gene tend to smoke more cigarettes per day and so are more exposed to harmful effects of smoking.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/I8LO9eXxjg8">NeONBRAND on Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>Your mutations do influence your survival</h2>
<p>In addition to examining one mutation at a time, we were also interested in considering sets of mutations that have all been shown to influence the same trait, and might have very subtle effects on survival individually. For example, researchers have identified approximately 700 common mutations that influence height, each contributing only millimeters. To this end, we considered tens to hundreds of mutations that shape variation in one of 42 traits.</p>
<p>We found genetic mutations linked to a number of diseases and metabolic traits that decrease survival rates: individuals who are genetically predisposed to have higher total cholesterol, LDL cholesterol, risk of heart disease, BMI, risk of asthma or lower HDL cholesterol tend to die younger than others.</p>
<p>Perhaps more surprisingly, we discovered that people who carry mutations that delay puberty or the age at which they have their first child tend to live longer. It was known from <a href="https://www.nature.com/articles/srep11208">epidemiological studies</a> that early puberty is associated with adverse effects later in life such as cancer and obesity. Our results indicate some of that effect is probably due to heritable factors.</p>
<p>So humans carry common mutations that affect their survival and natural selection appears to act on at least a subset, in some contemporary environments. But what is bad in one context may well not be in another; as one example, the CHRNA3 variant has an effect because people smoke. These are early days, however, and our findings offer only a first glimpse of what can soon be gleaned from millions of genomes, in combination with genealogical records. In future work, it will be important to study not only lifespan, but also the number of children and grandchildren individuals leave, as well as populations and environments worldwide.</p><img src="https://counter.theconversation.com/content/83621/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joe Pickrell works for and holds equity in the personal genomics company Gencove. </span></em></p><p class="fine-print"><em><span>Molly Przeworski receives funding from the National Institute of Health.</span></em></p><p class="fine-print"><em><span>Hakhamanesh Mostafavi does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Comparing genomes of more than 200,000 people, researchers identified genetic variants that are less common in older people, suggesting natural selection continues to weed out disadvantageous traits.Hakhamanesh Mostafavi, Ph.D. Student in Biological Sciences, Columbia UniversityJoe Pickrell, Adjunct Assistant Professor of Biological Sciences, Columbia UniversityMolly Przeworski, Professor of Biological Sciences, Columbia UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/828672017-08-24T10:22:19Z2017-08-24T10:22:19ZIntroducing ‘dark DNA’ – the phenomenon that could change how we think about evolution<figure><img src="https://images.theconversation.com/files/183142/original/file-20170823-13287-ckp3gp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>DNA sequencing technology is helping scientists unravel questions that humans have been asking about animals for centuries. By mapping out animal genomes, we now have a better idea of how the <a href="https://www.nature.com/news/genome-reveals-why-giraffes-have-long-necks-1.19931">giraffe got its huge neck</a> and why <a href="https://theconversation.com/how-the-snake-got-its-extra-long-body-63677">snakes are so long</a>. Genome sequencing allows us to compare and contrast the DNA of different animals and work out how they evolved in their own unique ways.</p>
<p>But in some cases we’re faced with a mystery. Some animal genomes seem to be missing certain genes, ones that appear in other similar species and must be present to keep the animals alive. These apparently missing genes have been dubbed “dark DNA”. And its existence could change the way we think about evolution. </p>
<p>My colleagues and I first encountered this phenomenon when sequencing the <a href="http://www.pnas.org/content/114/29/7677.abstract">genome of the sand rat</a> (<em>Psammomys obesus</em>), a species of gerbil that lives in deserts. In particular we wanted to study the gerbil’s genes related to the production of insulin, to understand why this animal is particularly susceptible to type 2 diabetes.</p>
<p>But when we looked for a gene called Pdx1 that controls the secretion of insulin, we found it was missing, as were 87 other genes surrounding it. Some of these missing genes, including Pdx1, are essential and without them an animal cannot survive. So where are they?</p>
<p>The first clue was that, in several of the sand rat’s body tissues, we found the chemical products that the instructions from the “missing” genes would create. This would only be possible if the genes were present somewhere in the genome, indicating that they weren’t really missing but just hidden.</p>
<p>The DNA sequences of these genes are very rich in G and C molecules, two of the four “base” molecules that make up DNA. We know GC-rich sequences cause problems for certain DNA-sequencing technologies. This makes it more likely that the genes we were looking for were hard to detect rather than missing. For this reason, we call the hidden sequence “dark DNA” as a reference to <a href="https://www.space.com/20930-dark-matter.html">dark matter</a>, the stuff that we think makes up about 25% of the universe but that we can’t actually detect.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=433&fit=crop&dpr=1 600w, https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=433&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=433&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=544&fit=crop&dpr=1 754w, https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=544&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/183148/original/file-20170823-13319-pf1uyx.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=544&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">I ain’t missing nothing!</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>By studying the sand rat genome further, we found that one part of it in particular had many more mutations than are found in other rodent genomes. All the genes within this mutation hotspot now have very GC-rich DNA, and have mutated to such a degree that they are hard to detect using standard methods. Excessive mutation will often stop a gene from working, yet somehow the sand rat’s genes manage to still fulfil their roles despite radical change to the DNA sequence. This is a very difficult task for genes. It’s like winning <a href="https://www.youtube.com/watch?v=VXpTMuW8q74">Countdown</a> using only vowels.</p>
<p>This kind of dark DNA has previously been <a href="https://genomebiology.biomedcentral.com/articles/10.1186/s13059-015-0724-z">found in birds</a>. Scientists have <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290089/">found that 274</a> genes are “missing” from currently sequenced bird genomes. These include the <a href="https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2015-1634">gene for leptin</a> (a hormone that regulates energy balance), which scientists have been unable to find for many years. Once again, these genes have a very high GC content and their products are found in the birds’ body tissues, even though the genes appear to be missing from the genome sequences.</p>
<h2>Shedding light on dark DNA</h2>
<p>Most textbook definitions of evolution state that it occurs in two stages: mutation followed by natural selection. DNA mutation is a common and continuous process, and occurs completely at random. Natural selection then acts to determine whether mutations are kept and passed on or not, usually depending on whether they result in higher reproductive success. In short, mutation creates the variation in an organism’s DNA, natural selection decides whether it stays or if it goes, and so biases the direction of evolution.</p>
<p>But hotspots of high mutation within a genome mean genes in certain locations have a higher chance of mutating than others. This means that such hotspots could be an underappreciated mechanism that could also bias the direction of evolution, meaning natural selection may not be the sole driving force.</p>
<p>So far, dark DNA seems to be present in two very diverse and distinct types of animal. But it’s still not clear how widespread it could be. Could all animal genomes contain dark DNA and, if not, what makes gerbils and birds so unique? The most exciting puzzle to solve will be working out what effect dark DNA has had on animal evolution.</p>
<p>In the example of the sand rat, the mutation hotspot may have made the animal’s adaptation to desert life possible. But on the other hand, the mutation may have occurred so quickly that natural selection hasn’t been able to act fast enough to remove anything detrimental in the DNA. If true, this would mean that the detrimental mutations could prevent the sand rat from surviving outside its current desert environment.</p>
<p>The discovery of such a weird phenomenon certainly raises questions about how genomes evolve, and what could have been missed from existing genome sequencing projects. Perhaps we need to go back and take a closer look.</p><img src="https://counter.theconversation.com/content/82867/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Adam Hargreaves does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Some animals seem to have missing genes – but the reality is a lot more intriguing.Adam Hargreaves, Postdoctoral Research Fellow, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/787672017-06-20T02:41:12Z2017-06-20T02:41:12ZWhat does DNA sound like? Using music to unlock the secrets of genetic code<p>I’ve been studying molecular biology for many years. I also have a keen interest in music, having played with Sydney pop band the Hummingbirds. Usually, there is little overlap between these two pursuits, but I recently became aware of people using DNA sequences to create music. </p>
<p>This is called sonification. The people doing this usually treat DNA sequences as random patterns to create nice-sounding music. But what if we <a href="http://blogs.biomedcentral.com/bmcseriesblog/2017/05/22/sounding-out-the-properties-of-dna/">used musical notes to find out something useful about DNA sequences</a>, like where mutations occur?</p>
<p>So I put on my coding hat and devised a <a href="http://dnasonification.org/example.php">tool</a> that converts a DNA sequence into an audio stream. The results were recently published in the journal <a href="https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-017-1632-x">BMC Bioinformatics</a>.</p>
<h2>Hear the difference</h2>
<p>DNA acts as a template for the production of proteins in our bodies. A DNA sequence is a long, continuous chain made up of only four chemical bases referred to as G, A, T, or C. They repeat in various defined patterns to make up a gene. Many genes are identical in sequence within a species; that is, from person to person, or from virus to virus. </p>
<p>But sometimes one of the chemical bases in sequence is different from the usual pattern – this is called a mutation, and it can indicate an error that could create problems for the person or microorganism involved.</p>
<p>In my online audio tool, any changes in a repetitive DNA sequence due to mutation give rise to a very distinctive change in sound.</p>
<p>To give you an idea of what I’m talking about, here’s an artificial test DNA sequence in my online audio tool that consists of a series of Gs:</p>
<p><audio preload="metadata" controls="controls" data-duration="20" data-image="" data-title="An artificial test DNA GGG sequence." data-size="640872" data-source="" data-source-url="http://dnasonification.org/example.php" data-license="Author provided (no reuse)" data-license-url="">
<source src="https://cdn.theconversation.com/audio/793/01-g-sequence-default.mp3" type="audio/mpeg">
</audio>
<div class="audio-player-caption">
An artificial test DNA GGG sequence.
<span class="attribution"><a class="source" rel="nofollow" href="http://dnasonification.org/example.php">DNASonification/Mark Temple</a>, <span class="license">Author provided (no reuse)</span><span class="download"><span>626 KB</span> <a target="_blank" href="https://cdn.theconversation.com/audio/793/01-g-sequence-default.mp3">(download)</a></span></span>
</div></p>
<p>By contrast, here’s an artificial test DNA sequence that includes a mutation: </p>
<p><audio preload="metadata" controls="controls" data-duration="18" data-image="" data-title="An artificial test DNA sequence with mutation." data-size="587373" data-source="DNASonification/Mark Temple" data-source-url="http://dnasonification.org/example.php" data-license="Author provided (no reuse)" data-license-url="">
<source src="https://cdn.theconversation.com/audio/794/mutated-g-sequence.mp3" type="audio/mpeg">
</audio>
<div class="audio-player-caption">
An artificial test DNA sequence with mutation.
<span class="attribution"><a class="source" rel="nofollow" href="http://dnasonification.org/example.php">DNASonification/Mark Temple</a>, <span class="license">Author provided (no reuse)</span><span class="download"><span>574 KB</span> <a target="_blank" href="https://cdn.theconversation.com/audio/794/mutated-g-sequence.mp3">(download)</a></span></span>
</div></p>
<p>In this natural DNA sequence, a change in the repetitive sound at approximately 0.13 indicates a subtle change (a mutation) in the sequence in that spot:</p>
<p><audio preload="metadata" controls="controls" data-duration="47" data-image="" data-title="Audio from repetitive DNA" data-size="1515243" data-source="" data-source-url="" data-license="" data-license-url="">
<source src="https://cdn.theconversation.com/audio/747/telomeric-dna.mp3" type="audio/mpeg">
</audio>
<div class="audio-player-caption">
Audio from repetitive DNA.
</div></p>
<h2>Coding the codons</h2>
<p>In real life, of course, DNA sequences are more complex than that. For starters, real DNA sequences include codons. A codon is a sequence of three bases which join up to create a unit of DNA information. One codon directs one building block known as an “amino-acid” in a protein. In nature, special codons mark the start and stop points of genes. In my approach, these special codons are used to start and stop the audio.</p>
<p>It is not intended that you can hear a note and relate it to a particular codon, however the landscape of the audio is characteristic of the underlying sequence (as you can hear in the examples).</p>
<p>So, how’s all this sound when you apply my sonification system to a real piece of DNA that makes a protein?</p>
<p>Take, for example, a <a href="https://www.ncbi.nlm.nih.gov/nuccore/BT019421">human DNA sequence</a> that codes for a protein (for the experts in the audience, its the <em>RAS</em> protein that is often involved in cancer). Here’s how it would look when expressed traditionally in written form:</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=248&fit=crop&dpr=1 600w, https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=248&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=248&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=312&fit=crop&dpr=1 754w, https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=312&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/174407/original/file-20170619-5756-nuly92.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=312&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Human Ras sequence.</span>
<span class="attribution"><span class="source">DNASonification/Mark Temple</span></span>
</figcaption>
</figure>
<p>And here’s how it sounds in my online audio tool:</p>
<p><audio preload="metadata" controls="controls" data-duration="99" data-image="" data-title="Human Ras cDNA (Highlight STOP START)" data-size="3168689" data-source="DNASonification/Mark Temple" data-source-url="http://dnasonification.org/example.php" data-license="Author provided (no reuse)" data-license-url="">
<source src="https://cdn.theconversation.com/audio/796/human-h-ras-cdna-highlight-stop-start.mp3" type="audio/mpeg">
</audio>
<div class="audio-player-caption">
Human Ras cDNA (Highlight STOP START)
<span class="attribution"><a class="source" rel="nofollow" href="http://dnasonification.org/example.php">DNASonification/Mark Temple</a>, <span class="license">Author provided (no reuse)</span><span class="download"><span>3.02 MB</span> <a target="_blank" href="https://cdn.theconversation.com/audio/796/human-h-ras-cdna-highlight-stop-start.mp3">(download)</a></span></span>
</div></p>
<p>The coding sequence above always has one instrument playing (the one that actually codes for the protein). </p>
<p>Lastly, when I “sonified” some sequences that encode for important RNA components of cells (not proteins), you can hear periods of silence in the audio – often interspersed with percussion sounds so you can hear spots where there are stop codons:</p>
<p><audio preload="metadata" controls="controls" data-duration="279" data-image="" data-title="Audio from noncoding RNA" data-size="8923151" data-source="" data-source-url="" data-license="" data-license-url="">
<source src="https://cdn.theconversation.com/audio/749/non-coding-rna.mp3" type="audio/mpeg">
</audio>
<div class="audio-player-caption">
Audio from noncoding RNA.
