tag:theconversation.com,2011:/global/topics/chromosomes-10409/articlesChromosomes – The Conversation2023-08-27T13:32:44Ztag:theconversation.com,2011:article/2120732023-08-27T13:32:44Z2023-08-27T13:32:44ZLearning from failures: Support for scientific research needs to include when things don’t work out<figure><img src="https://images.theconversation.com/files/544660/original/file-20230824-17-fr9wys.jpg?ixlib=rb-1.1.0&rect=10%2C0%2C2378%2C1084&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A failed experiment led to researchers showing that assumptions about chromosomal behaviour were wrong.</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/learning-from-failures-support-for-scientific-research-needs-to-include-when-things-dont-work-out" width="100%" height="400"></iframe>
<p>The cellular processes involved in gene regulation can be unexpectedly complicated. The expression of genes — the when, where and how much of gene activity — underlies all of biology, but is surprisingly poorly understood. </p>
<p>A recent paper published by our research group <a href="https://doi.org/10.1093/genetics/iyac181">generates as many questions as answers</a>, but gives some explanations to possible mechanisms underlying the tangle of gene function. And notably, this published research shouldn’t exist, given the way we generally fund and support scientific research.</p>
<h2>Complexity and genetic regulation</h2>
<p>Biological complexity — the gloriously complicated and convoluted living world around us — is driven by regulation and specificity. </p>
<p>Essentially, every cell in a multicellular organism has the same set of genes known as their genome. What gives cells their unique identity — what makes a skin cell a skin cell and not a muscle cell — is their specific set of genes that are turned on or off. This regulation process is incredibly specific but frustratingly messy, and follows staggeringly tangled webs of rules. </p>
<p>This complexity makes the details of regulation of gene activity one of the great unknowns of modern biology.</p>
<p>In our paper, we explore how chromosomes physically interact and share information, how that sharing substantially modifies gene expression, and how that modification varies drastically between individuals. All three of these points explain some of the complexity in gene expression, but all three have been largely ignored in conventional modelling of gene regulation.</p>
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<a href="https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="an x shaped 3-d figure coloured pink and yellow floating among other similar blue shapes" src="https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/544713/original/file-20230825-27-l9lc4q.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>
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<span class="caption">Geneticists have long assumed that chromosomes operate independently, but a failed research experiment showed that this was not the case.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<p>Geneticists have been taught that chromosomes are independent, don’t modify each other’s expression and that gene expression is similar between individuals. Except they aren’t, they do and it isn’t. </p>
<h2>Chromosomal communication</h2>
<p>In a process called <a href="https://doi.org/10.1016/j.cub.2017.08.001">transvection</a>, pairs of chromosomes physically couple, modifying the expression of the genes they contain. We studied the phenomena in fruit flies using an unusual genetic situation we had created by pairing a series of chromosomes with small genetic deletions that inactivate a gene with wild, functional chromosomes. </p>
<p>Other labs have shown that chromosome pairing is part of <a href="https://doi.org/10.1038/s41467-022-31737-y">normal gene regulation</a> and <a href="https://doi.org/10.1016/j.celrep.2022.111910">development</a>. But pairing errors similar to the ones in our study do occur, and they drive at least one type of <a href="https://doi.org/10.1371/journal.pgen.1000176">human cancer</a>. </p>
<p>Transvection is <a href="https://doi.org/10.1016/j.gde.2016.03.002">a widespread process</a> and a powerful example of the hidden complexity of gene regulation. </p>
<p>It is also an example of research we would not have pursued if not for some uncommon direction and mentoring Thomas Merritt, a co-author of this article, received just before starting his own lab.</p>
<p>Our transvection project started as a <a href="https://doi.org/10.1534/genetics.105.048249">failed experiment</a> while Merritt worked in evolutionary geneticist Walt Eanes’s <a href="https://life2.bio.sunysb.edu/ee/eaneslab/">lab at Stony Brook University</a>. As part of a study on metabolic interactions in flies, Merritt had edited a gene to produce a specific level of protein activity. Although the editing worked, there was much higher than expected levels of protein <a href="https://doi.org/10.1534/genetics.111.133231">and gene activity</a>. The experiment had failed. </p>
<p>Fortunately, Eanes explicitly guided researchers under his mentorship to pay attention to the unexpected, including failed experiments, and use them as an opportunity to question assumptions. </p>
<p>Two decades later, <a href="http://www.boscogeneticslab.com/people2">working alongside</a> <a href="https://www.bowdoin.edu/profiles/faculty/jbateman/">other scientists</a>, we’re still <a href="https://www.transvection.org/">finding new complications in genetics</a>.</p>
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<a href="https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="a small fly" src="https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/544715/original/file-20230825-17-rz04it.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">Studying the genome of Drosophila melanogaster reveals how chromosomes interact with and affect each genetic expression.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<h2>Failed experiments and scientific assumptions</h2>
<p>That initial experiment had failed — but it had done so for a very interesting reason. That failed experiment, and the series of studies that followed it, showed that what geneticists typically think of as “<a href="https://wyss.harvard.edu/news/light-shed-on-century-old-riddle-of-chromosome-pairing/">independent</a>” chromosomes actually interact with each other through direct physical connections.</p>
<p>That failed experiment illuminated a world of complex regulatory control. Not only do genes have incredibly complex on/off switches, these switches sometimes work across and between chromosomes. </p>
<p>Handled well, these unexpected failures in the lab pushed us to question the assumptions that led to the unexpected result. Here, the failed experiment forced us to rethink the independence of chromosomes. </p>
<p>Our further studies explored how this genetic conversation was dynamic, changed <a href="https://doi.org/10.1534/g3.114.012484">in response to the environment</a> and differed between <a href="https://doi.org/10.1534/genetics.111.133231">individuals</a>.</p>
<h2>Individual variation</h2>
<p>The dynamic gene regulation and individual variation that allows multicellularity is also a central player in disease and individuality. For example, why do some people, but not others, respond to cancer treatments or even fall victim to cancer in the first place? </p>
<p>A better appreciation of individual variation is one of the major advances of our paper. Knowing that the amount of communication between chromosomes varies substantially across individuals and our work begins to shed light on the genes and mechanisms behind that variation. </p>
<p>These are important steps towards a more complete understanding of gene regulation and the misregulation that leads to diseases like <a href="https://openoregon.pressbooks.pub/mhccmajorsbio/chapter/cancer-and-gene-regulation/">cancer</a>. </p>
<h2>Dynamic science</h2>
<p>Science advances when scientists push boundaries and explore, not when we repeat or timidly inch forward. Too often we try to avoid or prevent failure. Funding agencies may also hesitate to fund projects seen as <a href="https://www.science.org/content/article/audacity-part-3-funding-audacious-science">risky</a>. </p>
<p>Science needs a culture that promotes risk and exploring the unexpected.</p>
<p>And while we turn to science to address emerging crises, we are not supporting the necessary scientific development. Think of the increasingly frequent <a href="https://theconversation.com/canadians-are-unprepared-for-natural-hazards-heres-what-we-can-do-about-it-201863">climate disasters</a>, the <a href="https://theconversation.com/the-quest-for-delicious-decaf-coffee-could-change-the-appetite-for-gmos-153032">challenges of feeding an exploding global population</a>, <a href="https://doi.org/10.1038/s41586-019-1717-y">the ongoing global pandemic</a> and <a href="https://www.nytimes.com/2023/06/16/opinion/cancer-treatment-disparities.html">cancer</a>.</p>
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Read more:
<a href="https://theconversation.com/doctors-are-drowning-in-a-tsunami-of-liver-disease-and-cancer-98061">Doctors are drowning in a tsunami of liver disease and cancer</a>
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<p>All of these issues will require novel solutions and dynamic approaches that scientific funding agencies should <a href="https://www.forbes.com/sites/drdonlincoln/2021/06/28/why-you-should-care-about-federally-funded-science/">acknowledge and support</a>.</p>