</div></p>
<p>Normally, scientists rely heavily on visual inspection of DNA sequences to unlock their secrets. Sonification alone is not intended to replace visual inspection but rather complement it, in the same way that colour may highlight the properties of a DNA sequence. </p>
<p>Outside of the rigours of DNA research there is strong interest within the community to better understand how DNA sequences determine our physical form and how mutations we accumulate in DNA over time affect our health.</p>
<p>Hopefully, listening to audio derived from DNA may help scientists better understand how cell biology works.</p><img src="https://counter.theconversation.com/content/78767/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Temple does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Converting a DNA sequence into an audio could help us learn something useful about it, like where mutations occur.Mark Temple, Lecturer in Molecular Biology, Western Sydney UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/786382017-05-31T16:08:09Z2017-05-31T16:08:09ZCRISPR controversy raises questions about gene-editing technique<figure><img src="https://images.theconversation.com/files/171655/original/file-20170531-23531-1sfeuqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Laboratory mice are among the first animals to have their diseases treated by CRISPR</span> <span class="attribution"><a class="source" href="https://pixabay.com/en/animal-mouse-experiment-laboratory-1554745/">tiburi via Pixabay.com</a></span></figcaption></figure><p><em>Editor’s note: On March 30, 2018, journal Nature Methods <a href="https://retractionwatch.com/2018/03/30/nature-journal-retracts-controversial-crispr-paper-after-authors-admit-results-may-be-wrong/">retracted</a> the original research paper that reported high levels of off-target DNA edits produced by a CRISPR-based gene editing therapy. According to the journal, “<a href="https://doi.org/10.1038/nmeth.4293">it is not certain that the variants reported are due to CRISPR treatment</a>.”</em></p>
<p>A new research paper is stirring up controversy among scientists interested in using DNA editing to treat disease.</p>
<p>In a two-page article published in the journal Nature Methods on May 30, a group of six scientists <a href="https://doi.org/10.1038/nmeth.4293">report an alarming number of so-called “off-target mutations”</a> in mice that underwent an experimental gene repair therapy.</p>
<p>CRISPR, the hot new gene-editing technique that’s taken biology by storm, is <a href="https://theconversation.com/beyond-just-promise-crispr-is-delivering-in-the-lab-today-77596">no stranger to headlines</a>. What is unusual, however, is a scientific article so clearly describing a potentially fatal shortcoming of this promising technology.</p>
<p>The research community is digesting this news – with many experts suggesting flaws with the experiment, not the revolutionary technique.</p>
<h2>Unwanted DNA changes</h2>
<p>The research team sought to repair a genetic mutation known to cause a form of blindness in mice. This could be accomplished, <a href="https://doi.org/10.1038/mt.2016.107">they showed</a>, by changing just one DNA letter in the mouse genome.</p>
<p>They were able to successfully correct the targeted mutation in each of the two mice they treated. But they also observed an alarming number of additional DNA changes — more than 1,600 per mouse — in areas of the genome they did not intend to modify.</p>
<p>The authors attribute these unintended mutations to the experimental CRISPR-based gene editing therapy they used.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=587&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=587&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=587&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=738&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=738&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171677/original/file-20170531-25652-1ke2711.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=738&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Cas9, the CRISPR enzyme that snips DNA, in contact with its target.</span>
<span class="attribution"><span class="source">rcsb.org | PDB: 5FW2 | doi:10.2210/pdb5fw2/pdb</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>A central promise of CRISPR-based gene editing is its ability to pinpoint particular genes. But if this technology produces dangerous side effects by creating unexpected and unwanted mutations across the genome, that could hamper or even derail many of its applications.</p>
<p>Several previous research articles <a href="https://doi.org/10.1038/nmeth.3408">have reported off-target effects of CRISPR</a>, but far fewer than this group found.</p>
<h2>Reaction is skeptical</h2>
<p>The publicly traded biotech companies seeking to commercialize CRISPR-based gene therapies – <a href="http://www.editasmedicine.com">Editas Medicine</a>, <a href="http://www.intelliatx.com">Intellia Therapeutics</a> and <a href="http://www.crisprtx.com">Crispr Therapeutics</a> – <a href="https://www.statnews.com/2017/05/30/crispr-stocks-off-target/">all took immediate stock market hits</a> based on the news.</p>
<p>Experts in the field quickly responded.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869742617839448064"}"></div></p>
<p>“Either the enzyme is acting at near optimal efficiency or something fishy is going on here,” <a href="https://twitter.com/JMTali/status/869742617839448064">tweeted</a> Matthew Taliaferro, a postdoctoral fellow at MIT who <a href="http://genes.mit.edu/burgelab/index.html">studies gene expression and genetic disease</a>.</p>
<p>The Cas9 enzyme in the CRISPR system is what actually cuts DNA, leading to genetic changes. Unusually high levels of enzyme activity could account for the observed off-target mutations – more cutting equals more chances for the cell to mutate its DNA. Different labs use slightly different methods to try to ensure the right amount of cuts happen only where intended.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869705549453119489"}"></div></p>
<p>“Unusual methods were used,” <a href="https://twitter.com/LluisMontoliu/status/869705549453119489https://twitter.com/LluisMontoliu/status/869705549453119489">tweeted</a> Lluis Montoliu, who runs a lab at the Spanish National Centre for Biotechnology that specializes in <a href="http://wwwuser.cnb.csic.es/%7Emontoliu/indexe.html">editing mice genes using CRISPR</a>. He believes the authors used suboptimal molecular components in their injected CRISPR therapies – specifically a plasmid that causes cells to produce too much Cas9 enzyme – likely leading to the off-target effects they observed. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"869676177094393856"}"></div></p>
<p><a href="http://jcsmr.anu.edu.au/groups/groups/burgio-group">Gaétan Burgio</a>, whose laboratory at the Australian National University is working to understand the role that cellular context plays on CRISPR efficiency, believes the paper’s central claim that CRISPR caused such an alarming number of off-target mutations is “<a href="https://twitter.com/GaetanBurgio/status/869676177094393856">not substantiated</a>.”</p>
<p>Burgio says there could be a range of reasons for seeing so many unexpected changes in the mice, including problems with accurately detecting DNA variation, the extremely small number of mice used, random events happening after Cas9 acted or, he concedes, problems with CRISPR itself.</p>
<p>Burgio has been editing the DNA of mice using CRISPR since 2014 and has never seen a comparable level of off-target mutation. He says he’s confident that additional research will refute these recent findings.</p>
<h2>Continuing CRISPR work</h2>
<p>Although the news of this two-mouse experiment fired up the science-focused parts of the Twittersphere, the issue it raises is not new to the field.</p>
<p>Researchers have known for a few years now that off-target mutations are likely given certain CRISPR protocols. More precise variants of the Cas9 enzyme <a href="https://doi.org/10.1038/nature16526">have been shown to improve targeting</a> in human tissue the lab.</p>
<p>Researchers have also focused on developing <a href="https://doi.org/10.1101/gr.162339.113">methods to more efficiently locate off-target mutations</a> in the animals they study.</p>
<p>As scientists continue to hone the gene-editing technique, we recognize there’s still a way to go before CRISPR will be ready for safe and effective gene therapy in humans.</p><img src="https://counter.theconversation.com/content/78638/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Haydon does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A new research paper reports dangerous side effects in CRISPR-edited mice. Some scientists are pushing back, placing blame for the unwanted mutations on the experiment, not the technique.Ian Haydon, Doctoral Student in Biochemistry, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/656062017-04-07T01:35:28Z2017-04-07T01:35:28ZDNA dating: How molecular clocks are refining human evolution’s timeline<figure><img src="https://images.theconversation.com/files/164196/original/image-20170405-14615-pgkdmv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Our cells have a built-in genetic clock, tracking time... but how accurately?</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hand-holding-retro-stopwatch-black-white-256422460">Stopwatch image via www.shutterstock.com.</a></span></figcaption></figure><p>DNA holds the story of our ancestry – how we’re related to the familiar faces at family reunions as well as more ancient affairs: how we’re related to our closest nonhuman relatives, chimpanzees; how <em>Homo sapiens</em> mated with Neanderthals; and how people migrated out of Africa, adapting to new environments and lifestyles along the way. And our DNA also holds clues about the timing of these key events in human evolution.</p>
<p>When scientists say that <a href="http://doi.org/10.1038/nature18964">modern humans emerged</a> in Africa about 200,000 years ago and began their global spread about 60,000 years ago, how do they come up with those dates? Traditionally researchers built timelines of human prehistory based on fossils and artifacts, which can be directly dated with methods such as <a href="https://theconversation.com/explainer-what-is-radiocarbon-dating-and-how-does-it-work-9690">radiocarbon dating</a> and Potassium-argon dating. However, these methods require ancient remains to have certain elements or preservation conditions, and that is not always the case. Moreover, relevant fossils or artifacts have not been discovered for all milestones in human evolution.</p>
<p>Analyzing DNA from present-day and ancient genomes provides a complementary approach for dating evolutionary events. Because certain genetic changes occur at a steady rate per generation, they provide an estimate of the time elapsed. These changes accrue like the ticks on a stopwatch, providing a “molecular clock.” By comparing DNA sequences, geneticists can not only reconstruct relationships between different populations or species but also infer evolutionary history over deep timescales.</p>
<p>Molecular clocks are becoming more sophisticated, thanks to improved DNA sequencing, analytical tools and a better understanding of the biological processes behind genetic changes. By applying these methods to the ever-growing database of DNA from diverse populations (both present-day and ancient), geneticists are helping to build a more refined timeline of human evolution.</p>
<h2>How DNA accumulates changes</h2>
<p>Molecular clocks are based on two key biological processes that are the source of all heritable variation: mutation and recombination. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164195/original/image-20170405-14612-1cas5ot.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Mutations are changes to the DNA code, such as when one nucleotide base (A, T, G or C) is incorrectly subbed for another.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/vector-illustration-dna-structure-303407264">DNA image via www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Mutations are changes to the letters of DNA’s genetic code – for instance, a nucleotide Guanine (G) becomes a Thymine (T). These changes will be inherited by future generations if they occur in eggs, sperm or their cellular precursors (the germline). Most result from mistakes when DNA copies itself during cell division, although other <a href="https://doi.org/10.1146/annurev-genom-031714-125740">types of mutations</a> occur spontaneously or from exposure to hazards like radiation and chemicals.</p>
<p>In a single human genome, there are about <a href="https://doi.org/10.1038/nature11396">70 nucleotide changes per generation</a> – minuscule in a genome made up of six billion letters. But in aggregate, over many generations, these changes lead to substantial evolutionary variation.</p>
<p>Scientists can use mutations to estimate the timing of branches in our evolutionary tree. First they compare the DNA sequences of two individuals or species, counting the neutral differences that don’t alter one’s chances of survival and reproduction. Then, knowing the rate of these changes, they can calculate the time needed to accumulate that many differences. This tells them how long it’s been since the individuals shared ancestors.</p>
<p>Comparison of DNA between you and your sibling would show relatively few mutational differences because you share ancestors – mom and dad – just one generation ago. However, there are millions of differences between <a href="https://doi.org/10.1038/nature04072">humans and chimpanzees</a>; our last common ancestor lived over six million years ago.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=237&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=237&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=237&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=298&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=298&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164351/original/image-20170406-16660-iq0fym.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=298&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Bits of the chromosomes from your mom and your dad recombine as your DNA prepares to be passed on.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/phases-meiosis-1-172528943">Chromosomes image via www.shutterstock.com.</a></span>
</figcaption>
</figure>
<p><a href="https://doi.org/10.1038/nrg1947">Recombination</a>, also known as crossing-over, is the other main way DNA accumulates changes over time. It leads to shuffling of the two copies of the genome (one from each parent), which are bundled into chromosomes. During recombination, the corresponding (homologous) chromosomes line up and exchange segments, so the genome you pass on to your children is a mosaic of your parents’ DNA.</p>
<p>In humans, <a href="https://doi.org/10.1038/nature09525">about 36 recombination events</a> occur per generation, one or two per chromosome. As this happens every generation, segments inherited from a particular individual get broken into smaller and smaller chunks. Based on the size of these chunks and frequency of crossovers, geneticists can estimate how long ago that individual was your ancestor.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=699&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=699&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=699&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=879&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=879&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164352/original/image-20170406-16665-1ykda9r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=879&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Gene flow between divergent populations leads to chromosomes with mosaic ancestry. As recombination occurs in each generation, the bits of Neanderthal ancestry in modern human genomes becomes smaller and smaller over time.</span>
<span class="attribution"><span class="source">Bridget Alex</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Building timelines based on changes</h2>
<p>Genetic changes from mutation and recombination provide two distinct clocks, each suited for dating different evolutionary events and timescales.</p>
<p>Because mutations accumulate so slowly, this clock works better for very ancient events, like evolutionary splits between species. The recombination clock, on the other hand, ticks at a rate appropriate for dates within the last 100,000 years. These “recent” events (in evolutionary time) include gene flow between distinct human populations, the rise of beneficial adaptations or the emergence of genetic diseases.</p>
<p>The case of Neanderthals illustrates how the mutation and recombination clocks can be used together to help us untangle complicated ancestral relationships. Geneticists estimate that there are 1.5-2 million mutational differences between Neanderthals and modern humans. Applying the mutation clock to this count suggests the groups initially split between <a href="https://doi.org/10.1038/nature12886">750,000 and 550,000 years ago</a>.</p>
<p>At that time, a population – the common ancestors of both human groups – separated geographically and genetically. Some individuals of the group migrated to Eurasia and over time evolved into Neanderthals. Those who stayed in Africa became anatomically modern humans. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164194/original/image-20170405-14620-3re7gz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">An evolutionary tree displays the divergence and interbreeding dates that researchers estimated with molecular clock methods for these groups.</span>
<span class="attribution"><span class="source">Bridget Alex</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>However, their interactions were not over: Modern humans eventually spread to Eurasia and mated with Neanderthals. Applying the recombination clock to Neanderthal DNA retained in present-day humans, researchers estimate that the <a href="http://doi.org/10.1073/pnas.1514696113">groups interbred between 54,000 and 40,000 years ago</a>. When scientists analyzed a <em>Homo sapiens</em> fossil, known as Oase 1, who lived around 40,000 years ago, they found large regions of Neanderthal ancestry embedded in the Oase genome, suggesting that Oase had a <a href="http://doi.org/10.1038/nature14558">Neanderthal ancestor just four to six generations ago</a>. In other words, Oase’s great-great-grandparent was a Neanderthal. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=235&fit=crop&dpr=1 600w, https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=235&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=235&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=295&fit=crop&dpr=1 754w, https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=295&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/164193/original/image-20170405-14626-lvvz51.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=295&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Comparing chromosome 6 from the 40,000-year-old Oase fossil to a present-day human. The blue bands represent segments of Neanderthal DNA from past interbreeding. Oase’s segments are longer because he had a Neanderthal ancestor just 4–6 generations before he lived, based on estimates using the recombination clock.</span>
<span class="attribution"><span class="source">Bridget Alex</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>The challenges of unsteady clocks</h2>
<p>Molecular clocks are a mainstay of evolutionary calculations, not just for humans but for all forms of living organisms. But there are some complicating factors.</p>
<p>The main challenge arises from the fact that mutation and recombination rates have not remained constant over human evolution. The rates themselves are evolving, so they vary over time and may differ between species and even across human populations, albeit fairly slowly. It’s like trying to measure time with a clock that ticks at different speeds under different conditions.</p>
<p>One issue relates to a gene called <em>Prdm9</em>, which determines the location of those DNA crossover events. Variation in this gene in humans, chimpanzees and mice has been shown <a href="https://doi.org/10.1126/science.1183439">to alter recombination hotspots</a> – short regions of high recombination rates. Due to the evolution of <em>Prdm9</em> and hotspots, the fine-scale recombination rates <a href="https://doi.org/10.1126/science.1216872">differ between humans and chimps</a>, and <a href="https://doi.org/10.1038/nature10336">possibly also between Africans and Europeans</a>. This implies that over different timescales and across populations, the recombination clock ticks at <a href="http://www.nature.com/nrg/journal/v8/n1/execsumm/nrg1947.html">slightly different rates</a> as hotspots evolve.</p>
<p>Another issue is that mutation rates vary by sex and age. As fathers get older, they transmit <a href="https://doi.org/10.1038/ng.3597">a couple extra mutations to their offspring per year</a>. The sperm of older fathers has undergone more rounds of cell division, so more opportunities for mutations. Mothers, on the other hand, <a href="https://doi.org/10.1038/ng.3597">transmit fewer mutations</a> (about 0.25 per year) as a female’s eggs are mostly formed all at the same time, before her own birth. Mutation rates also <a href="https://doi.org/10.1073/pnas.1600374113">depend on factors like</a> onset of puberty, age at reproduction and rate of sperm production. These life history traits vary across living primates and probably also differed between extinct species of human ancestors.</p>
<p>Consequently, over the course of human evolution, the <a href="https://doi.org/10.1038/nrg3295">average mutation rate seems to have slowed</a> significantly. The average rate over millions of years since the split of humans and chimpanzees has been estimated as <a href="https://doi.org/10.1038/nature04072">about 1x10⁻⁹ mutations per site per year</a> – or roughly six altered DNA letters per year. This rate is determined by dividing the number of nucleotide differences between humans and other apes by the date of their evolutionary splits, as inferred from fossils. It’s like calculating your driving speed by dividing distance traveled by time passed. But when geneticists directly measure nucleotide differences between living parents and children (using human pedigrees), the mutation rate is half the other estimate: <a href="https://doi.org/10.1038/nature11396">about 0.5x10⁻⁹ per site per year</a>, or only about three mutations per year. </p>
<p>For the divergence between Neanderthals and modern humans, the slower rate provides an estimate between 765,000-550,000 years ago. The faster rate, however, would suggest half that age, or 380,000-275,000 years ago: a big difference.</p>
<p>To resolve the question of which rates to use when and on whom, researchers have been developing new molecular clock methods, which address the challenges of evolving mutation and recombination rates.</p>
<h2>New approaches for better dating</h2>
<p>One approach is to focus on mutations that arise at a steady rate regardless of sex, age and species. This may be the case for a special type of mutation that geneticists call <a href="http://www.nature.com/nature/journal/v287/n5782/abs/287560a0.html">CpG transitions</a> by which the C nucelotides spontaneously become T’s. Because CpG transitions mostly do not result from DNA copying errors during cell division, their rates should be mainly independent of life history variables – and presumably more uniform over time. </p>
<p>Focusing on CpG transitions, geneticists recently estimated the split between humans and chimps to have occurred <a href="https://doi.org/10.1073/pnas.1600374113">between 9.3 and 6.5 million years ago</a>, which agrees with the age expected from fossils. While in comparisons across species, these mutations seem to happen more like clockwork than other types, they are still not completely steady.</p>
<p>Another approach is to develop models that adjust molecular clock rates based on sex and other life history traits. Using this method, researchers <a href="https://doi.org/10.1073/pnas.1515798113">calculated a chimp-human divergence</a> consistent with the CpG estimate and fossil dates. The drawback here is that, when it comes to ancestral species, we can’t be sure of life history traits, like age at puberty or generation length, leading to some uncertainty in the estimates.</p>
<p>The most direct solution comes from analyses of ancient DNA recovered from fossils. Because the fossil specimens are independently dated by geologic methods, geneticists can use them to calibrate the molecular clocks for a given time period or population.</p>
<p>This strategy recently resolved the debate over the timing of our divergence with Neanderthals. In 2016, geneticists extracted ancient DNA from <a href="https://doi.org/10.1038/nature17405">430,000-year-old fossils that were Neanderthal ancestors</a>, after their lineage split from <em>Homo sapiens</em>. Knowing where these fossils belong in the evolutionary tree, geneticists could confirm that for this period of human evolution, the slower molecular clock rate of 0.5x10⁻⁹ provides accurate dates. That puts the Neanderthal-modern human split between 765,000 to 550,000 years ago.</p>
<p>As geneticists sort out the intricacies of molecular clocks and sequence more genomes, we’re poised to learn more than ever about human evolution, directly from our DNA.</p><img src="https://counter.theconversation.com/content/65606/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Bridget Alex has received research funding from the National Science Foundation (NSF).</span></em></p><p class="fine-print"><em><span>Priya Moorjani is supported by the NIH Ruth L. Kirschstein National Research Service Postdoctoral fellowship (grant number F32 GM115006-02).</span></em></p>How do scientists figure out when evolutionary events – like species splitting away from a common ancestor – happened? It turns out our DNA is a kind of molecular clock, keeping time via genetic changes.Bridget Alex, Postdoctoral College Fellow, Department of Human Evolutionary Biology, Harvard UniversityPriya Moorjani, Postdoctoral Research Fellow in Biological Sciences, Columbia UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/707502017-01-10T10:21:10Z2017-01-10T10:21:10ZA hidden code in our DNA explains how new pieces of genes are made<figure><img src="https://images.theconversation.com/files/151700/original/image-20170104-18668-8ody1h.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>We’re all here because of mutations. Random changes in genes are what creates variety in a species, and this is what allows it to adapt to new environments and eventually evolve into completely new species. But most random mutations actually disrupt the functions of our genes and so are a common source of genetic diseases.</p>
<p>This ambiguity creates a great challenge. On the one hand, mutations are needed for biological innovation, and on the other hand they cause diseases. How does nature resolve this conflict? Recent research by me and my colleagues suggests that one answer could lie in a genetic code that allows evolution to innovate while minimising the disruption this can create.</p>
<p>This code is hidden within a part of <a href="https://ghr.nlm.nih.gov/primer/hgp/genome">our genome</a> (the complete set of our genetic material) known as <a href="https://en.wikipedia.org/wiki/Repeated_sequence_(DNA)">repetitive genetic elements</a>, which we now know plays a key role in evolution. These elements are sequences within our DNA that can make many copies of themselves. In order to build the proteins that our bodies need, our cells <a href="http://science-explained.com/theory/dna-rna-and-protein/">take instructions</a> from our DNA by transcribing it into a similar molecule called RNA. But in rare cases, instead of building a protein, some RNA molecules convert back into DNA and insert themselves at new locations in our genome.</p>
<p>In this way, the repetitive elements can continually create new copies of themselves. As a result, the human genome contains <a href="http://www.sciencedirect.com/science/article/pii/S0002929707637045">thousands of repetitive elements</a> that are not present in any other species because they have copied themselves since humans evolved.</p>
<p>But repetitive elements aren’t just useless copies. Barbara McClintock, the scientist who discovered them in 1948, showed <a href="http://www.nature.com/scitable/topicpage/barbara-mcclintock-and-the-discovery-of-jumping-34083">they can act as switches</a> that switch genes on and off in maize. This was initially thought to be an obscure phenomenon with no relevance for humans. Yet now it has become clear that repetitive elements are an important toolkit for evolution. By turning genes on and off, the repetitive elements can influence what characteristics a species evolves. They have been useful for biological innovations, such as evolution of <a href="http://www.cell.com/cell-reports/fulltext/S2211-1247(14)01105-X">pregnancy in mammals</a>. </p>
<p>Perhaps the most elegant example of this is in the <a href="https://www.sciencedaily.com/releases/2016/06/160601141528.htm">evolution of the peppered moth</a>. This moth normally has light-coloured wings, but during Britain’s industrial revolution a repetitive element inserted itself into the gene that controls the colour pattern of the wings. As a result, a black strain of the peppered moth evolved and this allowed it to blend in and escape its predators amid the polluted environment.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/151723/original/image-20170104-18662-1xm6an2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Industrial camouflage.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>So what does all this have to do with managing the disruption of mutations? Our research looks at the repetitive elements that were copied within the genome of the ancestors of modern primates. There are over 1.6m of these “<a href="https://genomebiology.biomedcentral.com/articles/10.1186/gb-2011-12-12-236">Alu elements</a>” dispersed all over the human genome, and some of them have accumulated random mutations that enabled them to become functional parts of our genes.</p>