<p>Breakthroughs in understanding require dynamic science and scientists who are supported to explore, ask unusual questions and, occasionally, fail in the lab. Sometimes the most important results from an experiment are the questions it forces us to ask.</p><img src="https://counter.theconversation.com/content/212073/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Thomas Merritt receives funding from the Natural Sciences and Engineering Research Council of Canada.</span></em></p><p class="fine-print"><em><span>Teresa Rzezniczak 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>A failed experiment led the researchers to question their assumptions and realize that, contrary to popular belief, chromosomes interact with and affect genetic expression.Thomas Merritt, Professor, Chemistry and Biochemistry, Laurentian UniversityTeresa Rzezniczak, PhD Candidate, Biomolecular Sciences, Laurentian UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2121122023-08-24T04:51:52Z2023-08-24T04:51:52ZThe ‘weird’ male Y chromosome has finally been fully sequenced. Can we now understand how it works, and how it evolved?<p>The Y chromosome is a never-ending source of fascination (particularly to men) because it bears genes that determine maleness and make sperm. It’s also small and seriously weird; it carries few genes and is full of junk DNA that makes it horrendous to sequence. </p>
<p>However, new “<a href="https://www.nature.com/articles/s41592-022-01730-w">long-read</a>” sequencing techniques have finally provided a reliable sequence from one end of the Y to the other. The paper describing this Herculean effort has been <a href="https://www.nature.com/articles/s41586-023-06457-y">published</a> in Nature.</p>
<p>The findings provide a solid base to explore how genes for sex and sperm work, how the Y chromosome evolved, and whether – as predicted – it will disappear in a few million years.</p>
<h2>Making baby boys</h2>
<p>We have known for <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443938/#">about 60 years</a> that specialised chromosomes <a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">determine birth sex</a> in humans and other mammals. Females have a pair of X chromosomes, whereas males have a single X and a much smaller Y chromosome.</p>
<p>The Y chromosome is male-determining because it bears a gene <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/">called SRY</a>, which directs the development of a ridge of cells into a testis in the embryo. The embryonic testes make male hormones, and these hormones direct the development of male features in a baby boy.</p>
<p>Without a Y chromosome and a SRY gene, the same ridge of cells develops into an ovary in XX embryos. Female hormones then direct the development of female features in the baby girl.</p>
<h2>A DNA junkyard</h2>
<p>The Y chromosome is very different from X and the 22 other chromosomes of the human genome. It is smaller and bears few genes (only 27 compared to about 1,000 on the X).</p>
<p>These include SRY, a few genes required to make sperm, and several genes that seem to be critical for life – many of which have partners on the X.
Many Y genes (including the sperm genes RBMY and DAZ) are present in multiple copies. Some occur in weird loops in which the sequence is inverted and genetic accidents that duplicate or delete genes are common.</p>
<p>The Y also has a lot of DNA sequences that don’t seem to contribute to traits. This “junk DNA” is comprised of highly repetitive sequences that derive from bits and pieces of old viruses, dead genes and very simple runs of a few bases repeated over and over. </p>
<p>This last DNA class occupies big chunks of the Y that literally glow in the dark; you can see it down the microscope because it preferentially binds fluorescent dyes.</p>
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<strong>
Read more:
<a href="https://theconversation.com/we-discovered-a-missing-gene-fragment-thats-shedding-new-light-on-how-males-develop-147348">We discovered a missing gene fragment that's shedding new light on how males develop</a>
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<h2>Why the Y is weird</h2>
<p>Why is the Y like this? Blame evolution.</p>
<p>We have a lot of evidence that 150 million years ago the X and Y were just a pair of ordinary chromosomes (they still are in birds and platypuses). There were two copies – one from each parent – as there are for all chromosomes.</p>
<p>Then SRY evolved (from an ancient gene with another function) on one of these two chromosomes, defining a new proto-Y. This proto-Y was forever confined to a testis, by definition, and subject to a barrage of mutations as a result of a lot of cell division and little repair. </p>
<p>The proto-Y degenerated fast, losing about 10 active genes per million years, reducing the number from its original 1,000 to just 27. A small “pseudoautosomal” region at one end retains its original form and is identical to its erstwhile partner, the X.</p>