<p>We have <a href="http://www.cell.com/cell/abstract/S0092-8674(12)01545-0">found a code</a> in the RNA that controls Alu elements hiding inside human genes. This code combines competing positive and negative molecular forces, like a yin and yang in our cells. It is well known that <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028494">competing molecular forces</a> control many aspects of our genes. In our case, the positive force (acting through the protein called U2AF65) allows the Alu elements to remain part of RNA and the resulting protein. The negative force (acting through the protein called hnRNPC) opposes this and removes the elements from the RNA. </p>
<p>We’ve known for decades that evolution <a href="https://embryo.asu.edu/pages/evolution-and-tinkering-1977-francois-jacob">needs to tinker</a> with genetic elements so they can accumulate mutations while minimising disruption to the fitness of a species. Our most recent research, <a href="https://elifesciences.org/content/5/e19545">published in the journal eLife</a>, looked at over 6,000 Alu elements to show that our code does exactly this.</p>
<p>The two forces are tightly coupled in evolution, so that as soon as any mutations make the yin stronger, the yang catches up and stops them. This allows the Alu elements to remain in a harmless state in our DNA over long evolutionary periods, during which they accumulate a lot of change via mutations. As a result, they become less harmful and gradually start escaping the repressive force. Eventually, some of them take on an important function and became indispensable pieces of human genes.</p>
<p>To put it another way, the balanced forces buy the time needed for mutations to make beneficial changes, rather than disruptive ones, to a species. And this is why evolution proceeds in such small steps – it only works if the two forces remain balanced by complementary mutations, which takes time. Eventually, important new molecular functions can emerge from randomness. </p>
<p>These findings tell us that humans are not a fixed pinnacle of evolution. Our genomes are like those of any other species: a fluid landscape of DNA sequences that keep changing. This explains how our genome can host its ever-changing repetitive elements despite their potential to disrupt the existing order in our cells.</p><img src="https://counter.theconversation.com/content/70750/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jernej Ule receives funding from The European Research Council and The Wellcome Trust. </span></em></p>A cryptic part of DNA helps keep a species’ mutations in check until they become useful.Jernej Ule, Professor of Molecular Neuroscience, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/453342015-08-17T05:32:56Z2015-08-17T05:32:56ZOur ‘Rosetta Stone’ gene could unlock the secrets of schizophrenia<figure><img src="https://images.theconversation.com/files/91818/original/image-20150813-21432-1raz7ax.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Schizophrenia affects around <a href="http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml">1% of the global population</a> and can cause paranoia, hallucinations and a breakdown in patients’ thought processes, with a huge impact on their ability to carry out everyday tasks. Around 50% of people who suffer with the condition <a href="http://www.ncbi.nlm.nih.gov/pubmed/12511175">attempt suicide</a>. </p>
<p>There are currently relatively few treatments for the condition – and the drugs that are available can have <a href="http://www.rcpsych.ac.uk/healthadvice/treatmentswellbeing/antipsychoticmedication.aspx">unwanted side effects</a>, such as shakiness, weight gain and decreased libido. However, genetics may hold the key to developing more effective treatments. My colleagues and I <a href="http://www.sciencemag.org/content/349/6246/424">recently discovered</a> that one specific gene may allow us to decode the function of all genes involved in the disease. This “Rosetta Stone” gene has revealed a period early in the brain’s development when treatments may be most effective in preventing schizophrenia manifesting in the first place.</p>
<p>Mental health conditions are among the most challenging medical problems we face as scientists, partly because of the complexity of the biology underlying thought processes and partly because studying a living brain is very difficult. However, <a href="http://www.nimh.nih.gov/news/science-news/2013/five-major-mental-disorders-share-genetic-roots.shtml">recent studies</a> <a href="http://bjp.rcpsych.org/content/198/3/173">have begun to make</a> some headway in understanding the biology of mental health conditions by looking at the gene mutations carried by people diagnosed with such problems.</p>
<h2>Origins of genetic disease</h2>
<p>Gene mutations are present in all the cells in the body and can be examined by taking a blood sample. We now know that many of the genes involved in mental health conditions carry instructions for creating the proteins in the brain’s synapses. These are the connections between neurons that allow them to communicate with one another.</p>
<p>But despite knowing about hundreds of mutations associated with schizophrenia, we are relatively in the dark about what they all do. <a href="http://www.nature.com/nature/journal/v460/n7256/abs/nature08185.html">Many different mutations</a> can give rise to the same apparent condition. On the other hand, no single gene mutation necessarily gives rise to a discernible mental health problem.</p>
<p>One gene we do have some certainty about is known as “<a href="http://www.nature.com/mp/journal/v13/n1/full/4002106a.html">disrupted in schizophrenia gene 1</a>” (DISC1). It relates to a protein that, when mutated, can give rise to a number of mental health conditions including schizophrenia, bipolar disorder, major clinical depression and autism.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/91821/original/image-20150813-21432-2y1zp8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Thought breakdown.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>While schizophrenia may be inherited, the probability of inheritance from a mutation carried by one parent alone is relatively low. In contrast, DISC1 mutations are highly <a href="http://medical-dictionary.thefreedictionary.com/penetrance">penetrant</a>, meaning that carrying the mutation is highly likely to give rise to the characteristic problem.</p>
<p>This makes DISC1 a very useful experimental tool, because if a laboratory animal such as a mouse carries the mutation, it is highly likely to exhibit the functional problem and to give rise to offspring with the same problem. Studying DISC1 solves two problems at once: we do not need to look at human neurons because we can use mice instead – and we only need a single mutation rather than the several gene mutations that normally give rise to the condition.</p>
<p>In our studies on DISC1 mice, we have found that the gene has an important function during an early period of brain development. If you impair the function of DISC1 for just two days during the second week after birth, the animal grows up with a lack of brain plasticity (the ability to change neural pathways over time) in the synapses that were trying to form at the time.</p>
<h2>Targeting schizophrenia’s vulnerable period</h2>
<p>Different parts of the brain may mature at different times, but most cortical areas go through a similar sequence of development. Therefore, different areas are all likely to go through the vulnerable period at some point in their development. One of the challenges for the future is to discover what these “critical periods” are for different areas of the brain. </p>
<p>So how can studying DISC1 help us decode what is going wrong with other genes in schizophrenia? Our thought is that we may have identified a critical period in development, which is a common vulnerable period for all – or at least many – of the genes identified as risk factors in schizophrenia. DISC1 mutations have also been linked to autism and Asperger’s syndrome, suggesting that the developmental effects of DISC1 could also be important for understanding these mental health conditions.</p>
<p>The interaction between gene mutations and brain development may have made it difficult to understand how the long list of risk factors can cause problems in the adult brain. Now we know when to study the function of other risk factors and what the outcome is for adult function. We hope this will allow us to throw some light on what the other genes involved in schizophrenia are doing (or doing wrong) during development to give rise to the debilitating condition of schizophrenia.</p><img src="https://counter.theconversation.com/content/45334/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Fox receives funding from the Medical Research Council</span></em></p>Scientists have discovered that a single gene may reveal a weakness in the development of schizophrenia that could help doctors prevent the condition.Kevin Fox, Professor of neuroscience, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/394902015-07-30T20:15:42Z2015-07-30T20:15:42ZDifferences between men and women are more than the sum of their genes<figure><img src="https://images.theconversation.com/files/89607/original/image-20150724-3647-jx0xfk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It's naive to pretend there are no profound genetic and epigenetic differences between the sexes.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/srslymark/3139392279/">Elephant Gun Studios/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>Gender differences and sexual preferences are frequently a point of conversation. What produces the differences between men and women? Are they trivial or profound? Are they genetic or environmental, or both? </p>
<p>Some people claim that, genetically, men are <a href="http://www.theregister.co.uk/2010/01/14/chimp_genome_y_chromosome_gumble">more closely related to male chimpanzees</a> than to women. Others discount sex differences because they’re determined by a single gene, called SRY, on the Y chromosome. </p>
<p>But the key to difference between men and women – and chimps – lies not just in the number of their differing genes but in what these genes do.</p>
<h2>A little background</h2>
<p>Let me first explain a bit about genes and chromosomes. Mammals (all vertebrates, in fact) share pretty much the same collection of about 20,000 genes. Each of these is a short stretch of DNA whose base sequence is copied into RNA, and then translated into a protein. </p>
<p>Our 20,000 genes are arrayed on about a metre of DNA (the genome), which is cut up into smaller pieces, which we can see down a microscope as chromosomes when they coil up to divide. The base sequence of genes can differ slightly from person to person, and differ a lot from species to species.</p>
<p>We all have two copies of the genome, one from mother and one from father, so there are two copies of each chromosome – except for the sex chromosomes. Women have two X chromosomes. Men have a single X (from their mother) and the male-specific Y (from their father). The genetic differences between men and women lie in these sex chromosomes. </p>
<p>The X bears more than 1,000 genes. But the Y has only 45, which are <a href="http://www.ncbi.nlm.nih.gov/pubmed/16530039">all that are left</a> of a once ordinary pair of chromosomes that differentiated to be the X and the Y. One of these 45 Y-borne genes (SRY) determines that a baby with XY chromosomes will develop as a boy.</p>
<p>But the Y chromosome is not all male-specific; 24 genes in its top little bit are shared with the X. These are unlikely to cause differences because they’re present in both sexes. </p>
<h2>Difference and the Y chromosome</h2>
<p>The rest of <a href="http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">the Y lost most of its genes</a> over 150 million years of evolution. A few still cling on, but they’re fatally damaged by mutation, so we can’t count these inactive “pseudogenes”. Indeed, there are only 27 active protein-coding genes on the male-specific part of the Y, although several are present in multiple copies (most of which are inactive). </p>
<p>Nor can we count all 27 because at least 17 have copies on the X chromosome too. Most of these 17 <a href="http://www.nature.com/nature/journal/v508/n7497/full/nature13206.html">remain dedicated</a> to their original purpose, backed up by their X copy. Only three have diverged to <a href="http://www.nature.com/nature/journal/v346/n6281/abs/346240a0.html">acquire male-specific properties</a>, such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/10391206">making sperm</a>.</p>
<p>The remaining ten genes on the human Y have no copy on the X. They are specific to males, so could contribute to differences between men and women. Some of them started off as copies of genes on the X but diverged far from their original function and acquired male-specific roles. Three originated as copies of genes on other chromosomes that were important for male functions.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Many obvious differences between humans and chimps, like hairiness, may result from tiny alterations in one or a few genes.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/slightlyblurred/558000935/in/photolist-RiUeM-6P3si-4uhjG6-52yGZ8-qYjxE-7kWvYp-gLQhtK-9AXm4j-mNxeKR-ekynNF-8VyDXi-qYfNZ-8Go7dD-akAJLD-ekEhjW-9KDnq1-8Eoo8-4J9knx-8VAkLk-akkcax-a7thv8-48H5hV-33oZrf-5KWrJu-eAStQu-7gUS5e-4Q9c8y-zZ1P-5E4jTK-8hcfvW-qCmt4K-e9UKZp-qYfNX-arJixA-9KnNvq-5KSdGp-dKUnC-anFCTb-ed6MrT-rhFPRX-ajHCXZ-8g2VLa-8j31Xb-5KSd3V-rwRaVE-52zhxr-5KWsXC-dKUnP-9Z9bpD-989DZL">Willard Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>So the total number of genes possessed by men and completely absent from women may be as low as 13 (and no greater than 27) out of a total of 20,000 human genes. This proportion is clearly <a href="http://genome.cshlp.org/content/15/12/1746.full">not the equivalent to the supposed 4% genomic difference</a> between men and male chimps.</p>
<h2>‘Junk DNA’ on the Y</h2>
<p>A lot of the DNA of the Y chromosome doesn’t code for proteins and has been regarded as junk, sequences that were left over from old viruses and repeated many times. But hidden in this junk are sequences that are <a href="http://www.ncbi.nlm.nih.gov/pubmed/24296535">copied into long RNA molecules</a> but are not translated into protein. </p>
<p>We’re identifying more and more of these non-coding genes, some of which have remained the same in all vertebrates and presumably have some function. At least some non-coding Y genes may have important roles in regulating sex differentiation genes, though this has not yet been demonstrated.</p>
<p>Even more intriguing is new evidence that among the junk DNA on the Y chromosome of the bull are sequences that work to skew the ratio of sperm that bear the Y chromosome, favouring the birth of male calves. When these sequences are deleted, the skewing goes the opposite way, favouring female calves. </p>
<p>This suggests that the X chromosome, too, has some tricks to get preferentially into sperm. It seems there’s <a href="http://www.scientificamerican.com/article/a-battle-of-the-sexes-is-waged-in-the-genes-of-humans-bulls-and-more/?WT.mc_id=SA_BS_20150703">an arms race in the genome of every mammal</a> as these “sexually antagonistic” genes battle it out. There are many sexually antagonistic genes, <a href="http://theconversation.co.born-this-way-an-evolutionary-view%20of-gay-genes-s6051/">possibly including “gay genes”</a> that influence mate choice.</p>
<h2>X genes and sex differences</h2>
<p>A rarely recognised difference between the genomes of men and women is the different copy number of the more than 1,000 protein-coding genes on the X chromosome. There are two copies of these in women and one in men. </p>
<p>Differences in X gene dosage have been ignored because they were supposedly compensated for by a mechanism that silences all the genes on the whole of the X chromosome in females. Known as <a href="http://www.ncbi.nlm.nih.gov/pubmed/21643983">X chromosome inactivation</a>, this mechanism silences one or other X in the cells of the embryo, and this silencing is passed on into groups of cells in the adult. </p>
<p>This “epigenetic” silencing doesn’t change the base sequence of the DNA. But it changes the way the DNA binds to other molecules so it can’t be copied into RNA, and so produces no protein product.</p>
<p>But now we know that <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911101">more than 150 genes escape inactivation</a> on the human – but not the mouse – X. And independent of sex, the number of X chromosomes has <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669494">profound effects on some basic metabolic pathways</a>, such as fat and carbohydrate synthesis, which may underlie sex differences in susceptibility to many diseases. Mice that have two X chromosomes are fatter than mice with only one, for instance, even if they have been altered so that they’re male.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">There’s a supposed 4% genetic difference between chimps and men.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/animalrescueblog/17080088705/in/photolist-daVK98-daV5dJ-daVfVf-daVNEs-daV1HK-daVnwD-daVanz-daVhsW-daV7G5-daV9s7-daVHk2-daVAk1-daVcsF-daVaWL-daVwBB-daVqWT-daVhct-s2iVj2-fDPzfu-oCjMXd-5LFr83-8YJ451-fDPAUQ-fDPCyJ-h9YQx-feYyLJ-6RrB-6AS2xL-nLy7zj-nLJh8F-7emYiv-daVnzd-daVDKS-8e66aV-daVriN-djQ1zk-bpNmoY-hAHFGV-6jZjU-bDDgda-bqJkS3-bq32sq-c6yNs1-c6AjkW-fTxJ4a-s2bgjL-feHPbR-fDPUnf-feJgKV-feY7uS">International Fund for Animal Welfare Animal Rescue Blog/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>These 150 “escapee” X genes brings us to about 163 genes that are either male-specific, or are active in different doses in men and women. </p>
<h2>What the different genes do</h2>
<p>It’s naïve to think that these 163 genes will all have the same level of influence. Some will code for proteins that are critical for life, or for sex. Others might have only a minor effect, or no visible effect at all.</p>
<p>In fact, the effects of at least some of these 163 genes are profound. The male-determining SRY gene, for instance, kick-starts a <a href="http://www.ncbi.nlm.nih.gov/pubmed/17237341">cascade of dozens of genes</a> that are either turned on in male embryos or turned off in female embryos during testis or ovary development. </p>
<p>Most of these genes are not on sex chromosomes, so they are present in both sexes. But they are turned on to different extents – or at different times or in different tissues – in males and females. Counting these brings up the total to over a 1% genomic difference between the sexes.</p>
<p>What’s more, the downstream effects of SRY are much more profound than simply testis determination. Male hormones, such as testosterone, are synthesised by the embryonic testis and have far-flung effects all over the developing body. Androgens <a href="http://www.ncbi.nlm.nih.gov/pubmed/20399963">turn on hundreds (maybe thousands) of genes</a> that determine male genitalia, male growth, hair, voice and elements of behaviour.</p>
<p>If we count these, we are getting near 800 out of 20,000 human genes, which is closer to the 4% difference of men and male chimpanzees.</p>
<h2>Humans and chimps</h2>
<p>But this often-quoted difference is an average over the whole genome, only a minority of which consists of genes that code for proteins. It tells us little about which genetic differences are important. </p>
<p>Many obvious differences between humans and chimps, such as hairiness and perhaps even speech, may result from tiny alterations in one or a few genes. Differences in timing, or minor regulatory differences, may have massive effects on growth and development. </p>
<p>It’s naive to pretend there are no profound genetic and epigenetic differences between the sexes. But we’re not going to settle issues of how far-reaching the biological differences are just by counting gene differences. How these genes are regulated and their downstream effects are what make the difference between men and chimps, or men and women.</p><img src="https://counter.theconversation.com/content/39490/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves received funding from ARC and NHMRC for research into sex chromosome evolution.</span></em></p>What produces the differences between men and women? Are they trivial or profound? Are they genetic or environmental, or both? And are men really closer genetically to chimpanzees than to women?Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/402462015-06-30T20:10:43Z2015-06-30T20:10:43ZBrace yourself, genetic testing might give you more than you bargained for<p>Drink red wine to prevent cancer. But don’t drink too much! Get some exercise. But don’t overdo it. Give up, it’s all genetic anyway – think of Angelina Jolie! </p>
<p>We are constantly bombarded with conflicting information about our risk of developing cancer. It is difficult to know who to believe, let alone how to respond. </p>
<p>What if you could take a simple test that would reveal your individual risk of developing not only a range of cancers, but hundreds of other diseases? Imagine if it could also tell you which drugs would be most effective for you, if you did develop cancer or other diseases. </p>
<p>The rapidly reducing cost of DNA sequencing has made this one-time fantastical idea an emerging reality. Only 10 years ago it <a href="https://www.nhmrc.gov.au/health-topics/genetics-and-human-health/genetics-101-overview/sequencing-your-genome">cost about US$10 million</a> to sequence a human genome, so there was little prospect that individuals would, or could, seek out their own unique genetic maps to find out more about their ancestry or their inherited health risks. </p>
<p>Recent advances in genetics mean genetic sequencing is <a href="https://www.scienceexchange.com/services/whole-genome-seq">more affordable</a> (US$1,000 to US$3,000) and already guiding treatment across a range of illnesses from cancer to degenerative brain diseases. </p>
<p>New unregulated direct-to-consumer businesses are emerging, making it possible for anyone to order their individual genetic profile by posting off a saliva sample taken at home. But do you really know what you are signing up for?</p>
<h2>The age of personalised medicine</h2>
<p>Personalised medicine means using a patient’s genome to both predict their likelihood of developing certain diseases, and to guide which treatments are most likely to be effective in a particular individual. It’s also called customised medicine, precision medicine, individualised medicine, bespoke medicine and targeted medicine. </p>
<p>Our genes hold our hereditary information. Every cell in the human body is made up of about 20,000 genes that are passed down from parents to child. Genes contain information that instructs the growth, development and function of the human body. Some genes control simple characteristics such as hair colour and height, others influence complex characteristics such as intelligence. Some genes control how other genes work, telling them when to switch on and off. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/84995/original/image-20150615-6496-1eh4xg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Some genes control simple characteristics such as hair colour and height, others influence more complex characteristics like intelligence.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<p>We all have alterations, or mutations, in our DNA. Mutations can be passed down from parents to children, or can occur spontaneously, especially as we age. Some are harmless and may determine, for example, <a href="http://udel.edu/%7Emcdonald/mythearwax.html">whether our ear wax</a> is wet or dry.</p>
<p>However, a mutation in an important gene that prevents it from working properly, or a gene that is missing altogether, can have serious consequences. Early genetic testing focused on debilitating inherited diseases, such as cystic fibrosis and Huntington’s disease, that are caused by mutations in single genes. Tests looked only for a known mutation in a specific gene to confirm or rule out the associated condition. </p>
<p>As testing has become more sophisticated, we have been able to extend this approach to more complex conditions such as cancer. Mutations in two genes called BRCA1 and BRCA2 are associated with an increased risk of developing breast and ovarian cancer, and can be inherited within families. </p>
<p>BRCA1 and BRCA2 normally help clean up mistakes in our DNA that our cells can make when they divide, a process called DNA repair. When either of these genes is altered or mutated, this protective function is disabled, leading to uncontrolled replication of cells with mistakes. This can lead to cancer. </p>
<p>The good news is that we can test for these mutations, and patients can then use the results of this test to assess their risk of developing cancer, and make informed choices. This is the same hereditary genetic mutation that prompted Angelina Jolie to have a preventative <a href="http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html?_r=0">double mastectomy</a> two years ago, and preventative <a href="http://www.nytimes.com/2015/03/24/opinion/angelina-jolie-pitt-diary-of-a-surgery.html?referrer=&_r=3">surgery to remove her ovaries</a> this year.</p>
<p>The other good news is that in recent years scientists have discovered that patients with mutations in BRCA1 and BRCA2 are exquisitely sensitive to some forms of chemotherapy and a second type of drug called a PARP inhibitor. The same mutation that generates the mistakes in these cells can actually <a href="http://www.onclive.com/conference-coverage/mbcc-2015/Excitement-Building-for-PARP-Inhibitors-in-BRCA-Mutated-Breast-Cancer">make them more responsive</a> to this drug. Decisions about treatment can then be “personalised” to the individual.</p>
<h2>What does the future hold?</h2>
<p>Currently, health systems in Australia and overseas do not offer patients the option of sequencing their entire genome as a means of identifying and managing future health risks. Today genetic testing is only available in Australia for specific genes, is tightly regulated and is used only when symptoms are apparent, or a genetic risk is likely, such as a close relative developing a particular cancer or condition.</p>
<p>In five to 10 years’ time, however, we may be facing very different choices, including the option to look for future diseases before they actually occur. </p>
<p>As many cancers do not appear until middle age or later, a young healthy person might discover they have various elevated risks among the many anomalies a DNA test could throw up. Such results might not be provided by a medical professional, but by a commercial operator, and without genetic counselling to explain what they mean to the individual and their family.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=705&fit=crop&dpr=1 600w, https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=705&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=705&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=886&fit=crop&dpr=1 754w, https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=886&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/84996/original/image-20150615-6479-enisbm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=886&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Insurance companies could use genetic profiles to deny higher-risk individuals various types of insurance, or increase their premiums.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<p>What might the implication be of a high-risk result? Should an individual’s relatives be informed, as their risk may also be high, or do they have a right not to know? And what about minors: will parents have the right, or even an obligation, to test babies and children for potential genetic risks, even if medical science offers no prevention or treatment options? </p>
<p>Are we psychologically equipped for these kinds of dilemmas and scientifically literate enough to interpret our own results? </p>
<p>There are currently many reasons to be cautious. First, there are potentially millions of genetic alterations. Most are still not understood. Personalised medicine cannot currently give anyone a comprehensive picture of individual risk simply because far too much remains unknown.</p>
<p>Second, personalised medicine can only indicate elevated risks, it cannot determine whether or not a patient will actually go on to develop a certain type of cancer. Environment and lifestyle also play a big role in our health. </p>
<p>Insurance companies, however, deal entirely in risk. That means genetic profiles could be used to deny higher-risk individuals various types of insurance, or increase their insurance premiums.</p>
<p>Third, health outcomes for some individuals may be based on the financial viability of developing drugs. Many drugs and therapies are currently used for large numbers of patients, making them financially viable for pharmaceutical companies to develop. Genetically targeted cancer drugs, suitable for much smaller groups of patients, may be extremely expensive or might not be brought onto the market at all if society is not willing or cannot afford to pay for them. </p>
<p>Fourth, we may be at risk of eroding our quality of life by creating a new state of “worried wellness”, waiting for disease to strike.</p>
<p>Finally, we may not be sufficiently savvy consumers. New commercial operators are coming onto the global market offering a range of largely unregulated services. Currently, you don’t get much more than details of your ancestry for a US$99 DNA test. But more specialised businesses are emerging that <a href="https://lifeletters.com/">offer</a>, for example, to “identify potential health risks that are present now or may develop in the future”. </p>
<p>Is this just hype, and offering unsubstantiated hope to consumers, or does this represent the first stage of patient empowerment over their own health and lifestyle choices? It will be fascinating to watch this new age of personalised medicine develop in the coming years.</p><img src="https://counter.theconversation.com/content/40246/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>What if you could take a simple test to reveal your individual risk of developing a range of cancers and hundreds of other diseases?Caroline Ford, Lab Head, Metastasis Research Group, Lowy Cancer Rearch Centre, UNSW SydneyOrin Chisholm, Program Authority and Senior Lecturer, Pharmaceutical Medicine, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/415932015-05-13T22:37:20Z2015-05-13T22:37:20ZTurning the tables: using genetic mutations to fix nature’s problems<figure><img src="https://images.theconversation.com/files/81180/original/image-20150511-22733-1ho81lx.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Genetic therapy might be able to reverse the harmful effects of sickle cell anaemia.</span> <span class="attribution"><a class="source" href="http://commons.wikimedia.org/wiki/Category:Sickle-cell_anemia?uselang=en-gb#/media/File:Sickle_Cell_Blood_Smear.JPG">Keith Chambers</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Everyone is different. That’s a simple truism, but it’s is also true when it comes to how people respond to diseases; some people are laid low and others shrug off the same ailment.</p>