<p>There has been great debate about whether this <a href="http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">degradation continues</a>, because at this rate the whole human Y would disappear in a few million years (as it already has in some rodents).</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/men-are-slowly-losing-their-y-chromosome-but-a-new-sex-gene-discovery-in-spiny-rats-brings-hope-for-humanity-195903">Men are slowly losing their Y chromosome, but a new sex gene discovery in spiny rats brings hope for humanity</a>
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<h2>Sequencing Y was a nightmare</h2>
<p>The first draft of the human genome was completed in 1999. Since then, scientists have managed to sequence all the ordinary chromosomes, including the X, with just a few gaps. </p>
<p>They’ve done this using short-read sequencing, which involves chopping the DNA into little bits of a hundred or so bases and reassembling them like a jigsaw.</p>
<p>But it’s only recently that new technology has allowed sequencing of bases along individual long DNA molecules, producing long-reads of thousands of bases. These longer reads are easier to distinguish and can therefore be assembled more easily, handling the confusing repetitions and loops of the Y chromosome.</p>
<p>The Y is the last human chromosome to have been sequenced end-to-end, or T2T (telomere-to-telomere). Even with long-read technology, assembling the DNA bits was often ambiguous, and researchers had to make several attempts at difficult regions – particularly the highly repetitive region.</p>
<h2>So what’s new on the Y?</h2>
<p>Spoiler alert – the Y turns out to be just as weird as we expected from decades of gene mapping and the previous sequencing.</p>
<p>A few new genes have been discovered, but these are extra copies of genes that were already known to exist in multiple copies. The border of the pseudoautosomal region (which is shared with the X) has been pushed a bit further toward the tip of the Y chromosome.</p>
<p>We now know the structure of the centromere (a region of the chromosome that pulls copies apart when the cell divides), and have a complete readout of the complex mixture of repetitive sequences in the fluorescent end of the Y.</p>
<p>But perhaps the most important outcome is how useful the findings will be for scientists all over the world.</p>
<p>Some groups will now examine the details of Y genes. They will look for sequences that might control how SRY and the sperm genes are expressed, and to see whether genes that have X partners have retained the same functions or evolved new ones.</p>
<p>Others will closely examine the repeated sequences to determine where and how they originated, and why they were amplified. Many groups will also analyse the Y chromosomes of men from different <a href="https://www.biorxiv.org/content/10.1101/2022.12.01.518658v2.abstract">corners of the world</a> to detect signs of degeneration, or recent evolution of function.</p>
<p>It’s a new era for the poor old Y.</p><img src="https://counter.theconversation.com/content/212112/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council.</span></em></p>DNA of the male-determining Y chromosome has been completely sequenced end-to-end, and it’s just as weird as we expected. Will we finally be able to understand how it works?Jenny Graves, Distinguished Professor of Genetics and Vice Chancellor's Fellow, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2069242023-06-05T15:01:08Z2023-06-05T15:01:08ZSeveral Down syndrome features may be linked to a hyperactive antiviral immune response – new research<figure><img src="https://images.theconversation.com/files/529898/original/file-20230603-15-so1fli.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3679%2C2647&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Addressing the increased risks of certain diseases among those with Down syndrome could help improve their quality of life.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/boy-with-down-syndrome-playing-outdoors-in-garden-royalty-free-image/1271658791">Halfpoint Images/Moment via Getty Images</a></span></figcaption></figure><p>People with <a href="https://www.globaldownsyndrome.org/about-down-syndrome/facts-about-down-syndrome/">Down syndrome</a>, or trisomy 21, a genetic condition caused by an extra copy of human chromosome 21, experienced a remarkable increase in life expectancy during the 20th century. In the early 1900s, less than 20% of newborns with Down syndrome <a href="https://doi.org/10.1038/gim.2016.127">survived past age 5</a>. In the U.S. today, more than 90% of babies with this condition <a href="https://doi.org/10.1038/gim.2016.127">live past age 10</a> and have a life expectancy of <a href="https://doi.org/10.1001/jamanetworkopen.2022.12910">nearly 60 years</a>. These increases were <a href="https://doi.org/10.1016%2FS0074-7750(10)39004-5">likely fueled</a> by greater inclusion in general society, the discontinuation of institutionalization in psychiatric facilities and better medical care.</p>
<p>Despite these advances, people with trisomy 21 experience an increased risk of many <a href="https://doi.org/10.1038/s41572-019-0143-7">co-occurring conditions</a>, such as congenital heart defects, autoimmune conditions, autism spectrum disorders and Alzheimer’s disease. On the other hand, people with Down syndrome tend to have <a href="https://doi.org/10.17294/2330-0698.1824">lower levels of hypertension</a> and <a href="https://doi.org/10.1038/gim.2016.23">certain types of cancers</a>.</p>
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<a href="https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Karyotype of Down syndrome, with a circle around three copies of chromosome 21" src="https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=480&fit=crop&dpr=1 600w, https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=480&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=480&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=603&fit=crop&dpr=1 754w, https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=603&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/529897/original/file-20230603-25-nrpa24.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=603&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">Down syndrome is also called trisomy 21 because those with the condition have three copies of chromosome 21.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/downs-syndrome-karyotype-illustration-royalty-free-illustration/685025123">Kateryna Kon/Science Photo Library via Getty Images</a></span>
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<p>Understanding how an extra chromosome 21 causes these risks and resiliencies could advance collective understanding of major medical conditions that also affect the general population. For example, the <a href="https://doi.org/10.1038/s41582-018-0132-6">increased risk of Alzheimer’s disease</a> among adults with Down syndrome can be explained in part by the presence of a gene on chromosome 21 that leads to excess production of the beta-amyloid proteins and plaques characteristic of Alzheimer’s.</p>
<p>In our newly published research, my research team <a href="https://scholar.google.com/citations?user=6gRbVeAAAAAJ&hl=en">and I</a> found that <a href="https://www.nature.com/articles/s41588-023-01399-7">genes involved in controlling the immune system</a> are critical to the development of multiple hallmarks of Down syndrome. Our findings contribute to a growing body of research on the immune system’s important role in the appearance and severity of some of the negative health effects of trisomy 21, supporting the idea that restoring immune balance could help improve the quality of life of people with the condition.</p>
<h2>When too much of a good thing is bad</h2>
<p>The genes we identified, which encode what are called <a href="https://doi.org/10.1038%2Ficb.2012.9">interferon receptors</a>, are an important part of the immune system’s antiviral defense. These genes enable our cells to recognize a set of proteins called interferons, which virus-infected cells produce to alert the yet uninfected cells around them about the presence of a virus during an infection.</p>
<p>While interferons do trigger a beneficial immune response against viral infections, chronic interferon hyperactivity could have detrimental effects. Too much interferon signaling is known to be harmful in medical conditions such as <a href="http://dx.doi.org/10.1136/lupus-2018-000270">systemic lupus erythematosus</a>, a group of genetic disorders known as <a href="https://doi.org/10.1038/s41577-021-00633-9">interferonopathies</a> and <a href="https://doi.org/10.1038/s41577-020-00429-3">severe COVID-19</a>.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="3D model of human interferon-beta structure" src="https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=418&fit=crop&dpr=1 600w, https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=418&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=418&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=526&fit=crop&dpr=1 754w, https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=526&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/529899/original/file-20230603-17-pq5zrq.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=526&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Interferons are involved in antiviral immune responses.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:1AU1_Human_Interferon-Beta05.png">Nevit Dilmen/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Notably, four of the six human interferon receptor genes are <a href="https://doi.org/10.1038%2Ficb.2012.9">located on chromosome 21</a>. Most people have only two copies of each chromosome and so would have only two copies of these genes. Because people with Down syndrome have three copies of chromosome 21, they also have three copies of the interferon receptor genes on it. This contributes to the <a href="https://doi.org/10.7554/eLife.16220">overproduction of interferon receptors</a> seen in those with Down syndrome.</p>