<p>And it’s true of genetic diseases. Even when two individuals carry the same mutation, the severity of the disease may vary between them.</p>
<p>Sometimes this is due to environmental variation, but in other cases it reflects additional genetic changes that also influence how the disease affects that person. Some people will have other harmful mutations that combine with the main disease gene to make the condition worse, while more fortunate people may have inherited other variations, actual beneficial mutations, that reduce or even eliminate symptoms.</p>
<p>One of the best known illustrations of this phenomenon centres around the inherited blood disorder <a href="https://theconversation.com/explainer-one-day-science-may-cure-sickle-cell-anaemia-28153">sickle cell anaemia</a>. This lifelong condition is due to mutations in the adult <a href="http://en.wikipedia.org/wiki/Globin">globin gene</a> – a <a href="http://ghr.nlm.nih.gov/glossary=pointmutation">point mutation</a> in that gene renders it defective and patients suffer from anaemia throughout their lives. The symptoms can be severe. Damaged blood cells can block blood vessels leading to intense pain and even loss of life.</p>
<h2>In the blood</h2>
<p>But, as mentioned above, symptoms vary between individuals. Environmental variability also influences symptoms, so affected individuals may be advised to avoid high altitude and oxygen stress, for example. But genetic variations also exist. Some individuals carry a second mutation in the regulatory region of another globin gene that alleviates symptoms of sickle cell anaemia.</p>
<p>These individuals have a benign condition called Hereditary Persistence of Foetal Haemoglobin (<a href="http://www.chime.ucl.ac.uk/APoGI/data/pdf/hb/carriers/b/pfh/carbook.pdf">HPFH</a>). They have an “<a href="http://www.biology-online.org/dictionary/Up_mutation">up-mutation</a>” in the control region of a separate globin, the foetal globin gene, which boosts expression of that gene. The extra foetal globin can replace the defective beta globin.</p>
<p>I realise that is fairly complicated. But, put simply: humans have several globin genes. The foetal globins are turned on before birth and have a high affinity for oxygen; they enable the baby to snatch oxygen from its mother’s blood. After we are born the adult, or beta globin, gene comes on and the foetal globin gene is shut off. </p>
<p>But in a few people with HPFH the foetal globin gene stays on throughout life. Interestingly, this doesn’t seem to cause any health problems. Individuals with HPFH can even have normal pregnancies. They just have extra foetal globin in their blood.</p>
<p>The crux of the matter is this: if an individual inherits the sickle cell mutation and an HPFH mutation, they have few if any symptoms, because the extra foetal globin does the work of the defective adult globin gene.</p>
<p>So could one effectively “cure” sickle cell anaemia by introducing the HPFH mutation into blood cells affected by the defective adult globin gene?</p>
<h2>Switching on the backup</h2>
<p>Well, this is precisely <a href="http://dx.doi.org/10.1038/ncomms8085">the approach we have taken</a>. Using the new technique of “<a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">genome editing</a>”, we have introduced one of the best characterised HPFH mutations, and we find that we can successfully turn on the sleeping foetal globin gene.</p>
<p>At this stage we have only done this in cell lines in the laboratory. To turn this into a therapy, one would have to do it in haematopoietic stem cells – i.e. blood-<a href="http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx">forming stem cells</a> – from the patient. It would be necessary to achieve a high frequency of editing in enough stem cells to enable repopulation of the patient’s blood with genetically enhanced cells.</p>
<h2>Gene repair</h2>
<p>But if it is so easy to edit the genome now, why don’t we just correct the sickle cell mutation rather than introducing a new mutation, albeit a beneficial and benign mutation?</p>
<p>Well, that is certainly a good strategy in the case of sickle cell anaemia, and many people are working on just that. But it may be a less ideal strategy for other blood diseases and various genetic diseases where large genes or regions of the genome are deleted. </p>
<p>In the case of the <a href="http://www.thalassaemia.org.au/thalassaemia-and-related-blood-disorders">thalassaemias</a>, for example, many different gene deletions occur. It may not be practical to edit in large gene replacement cassettes, and one would have to design a different insert for each mutation. In contrast, building in the foetal globin activating mutation should provide additional globin and work to compensate in many of these conditions.</p>
<h2>Towards gene therapy using genome editing</h2>
<p>A new age of genetic engineering is beginning, due to the ability to <a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">edit the genome</a> using new DNA-cutting tools, with the technical names: <a href="https://www.addgene.org/CRISPR/guide/">CRISPRs</a>, <a href="https://www.addgene.org/talen/guide/">TALENs</a> and <a href="http://www.sigmaaldrich.com/life-science/zinc-finger-nuclease-technology/learning-center/what-is-zfn.html">ZFNs</a>. </p>
<p>Gene correction or the introduction of beneficial mutations may be important in treatments in the future. </p>
<p>In agriculture they may also be important. Many <a href="http://ghr.nlm.nih.gov/handbook/genomicresearch/gwastudies">genome wide association studies</a> have identified beneficial mutations associated with particular prised qualities. <a href="https://theconversation.com/explainer-what-is-genomic-editing-25072">Genome editing</a> can also be used to introduce beneficial mutations in this context and may give rise to a new generation of crops and livestock.</p>
<p>The techniques are also interesting because no new or artificial material need be introduced. All one is doing is mimicking a naturally occurring beneficial mutation. The introduction of artificial <a href="http://en.wikipedia.org/wiki/Transgene">transgenes</a> has <a href="http://www.fao.org/docrep/006/y4955e/y4955e0a.htm">alarmed</a> some parts of society. </p>
<p>Additionally, transgenes are recognised as foreign by some organisms and are shut down by <a href="https://theconversation.com/explainer-what-is-epigenetics-13877">epigenetic silencing</a>, just as computer viruses are recognised and shut down by anti-virus software. </p>
<p>Beneficial mutations are unlikely to be subject to the same limitations. They are already known to work in nature and introducing them to improve human health or in agriculture may have many advantages.</p><img src="https://counter.theconversation.com/content/41593/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Merlin Crossley works for the University of New South Wales. He receives funding from the National Health and Medical Research Council and the Australian Research Council.</span></em></p>Gene therapy is allowing us to switch on natural beneficial mutations to counteract the effects of negative mutations in diseases such as sickle cell anaemia.Merlin Crossley, Dean of Science and Professor of Molecular Biology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/393222015-03-26T11:08:39Z2015-03-26T11:08:39ZAngelina Jolie’s surgery got you worried? Here’s what you should know about ovarian cancer risk<p>Following <a href="http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html">her 2013 announcement</a> in the op-ed pages of The New York Times that she was having a double mastectomy, US actress <a href="http://www.nytimes.com/2015/03/25/science/experts-back-angelina-jolie-pitt-in-choices-for-cancer-prevention.html">Angelina Jolie Pitt has published another piece</a> this week discussing her decision to have her ovaries and fallopian tubes removed to mitigate her high genetic risk of cancer. </p>
<p>Jolie Pitt carries a faulty BRCA1 gene, which predisposes women to developing breast and ovarian cancer. Three women in her family – her mother, aunt and grandmother – were diagnosed with breast or ovarian cancer while still under the age of 60. All three died of their illness.</p>
<p>The publicity surrounding her double mastectomy led to what researchers and <a href="http://www.usatoday.com/story/life/movies/2015/03/24/angelina-jolie-alerts-women-to-cancer-threat-again/70372166/">the media have dubbed</a> the “Jolie effect”. An <a href="https://www.mja.com.au/insight/2013/44/genetic-testing-appropriate">Australian study</a> published six months after Jolie Pitt’s disclosure found referrals to familial cancer centres in Victoria more than doubled, and 64% involved people with a high risk of breast cancer. A <a href="http://breast-cancer-research.com/content/16/5/442">similar UK study</a> showed that in the year following her May 2013 announcement, referrals to 12 family history clinics increased over twofold. </p>
<p>But ovarian cancer, as you will see, is very different to breast cancer in that it’s very rare. So those of us who work in the field actually hope there’s no Jolie effect in this instance because it’s likely to cause a lot of worry to women who don’t need to be concerned and to divert resources away from those who do.</p>
<h2>BRCA and cancer risk</h2>
<p>The genes known as BRCA1 and BRCA2 usually help prevent cancers. Everyone has two copies of both but, in some people, one of the copies of either has an error or fault so it doesn’t work properly. The result is a high risk of developing breast and ovarian cancer at younger ages than usual.</p>
<p>The <a href="http://ovarian.org.uk/about-ovarian-cancer/ive-tested-positive-for-a-genetic-mutation">lifetime risk of ovarian cancer</a> for a woman with a faulty BRCA1 gene is about 40% to 60%. This risk increases from her late 30s and continues on an upward trajectory with age. Breast cancer risk is also higher for these women and can be up to 80% depending on family history. </p>
<p>The ovarian cancer risk for a BRCA2 fault is not as high as for BRCA1, at between 15% and 25%. </p>
<p><a href="http://jco.ascopubs.org/content/early/2012/06/18/JCO.2011.39.8545.abstract">An estimated one in five ovarian cancers</a> occurring at or before the age of 60 is due to a faulty BRCA gene. But only around 1% to 2% of women carry a faulty BRCA gene. Most women without it have only a 1% risk of developing ovarian cancer and a 10% risk of developing breast cancer. </p>
<p>Other gynaecological cancers, such as cervical or uterine cancer, are not known to be associated with the BRCA genes. </p>
<h2>Mitigating risk</h2>
<p>The surgery Jolie Pitt has just undergone involved the removal of both her ovaries, as well as fallopian tubes. That’s because <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380637/">evidence suggests</a> cancer can start in the tubes and travel to the ovaries. </p>
<p>Removing both ovaries and tubes of women with a BRCA fault reduces ovarian cancer risk by 90%. The remaining risk is due to cancer cells that may have already travelled to other sites. </p>
<p>It’s important to note that some women with a BRCA fault who have had their ovaries and tubes removed go on to develop what’s called primary peritoneal cancer some years later. This can happen even if the tubes looked normal when they were removed. A cancerous cell may have already spread into the peritoneal cavity before surgery, or cancer could have developed there independently. Cells lining the peritoneum can cause a cancer that looks indistinguishable from ovarian cancer. </p>
<p>Removing both ovaries also has the benefit of reducing breast cancer risk by 50%, likely due to the onset of early menopause. A downside of having this surgery is that it prompts the change of life, or menopause, at a younger age. Most women having their ovaries and tubes removed because of a high ovarian cancer risk do so five to ten years before the age of natural menopause, which is around 50-years-old. </p>
<p>Early menopause can result in health issues such as an increased risk of heart disease and osteoporosis, which can be mitigated by hormone replacement therapy. Because of this, a doctor will advise the woman about whether she should use hormone replacement, which may also help delay or reduce the onset of menopausal symptoms, such as hot flushes, premature ageing of tissues, vaginal thinning (causing sexual discomfort) and decreased libido. </p>
<p>One way to reduce the risk of ovarian cancer is by using the oral contraceptive pill, <a href="http://www.ncbi.nlm.nih.gov/pubmed/19190154">which can halve your risk with five years of use</a>. </p>
<h2>Don’t panic</h2>
<p>Of course, it would be far better to have a reliable screening test to detect ovarian cancer at an early, curable stage before women develop symptoms. Sadly, neither of the two tools we have now can do this. </p>
<p>The CA-125 blood test is no longer recommended because it detects cancer at a point when it can no longer be cured. And internal pelvic ultrasounds, which look for abnormalities in the ovary, are not sensitive enough to pick up early changes. Both help diagnose established cancers that would usually be picked up within three months anyway because of symptoms. </p>
<p>Jolie said she had planned to have her ovaries and tubes removed ten years before the youngest woman in her family was diagnosed, but this is not a universal rule for women who carry a BRCA fault. Usually, we use the more blanket approach of surgery around 40 years of age, which is when most women have had their children. Earlier surgery would further increase the risk of problems associated with early menopause.</p>
<p>Women who have had ovarian cancer and are concerned about others in their family should ask their doctor whether the BRCA genes might have played a role in their illness. Those who have a close relative, such as a mother or a sister, who was diagnosed with ovarian cancer while younger than 70 should contact <a href="http://ovarian.org.uk/">Ovarian Cancer Action (UK)</a>, <a href="https://ovariancancer.net.au/">Ovarian Cancer Australia</a>, <a href="http://www.ovariancancer.org/">Ovarian Cancer National Alliance (US)</a> or consult their doctor. </p>
<p>Genetic counselling and testing through a familial cancer centre may be recommended for some. For women who have the faulty BRCA genes, there’s ongoing peer and professional support.</p>
<p>Women who don’t have a close relative with ovarian cancer do not need to seek advice based on the surgery Jolie has just undergone. </p>
<p>Jolie Pitt’s op-ed about her double mastectomy had a positive impact as it galvanised many women to have their risk of breast cancer assessed, including some who needed to be tested for the BRCA mutation. This latest announcement should not have the same effect as far fewer women are at high risk of ovarian cancer.</p>