<p>Our team wanted to know whether this <a href="https://www.nature.com/articles/s41588-023-01399-7">extra copy of interferon receptor genes</a>, compared with the roughly 200 other genes located on chromosome 21, contribute to features of Down syndrome. To do this, we used a mouse model of Down syndrome. In this mouse model, a large region of its genome that is equivalent to a large portion of human chromosome 21 is triplicated to reproduce many features of Down syndrome.</p>
<p>Using <a href="https://theconversation.com/human-genome-editing-offers-tantalizing-possibilities-but-without-clear-guidelines-many-ethical-questions-still-remain-200983">CRISPR gene editing</a> technology, we reduced the number of interferon receptor genes from three to the typical two, leaving all other triplicated genes intact. We found that <a href="https://www.nature.com/articles/s41588-023-01399-7">correcting the number of interferon receptor genes</a> significantly reduced abnormal gene expression patterns across multiple tissue types, both during embryonic development and in adult mice. These mice also had more regulated immune responses, normal heart development, reduced developmental delays, improved performance on memory and learning tasks and even a more typical skull and facial morphology.</p>
<p>Overall, our findings suggest that the tripling of interferon receptor genes may cause a number of key traits of Down syndrome.</p>
<h2>Therapeutic implications and future directions</h2>
<p>Our research indicates that many, though not all, aspects of Down syndrome may be associated with hyperactivity of the immune system’s interferon response. It also supports the possibility of using drugs that attenuate this response to treat some of the negative health effects of trisomy 21.</p>
<p>Our team is currently leading two clinical trials to test the safety and efficacy of one such drug, <a href="https://www.uptodate.com/contents/tofacitinib-drug-information">tofacitinib (Xeljanz)</a>. This drug belongs to a class of drugs known as JAK inhibitors used to treat autoinflammatory conditions. One trial <a href="https://clinicaltrials.gov/ct2/show/NCT04246372">focuses on autoimmune skin conditions</a> more common in Down syndrome. The second trial <a href="https://clinicaltrials.gov/ct2/show/NCT05662228">focuses on Down syndrome regression disorder</a>, or DSRD, a rare but devastating <a href="https://doi.org/10.3389%2Ffneur.2022.940175">neurological condition</a> that can result in loss of speech, sleep disruptions, difficulty moving and hallucinations. There is evidence that suggests that a subset of DSRD cases may be caused by <a href="https://doi.org/10.1186/s11689-022-09446-w">immune dysregulation affecting the brain</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person with Down syndrome holding a potted plant in a nursery" src="https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/529900/original/file-20230603-27-v9th5q.png?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">Treating the common health risks that occur with Down syndrome could help improve quality of life.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/portrait-of-happy-confident-florist-in-flower-shop-royalty-free-image/1327764759">Flashpop/DigitalVision via Getty Images</a></span>
</figcaption>
</figure>
<p>Our study findings also support further investigation into the effects of interferon hyperactivity on fetal development more generally. Two of the key traits of Down syndrome that we found were affected by the tripling of interferon receptors – congenital heart disease and skull and facial shape – develop in utero.</p>
<p>Though our research shows promise on the potential of JAK inhibitors and other drugs that modulate the immune system to improve health outcomes in Down syndrome, more research in people is needed to determine their safety and efficacy.</p><img src="https://counter.theconversation.com/content/206924/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joaquin Espinosa receives funding from the National Institutes of Health, the Global Down Syndrome Foundation, and the Anna and John J. Sie Foundation. Dr. Espinosa has provided consulting services to Elli Lily and Co. and Gilead Sciences Inc. and currently serves in the advisory board of Perha Pharmaceuticals.</span></em></p>People with Down syndrome have an extra chromosome 21. Understanding the effects of those triplicated genes could help improve the health of those with Down syndrome and other medical conditions.Joaquin Espinosa, Professor of Pharmacology, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2030552023-04-19T20:07:51Z2023-04-19T20:07:51ZSex and the single gene: new research shows a genetic ‘master switch’ determines sex in most animals<figure><img src="https://images.theconversation.com/files/521535/original/file-20230418-784-rphstd.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C2366%2C1767&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>In humans and other animals, sex is usually determined by a single gene. However, there are <a href="https://www.cell.com/current-biology/fulltext/S0960-9822(13)00412-0">claims</a> that in some species, such as platyfish, it takes a whole “parliament” of genes acting together to determine whether offspring develop as a male or female. </p>
<p>In <a href="https://doi.org/10.1016/j.tig.2022.12.002">a new analysis</a>, we took a close look at these claims. We found they describe abnormal situations, such as hybrids between two species with different sex-determining systems, or when one sex system is in the process of replacing another. </p>
<p>We conclude that sex is normally determined by a single gene. Evolutionary theory suggests this is the most stable state of affairs, as it ensures a 1:1 ratio of male and female animals. </p>
<h2>The human ‘master switch’ for sex</h2>
<p>In mammals, females have two X chromosomes, whereas males have an X and a Y. The Y chromosome bears a gene called SRY, which acts as a “<a href="http://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">master switch</a>”: an XY embryo, carrying SRY, develops into a biological male, and an XX embryo, lacking SRY, develops into a biological female.</p>
<p>This makes the inheritance of sex simple. Females make eggs, which carry a single X chromosome, while males make sperm, half carrying an X and half carrying a Y. </p>
<p>Random fusion of eggs and sperm delivers half XX females and half XY males, for a 1:1 sex ratio.</p>
<h2>Sex in other vertebrates</h2>
<p>Among animals with backbones (vertebrates), there is a huge variety of systems that determine sex. However, they usually come down to the action of a single gene.</p>
<p>Many fish, frogs and some turtles have <a href="https://www.mdpi.com/2073-4425/12/4/483">systems like ours</a>, in which a male-dominant gene on the Y chromosome directs testis development. Some vertebrates have the opposite – a female-dominant gene on the X chromosome. </p>
<p>Other vertebrates use <a href="https://www.nature.com/articles/nature08298">a dosage difference of a single gene</a>. In birds, males have two copies of a Z chromosome with the sex-determining gene DMRT1. Females have a single Z and a W chromosome that lacks DMRT1. Sex depends on DMRT1 dosage: two copies in ZZ males, versus one in ZW females.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-birds-become-male-or-female-and-occasionally-both-112061">How birds become male or female, and occasionally both</a>
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</em>
</p>
<hr>
<p>Surprisingly, <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001899">many different genes</a> act as the master switch in different species. But they all act by triggering the same male or female differentiation pathway. </p>
<p>These single-gene systems deliver equal numbers of males and females, which theory says is the optimal balance for a stable system. If the ratio favours one sex, individuals that produce more of the other sex will leave more descendants and their genes will spread until a 1:1 ratio is achieved.</p>
<h2>Some exceptional species</h2>
<p><a href="https://link.springer.com/article/10.1007/BF02135395">Some aquarium fish</a> have <a href="https://www.biodiversitylibrary.org/page/51116062">more complex systems</a>. Genetic crosses in platyfish appear to show two or more genes that determine male or female development; the sea bass seems to have at least three sex genes. </p>
<p>Some <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/mec.14831">frogs</a> and lizards seem to determine sex using two or more sex genes. </p>
<figure class="align-center ">
<img alt="A photo of a platypus swimming with a worm dangling from its beak." src="https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=430&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=430&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=430&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=541&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=541&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=541&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The platypus genome carries five X chromosomes and five Y chromosomes.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Then there are species with two or more pairs of sex chromosomes. The platypus has <a href="https://www.nature.com/articles/nature03021">five X and five Y chromosomes</a>. Is there a sex gene on each Y? How will a poor baby platypus know how to develop if it gets three Ys and two Xs from its dad? </p>
<p>And what about species, like the <a href="https://www.nature.com/articles/nature19840">African clawed toad</a>, which have two copies of their whole genome, so should have two pairs of sex chromosomes and sex genes?</p>
<p>So there are lots of exceptional species that seem to have multiple sex chromosomes and sex genes in defiance of the expectation that only a single sex gene can produce a stable system.</p>