<p><em><strong>Acknowledgement</strong>: This article was co-authored by Maira Kentwell, senior genetic counsellor and manager of the Department of Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital.</em></p><img src="https://counter.theconversation.com/content/39322/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Clare Scott does not work for or own shares in or receive funding from any company or organisation that would benefit from this article. She acts in an advisory capacity to AstraZeneca (all Honoraria donated to Medecins Sans Frontiers) and has received travel support from AstraZeneca.</span></em></p>Jolie Pitt has announced more surgery, this time to mitigate her risk of developing ovarian cancer. But this should ideally not have the same “Jolie effect” as her last operation.Clare Scott, Medical Oncologist and Laboratory Head, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/380242015-03-03T04:06:34Z2015-03-03T04:06:34ZShould doctors share gene tests after a death in the family?<figure><img src="https://images.theconversation.com/files/73547/original/image-20150303-15981-tq7j2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Families share genes but that doesn't mean no individual in a family should be accorded privacy about their genetic tests.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/magw21/126452964">magw21/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Would you want your family members to be told about your genetic tests after your death if it meant saving their lives through early medical intervention? The authors of a <a href="http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(15)00003-9">paper just published</a> in Trends in Molecular Medicine argue doctors may only have a duty to disclose such information if asked by a living relative.</p>
<p>Consider the following case. Mary recently died from thyroid cancer, but some of her tissue is stored in the pathology laboratory where it was tested. For her particular cancer, early detection can mean the difference between life and death.</p>
<p>Mary’s sister Sally may want to know her own risk of developing the cancer, so she can take precautions if she has a genetic mutation. But she may, equally, not want to know, as some people don’t want to be influenced by the results of genetic tests. </p>
<h2>An ethical dilemma</h2>
<p>Mary’s doctor has two options.</p>
<p>The first is active disclosure, which places a legal or ethical duty on Mary’s doctor to warn her living relatives about their genetic risk. This duty violates Mary’s right to privacy and confidentiality. It also violates her autonomy (if autonomy is thought to continue after death), especially if Mary had stipulated that she didn’t want her relatives to know her medical details. </p>
<p>Being contacted by her late sister’s doctors could distress Sally and breach her right not to know her risk. What’s more, it might not be feasible to find or contact Mary’s relatives. </p>
<p>The second option is passive disclosure, which the authors of the paper prefer. For this option, Mary’s doctor would be justified in telling Sally about Mary’s condition if Sally asks. But the doctor does not have to contact Sally to tell her without prompting.</p>
<p>Concerns about the breach of Mary’s rights of privacy, confidentiality and autonomy could be minimised if there was counselling before all tests about possible postmortem disclosure to close relatives. This would also allay any concerns Mary’s doctor might have about breaching her privacy or autonomy.</p>
<p>The authors of the paper say active disclosure may be morally justified only if the risk of severe disease is very high and clinical action makes it possible to avoid disease. </p>
<h2>Australian law</h2>
<p>Australian law supports the authors’ stance, encouraging passive rather than active disclosure. Here, Mary’s doctor wouldn’t have a duty to contact Sally but, if Sally asked about her risk, the doctor could lawfully tell her about the risk revealed by Mary’s test. </p>
<p>The federal <a href="http://www.comlaw.gov.au/Series/C2004A03712">Privacy Act 1988</a> allows personal information about a patient to be disclosed to a genetic relative if the person holding the information: </p>
<blockquote>
<p>reasonably believes that the use or disclosure is necessary to lessen or prevent a serious threat to the life, health or safety of another individual who is a genetic relative of the first individual.</p>
</blockquote>
<p>Mary’s information can be disclosed to Sally without Mary having been counselled about such a possibility when she was tested. But there’s an important point here that the authors of the <a href="http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(15)00003-9">Trends in Molecular Medicine</a> paper do not mention. </p>
<p>Genetic information is of two kinds. The first is that a gene mutation exists in the family. The second is the status of particular family members for that mutation – positive or negative. </p>
<p>In Australia, Sally would be entitled to know the familial information – that the mutation exists in the family, but not whether Mary was positive or negative for the mutation. That part of Mary’s medical information remains confidential as Sally doesn’t need to know it for her own health care.</p>
<p>The Australian law makes it clear that doctors can breach confidentiality where it is necessary to protect the health of a close relative. That person’s health is more important than the privacy of the deceased.</p>
<p>The principle also emphasises the familial nature of genetic information, which is vital in the delivery of genetic services in the future.</p><img src="https://counter.theconversation.com/content/38024/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Loane Skene is a member of the NHMRC Australian Health Ethics Committee and Chair of the Ethics Committee of Peter McCallum Cancer Centre.</span></em></p>When a family member dies from a disease caused by a genetic mutation, doctors have to decide whether to share the deceased person’s test results with the rest of the family.Loane Skene, Professor of Law & Adjunct Professor, Faculty of Medicine Dentistry and Health Sciences, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/376322015-02-17T00:15:44Z2015-02-17T00:15:44ZGene patents may sound scary but soon they may no longer matter<figure><img src="https://images.theconversation.com/files/72198/original/image-20150217-4573-i71zpz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Challenges to the patents for BRCA mutation tests in Australia and the United States resulted in opposing conclusions.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/christianacare/6332853828/in/photolist-aDBwNY-aDB7U7-aDx8Ur-aDxJMZ-aDB9gL-aDBVvU-aDxmuk-aDxStF-aDxkyk-aDBa1u-aDBkDq-aDxjWx-aDyayF-aDxUhK-aDBShu-aDxxft-aDBUoU-aDxWV8-aDBGSf-aDBom1-aDBHVS-aDBFL3-aDxYPD-aDBak7-aDBCC9-aDxHMR-aDBHpo-aDxFZt-aDxoE8-aDxKrx-aDBc7U-aDy5Xe-aDBLr5-aDBYRy-aDBWuy-aDxxQc-aDxvFR-aDxPa4-eES1EY-eEKTTn-i2nSi5-i2ou66-i2nFpJ-i2otEX-i2otSa-i2nuVB-i2otBR-jA2pb5-i2oxan-i2otDz">Christiana Care/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p>Recent cases in Australia and the United States and a new case in Canada show how controversial the subject of gene patents is. But technological advances and the cost of patenting may soon mean gene patents no longer matter.</p>
<p>On February 13, 2015, the High Court of Australia <a href="http://www.mauriceblackburn.com.au/about/media-centre/media-statements/2015/high-court-to-hear-breast-cancer-gene-patent-case/">granted special leave</a> to hear an appeal against the Federal Court decision in <a href="http://www.austlii.edu.au/au/cases/cth/FCAFC/2014/115.html">D'Arcy v Myriad Genetics Inc</a>. The case centred on whether the BRCA gene, certain mutations of which predispose women to breast cancer, could be patented. The full Federal Court had decided late last year that <a href="https://theconversation.com/australian-federal-court-upholds-gene-patents-31350">patent claims for the isolated genes were valid</a>. </p>
<p>The special leave means the High Court has agreed to review the decision; we can expect its judgment towards the end of this year, or possibly next year.</p>
<h2>Different jurisdictions</h2>
<p>The Australian case is indicative of global concern about gene patenting. </p>
<p>In June 2013, the <a href="https://theconversation.com/top-us-court-blocks-patents-on-breast-cancer-genes-15193">United States Supreme Court</a> found patents for isolated genes were not valid, also based on a challenge to the BRCA patents. The relevant legal test in the United States is whether the invention is “markedly different” from what occurs in nature. The Supreme Court focused on the information content of the isolated gene, finding it was not sufficiently different. </p>
<p>The relevant test in Australia is whether an invention constitutes an “artificially created state of affairs”. On this point, the Federal Court found the term “isolated” as used in the patent had a specific meaning – that the genetic material had been removed from its native environment and undergone a series of chemical alterations.</p>
<p>The Federal Court accepted that genetic material claimed in the patent may well have the same informational content as that found in nature. What made it artificial was that it differed chemically, structurally and functionally. The court drew attention to the fact that the material would not function properly if re-inserted into human cells. </p>
<p>In Canada, the Children’s Hospital of Eastern Ontario <a href="http://www.cbc.ca/news/health/u-s-gene-patents-patient-care-stymied-in-canada-hospital-claims-1.2820211?utm_medium=twitter&utm_source=twitterfeed&cmp=rss">is also challenging</a> the patentability of isolated genes. While the Australian and US cases were directed to a gene associated with breast cancer, this case concerns long QT syndrome, a rare disease that can <a href="https://theconversation.com/explainer-can-you-just-die-suddenly-25423">lead to heart arrhythmia and sudden death</a>. </p>
<p>Onset of the disease has been linked with mutations in a number of genes. And every one of these genes has to be tested to ensure they perform their job properly. The owner of the Canadian patents is trying to prevent hospitals from doing some tests.</p>
<p>The Canadian case will also ask whether isolated genes are valid subject matter for a patent. But other important questions – including whether methods of analysing genes are patentable, whether aspects of the inventions were so obvious that patents should not have been granted, and whether the Canadian diagnostic organisation is actually infringing any patent claims – are also being raised by the case.</p>
<p>Answers to all these questions are vital to modern genetic diagnostic testing. But the infringement question is particularly interesting because diagnostic technology is constantly changing. </p>
<p>There are good arguments that new types of diagnostic testing and whole genome sequencing may not actually infringe patents claiming isolated genetic material because genes do not have to be chemically and structurally “isolated” to carry out the test.</p>
<p>It is possible for the Australian High Court to reach a different conclusion from both the Canadian and US courts on the patentability of genes. By itself, this does not mean that any one country’s laws are better than any other. What should and should not be patentable is a complex ongoing debate without a clear answer.</p>
<h2>Australian law and practise</h2>
<p>In light of this, there are three particular aspects of Australian patent law and practice that we would like to clarify to encourage informed discussion.</p>
<p>First, no patent can directly claim elements of any naturally occurring organism. Although some patents claim similar subject matter to that in nature, it must still be different. This means there are no valid patent claims to things as they exist in nature.</p>
<p>A patent provides the right to stop others from using the invention that it claims, but it does not provide ownership of tangible things. It’s the stuff of fiction that “corporations own your genes” and can exercise rights to them in your body.</p>
<p>Second, Australian patent law explicitly allows <a href="http://www.austlii.edu.au/au/legis/cth/consol_act/pa1990109/s119c.html">experiments on inventions</a> claimed in patents aimed at improving or modifying them. Any concerns that patents significantly and negatively affect basic research in Australia are exaggerated or represent a misunderstanding of our patent laws.</p>
<p>Third, patents often lead to higher prices because they provide a period of exclusivity in the market. The system is specifically designed this way to encourage research and development. Despite this, our <a href="http://www.publish.csiro.au/view/journals/dsp_journal_fulltext.cfm?nid=270&f=AH13029">recent survey</a> shows that, aside from the cost of materials and reagents, there is no evidence of Australian public testing facilities paying a fee or royalty to provide BRCA genetic tests - or any other genetic test. And anyway, the BRCA patent in question expires on August 11, 2015.</p>
<p>That’s not to say the patent holder, Myriad Genetics, hasn’t pursued royalties or asked companies to stop testing for BRCA mutations around the world – it has. The company’s Australian licensee, Genetic Technologies, has also considered having all tests run through them but decided against it. Currently, any accredited testing organisation can perform the test for BRCA mutations in Australia. </p>
<p>Whatever the High Court ultimately decides in the D’Arcy case, it’s unlikely there will be a surge in gene patent applications. A recent government-sponsored investigation has found such applications have been significantly <a href="http://www.ipaustralia.gov.au/pdfs/IPA_Final_Report__Human_Gene_Patents_2013.pdf">decreasing in number</a>, following a global trend. The reason is not entirely clear, but commentators have <a href="http://www.nature.com/nrg/journal/v13/n6/full/nrg3255.html">suggested</a> that because patents have annual fees and many are not profitable or useful in other ways, they are now being discarded.</p><img src="https://counter.theconversation.com/content/37632/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dianne Nicol receives funding from the Australian Research Council and National Health and Medical Research Council.</span></em></p><p class="fine-print"><em><span>John Liddicoat does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Recent cases in Australia and the United States and a new case in Canada show how controversial the subject of gene patents is. But technological advances and the cost of patenting may soon mean gene patents…John Liddicoat, Research Fellow, University of TasmaniaDianne Nicol, Professor of Law, University of TasmaniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/362502015-02-10T03:23:16Z2015-02-10T03:23:16ZWhy the causes of cancer are more than just random ‘bad luck’<figure><img src="https://images.theconversation.com/files/71552/original/image-20150210-24704-b63age.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Is cancer just a mathematical game of chance? </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/stuartpilbrow/2938100285">stuartpilbrow/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>What causes cancer? This deceptively simple question has a devilishly complex answer. So when US researchers proposed a relatively simple mathematical formula to explain a long-standing conundrum in cancer earlier this year, it was bound to get a lot of attention. </p>
<p>The study <a href="http://www.sciencemag.org/content/347/6217/78">published in the journal Science</a> suggested a correlation between the variation in cancer occurrence between different tissues and the number of stem cell divisions in each tissue. In other words, it said the tissues most vulnerable to cancer are those with the greatest number of stem cell divisions. </p>
<p>Most of the <a href="http://www.express.co.uk/life-style/health/549764/Study-reveals-cancer-down-to-just-sheer-bad-luck">reporting about the research</a> ran with the line that “cancer is all down to bad luck”, implying that developing the disease is out of our hands and that preventative efforts might be useless. But is that really the case?</p>
<p>Much of the misunderstanding seems to have arisen from the authors’ statement that a third of the variation in cancer risk among tissues is attributable to environmental or inherited factors, with the majority due to random mutations during DNA replication in normal cells. This statement about <em>relative</em> risk was overblown into blanket conclusions about the underlying causes of cancer.</p>
<h2>The wonder of replication</h2>
<p><a href="https://theconversation.com/explainer-what-is-cancer-1673">Cancer</a> emerges when one of the cells that make up your tissues (and organs) grows and divides without control, losing its specialised function and invading other tissue. This happens when normal control of cell growth and division is compromised through changes, or mutations, in your genome (the chemical instruction book for life). </p>
<p>Mutations lie at the heart of cancer biology.</p>
<p><a href="https://theconversation.com/an-insiders-account-of-the-human-genome-project-13040">The genome</a> is made from a chemical alphabet of just four letters (A,T,G, and C) “written” into DNA. It works like a kind of computer software for our cells, with strict instructions for growth and function. </p>
<p>Each of the 100 trillion cells in your body contains roughly six billion letters (called nucleotides) of this code, condensed into a thin strand of DNA about two metres long. To put this into perspective, if you stretched out all the DNA in a human body it would reach around the moon and back several times.</p>
<p>Every time a cell divides, the genome must be copied accurately and quickly. This synthesis of new DNA is called replication, and the numbers behind it are staggering. <a href="http://www.london-research-institute.org.uk/research/john-diffley">UK researcher John Diffley</a> has calculated that you will have synthesised the equivalent of a light-year of DNA (10 trillion kilometres) by the time you’re 50.</p>
<p>Words simply cannot do this amazing process justice, but this <a href="http://www.hhmi.org/biointeractive/dna-replication-advanced-detail">short video by award-winning animator Drew Berry</a> will blow your mind:</p>
<p></p>
<p>DNA replication has evolved to be incredibly efficient and reliable, but random mistakes (mutations) occasionally happen. Still, they occur at a rate of less than once per genome per cell division, thanks to some impressive molecular proofreading machines, which constantly survey the newly copied DNA and correct errors. </p>
<p>But with so many cells dividing so often, DNA replication still represents a major source of mutations. And every cell division increases the chance of accumulating mutations in important genes, increasing the likelihood of cancer.</p>
<h2>Other sources of mutation</h2>
<p>Mutations can take many forms and can emerge in a number of ways – not just through replication errors. We inherit between 50 and 100 mutations from our parents at birth, for instance, and any new or <em>de novo</em> mutations act on this inherited genetic background. </p>
<p>Even normal cellular metabolism damages DNA through the production of reactive oxygen. And, in a sinister twist, many of the inherited mutations that predispose people to cancer hit genes that control the DNA proofreading and repair systems (such as the <a href="http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA">breast cancer genes BRCA1 and BRCA2</a>). This has the effect of amplifying the rate of new mutations.</p>
<p>The other major causes of DNA mutation are lifestyle or environmental factors. We are exposed to a range of these in our everyday lives, such as <a href="https://theconversation.com/sun-damage-and-cancer-how-uv-radiation-affects-our-skin-34538">UV radiation from sunshine</a>, and chemicals including <a href="https://theconversation.com/health-harms-of-asbestos-wont-be-known-for-decades-14845">asbestos</a> or from <a href="https://theconversation.com/chemicals-in-cigarette-smoke-linked-to-lower-fertility-5375">smoking cigarettes</a>. </p>
<p>Lifestyle factors including <a href="https://theconversation.com/better-diet-exercise-could-prevent-43-000-cancers-and-save-674-million-5904">diet</a> and <a href="https://theconversation.com/health-check-does-alcohol-cause-cancer-22959">alcohol consumption</a> may also contribute. Some viruses and bacteria are known to cause DNA damage leading to cancer. They include the <a href="https://theconversation.com/four-things-you-should-know-about-hpv-vaccinations-15178">human papillomavirus (HPV) for cervical cancer</a> and <em>H. pylori</em> for gastric cancer.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/71554/original/image-20150210-24660-8iq0wb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Not off the hook: alcohol and diet can contribute to DNA mutations.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/calaveth/3862284313">Erik/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>Although these <a href="http://www.nature.com/nature/journal/v500/n7463/full/nature12477.html">different agents leave unique chemical signatures in the DNA</a>, they are still essentially random events. Random mutations are, in fact, the raw material driving evolution. And the processes of mutation and evolution are accelerated in cancer. Indeed, we are only now starting to understand the <a href="http://www.nejm.org/doi/full/10.1056/NEJMra1204892">importance of evolution in driving cancer</a> emergence and spread, as well as its resistance to therapy.</p>
<h2>Minimising risk</h2>
<p>Where does this leave the idea that cancer is all down to bad luck? Is modifying your lifestyle to minimise exposure to risk factors futile?</p>
<p>As usual, reality lies somewhere in the middle of competing narratives. Life is a kind of genetic gamble. We have to play the cards dealt us, but we can stack the odds in either direction by altering our exposure to environmental and lifestyle factors. Suggesting cancer is all down to bad luck dilutes the important message that risk can be modified by behaviour.</p>
<p>The cancer lexicon is littered with <a href="http://well.blogs.nytimes.com/2012/06/14/life-interrupted-feeling-guilty-about-cancer/?_r=0">notions of guilt</a> and blame. Death is often framed as “losing the battle with cancer”, for instance. And patients and their families are bombarded by gurus profiteering from various diet and lifestyle interventions. Their implicit messages can often leave people feeling that their cancer is all their own fault and wondering if there was something they could have done differently.</p>
<p>The fact remains that, in many cases, there isn’t.</p><img src="https://counter.theconversation.com/content/36250/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Darren Saunders receives funding from the NHMRC, Mostyn Family Foundation and Garvan Research Foundation</span></em></p>What causes cancer? This deceptively simple question has a devilishly complex answer. So when US researchers proposed a relatively simple mathematical formula to explain a long-standing conundrum in cancer…Darren Saunders, Laboratory Head, Garvan InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/307472014-08-21T14:09:59Z2014-08-21T14:09:59ZPersonalised medicine: how science is using the genetics of disease to make drugs better<figure><img src="https://images.theconversation.com/files/57056/original/cwr4nsfr-1408619766.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Treated as an individual.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/d35ign/11314250034/sizes/l/in/photolist-ieNums-bqzkoN-cecKjN-78mX8J-5zG4WH-aV1rH2-5Xp2pi-6kfGoE-beX2ZP-9N744v-9nNEzL-5NFk8Q-68e22U-e3H7Tw-44H7CX-75Amai-tEsAP-8gCwQk-fhv2FT-9oNDQR-r7w3U-8MCUGP-bqCCG9-7sZ8f2-bDDNm-dyaVzV-oGtHz4-7sS39E-D9JLg-7NEv3i-5UruTn-75uXj3-3CRNw-7NaLBQ-pPvee-7hqxk-ibVAX9-75AaE6-dMYgJu-9FWDZ1-bugQoK-5pdy6J-79qZHJ-5uKW37-9datjS-bqFpMu-3KrVNW-5ZP5w3-9X5UWj-5NHCg-8E715f/">Whatmatdoes</a></span></figcaption></figure><p>Personalised medicine is the ability to tailor therapy to an individual patient so that, as it’s often put, the right treatment is given to the right patient at the right time. But just how personal is it? </p>
<p>While the phrase might conjure up images of each patient getting their own individual therapeutic cocktail – this isn’t actually the case. Designing an individually tailored package would be too labour intensive and (at least currently) too expensive. Instead, the answer lies in understanding the genetics of patients and disease.</p>
<h2>Diseases are not (genetically) equal</h2>
<p>Up until the end of the 1990s (and in some diseases much more recently), we tended to employ a one-size-fits-all approach to the treatment of human disease. The traditional dogma has been as follows: a patient has a particular disease, say bowel cancer; we develop a drug or therapy that appears to be effective against it, and all patients with bowel cancer are given this drug or therapy. While some patients respond positively to the treatment and may even be cured, others show no response and derive no benefit from the treatment (perhaps even some side-effects). The drug continues to be prescribed. </p>
<p>This raises an issue: if all bowel cancer patients have the same disease, surely the treatment should work the same? Not true. How we respond to drugs and treatment can depend on our genetic makeup, or more precisely with this example, in the genetic make-up of the bowel cancer cells. </p>
<p>Recent technological developments have essentially allowed us to take a molecular snap-shot <a href="http://www.cancer.gov/ncicancerbulletin/072412/page12">of bowel cancer cells</a> (or any other disease cell type we wish to study) and these have revealed that not all bowel cancers are the same. The precise annotation of the genetic/molecular changes or mutations in bowel cancer cells varies.</p>
<p>What’s more, mutations or molecular changes in one or many genes in different individuals can govern whether patients with the “same” disease will respond in a similar fashion to the same treatment. Understanding this “genetic context” allows us to rethink how we approach therapy; if we know about the molecular change in a patient, we can design a specific drug that “targets” it. So although all patients may have different genetics (making an individual therapy for each patient unrealistic), subgroups of patients can share common mutations/changes which allows medicines to be designed for patient subgroups. </p>
<h2>Testing it out on leukaemia</h2>
<p>One of the first diseases where this approach was successfully used was in <a href="http://www.cancerresearchuk.org/cancer-help/type/cml/">Chronic Myeloid Leukaemia</a> (CML). A one-size-fits-all approach to chemotherapy <a href="http://www.cml-info.com/de/healthcare-professionals/about-cml/treatment-options/conventional-chemotherapy.html">wasn’t working</a> and were potentially toxic. Bone marrow transplants, though effective, were limited to those patients who had a donor. </p>
<p>CML patients have a genetic change in their bone marrow cells that leads to the production of a leukemia-specific protein (called BCR-ABL) that is hyperactive in CML cells. CML was a perfect candidate for developing a personalised medicine because a single genetic change in the disease cell characterises an entire condition. Because of this, researchers – from both the academic and pharmaceutical sectors – were able to develop Imatinib Mesylate, a drug that simply inhibited the activity of BCR-ABL. The drug <a href="http://www.cancerresearchuk.org/cancer-help/type/cml/treatment/biological-therapies-for-chronic-myeloid-leukaemia">has been so successful</a> that it has replaced both chemotherapy and bone marrow transplantation as the treatment for CML.</p>
<h2>Stratifying disease</h2>
<p>While Imatinib Mesylate has become the poster child for personalised medicine, most conditions aren’t characterised by a single genetic change in a disease cell. There may be five or even ten molecular sub-types of bowel cancer, for example, each defined by particular genetic/molecular changes called predictive biomarkers, that can also be thought of as “signatures”. </p>
<p>Knowing these biomarkers can help us to tell us who will and won’t respond to certain drugs and treatments and doctors can use this information to separate or “stratify” patients. This is particularly beneficial for cancer chemotherapy – if we know that the genetic make-up of a patient’s cancer cells won’t respond to the treatment, alternative treatment can be considered and they can be spared the potential toxic side effects chemotherapy can bring. </p>
<p>This method (sometimes called the stratified medicine approach) is a key component of personalised medicine and is <a href="http://www.ecmcnetwork.org.uk/collaborations/stratified-medicine/">increasingly being used</a> in modern cancer therapy and work that is being done to find an even more precise definition of the genetic architecture of cancer cells is also identifying new targets for therapy , so there is still more scope for how far we can go in personalising medicine.</p>
<p>Although many of the early successes of personalised medicine have been in cancer, there is now evidence that this approach can be applied in other diseases <a href="http://www.sciencedaily.com/releases/2011/11/111102190402.htm">such as cystic fibrosis</a> (with significant success using a drug called ivacaftor which targets a particular mutation in the disease), <a href="http://www.sciencedaily.com/releases/2013/10/131008091245.htm">cardiovascular disease and diabetes</a>. And progress <a href="http://medicalxpress.com/news/2014-08-major-personalised-medicine-hereditary-autoimmune.html">is also being made</a> in the field of autoimmune and infectious disease. </p>
<p>The era of personalised medicine has well and truly arrived.</p><img src="https://counter.theconversation.com/content/30747/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Lawler does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Personalised medicine is the ability to tailor therapy to an individual patient so that, as it’s often put, the right treatment is given to the right patient at the right time. But just how personal is…Mark Lawler, Chair in Translational Cancer Genomics, Queen's University BelfastLicensed as Creative Commons – attribution, no derivatives.