<h2>Polygenic sex – is there any such thing?</h2>
<p>In species where we cannot find a single master switch gene, it is common to talk about “<a href="https://www.mdpi.com/2073-4409/11/11/1764">polygenic sex</a>”. But how robust are these examples?</p>
<p>In our <a href="https://doi.org/10.1016/j.tig.2022.12.002">recent paper</a> we examine classic examples and recent claims for polygenic sex determination. We conclude the few systems that qualify represent abnormal and transient situations.</p>
<p>Multiple sex chromosomes need not mean multiple sex genes. <a href="https://www.nature.com/articles/nature13151">In the platypus</a>, all five Y chromosomes move together into sperm, and a single gene on the smallest Y directs male development. The African clawed toad <a href="https://www.pnas.org/doi/10.1073/pnas.0712244105">solved</a> the problem of its doubled genome by evolving a novel female-determining gene on a newly minted W chromosome.</p>
<p>In several systems, two sex genes are detected, but they control different steps of the same pathway that are regulated by a single master gene. </p>
<p>In some of the classic fish systems, like platyfish, the different variants <a href="https://www.biodiversitylibrary.org/page/51116062">all spring from the same chromosome</a>, suggesting sex is controlled by different variants of the same gene. A Japanese frog has <a href="https://link.springer.com/article/10.1007/s10577-008-1217-7">different sex chromosomes on different islands</a>, but they are all variants of the same chromosome. </p>
<figure class="align-center ">
<img alt="A photo of zebrafish swimming" src="https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?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">Laboratory zebrafish have lost a chromosome and evolved new systems for determining sex.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Other examples suggest systems in transition. <a href="https://www.nature.com/articles/s41437-018-0157-z">Sea bass</a> shows different frequencies of variants over its range. There are signs of a new system gradually replacing an old one in <a href="https://www.nature.com/articles/hdy201622">a European frog</a>.</p>
<p>The zebrafish is <a href="https://academic.oup.com/genetics/article/198/3/1291/6065698">particularly interesting</a>. Strains bred independently in laboratories for 30 or 40 years have aberrant sex ratios and multiple sex genes.</p>
<p>But it turns out wild zebrafish have a regular ZW sex chromosome system. Lab stocks independently lost their W chromosome during lab breeding. All the lab fish are ZZ, and sex of the hatchlings is determined by weaker sex-differentiating genes that were lurking in the background. </p>
<h2>Winning the war of the sex genes</h2>
<p>Many “polygenic” systems turn out to be hybrids between two species. Species hybrids often have problems with reproduction, such as sterility or skewed sex ratios.</p>
<p>Their problem is incompatibility of different sex chromosomes and sex genes. If an XY male mates with a ZW female, offspring have all sorts of combinations of sex genes. </p>
<p>Incompatibilities can play out differently. For instance, <a href="https://academic.oup.com/evolut/article-abstract/64/2/486/6854216?redirectedFrom=fulltext">two species of cichlid fish</a> living side by side in Lake Malawi in Africa have unrelated XY and ZW systems. In their XYZW offspring, the W partially overrides the male determining effect of the Y, so XYZW fish have intersex traits. But, in another species combination, the W gene triumphs and XYZW fish are fertile females.</p>
<figure class="align-center ">
<img alt="A photo of cichlid fish" src="https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Some species of cichlid fish with different sex-determining systems can interbreed, with complicated results.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>Species hybrids may reveal many genes with major and minor effects on sex determination. For instance, <a href="https://www.frontiersin.org/articles/10.3389/fgene.2022.789573/full">crossing two catfish species</a>s revealed seven male-associated and 17 female-associated genes on different chromosomes.</p>
<p>So there are certainly species where two or more genes act together or in opposition. However, in the long term there is strong selection for one or the other to gain the upper hand. This will turn an inefficient polygenic system into a single-gene system, delivering fertile males and females in a 1:1 ratio.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/men-are-slowly-losing-their-y-chromosome-but-a-new-sex-gene-discovery-in-spiny-rats-brings-hope-for-humanity-195903">Men are slowly losing their Y chromosome, but a new sex gene discovery in spiny rats brings hope for humanity</a>
</strong>
</em>
</p>
<hr>
<img src="https://counter.theconversation.com/content/203055/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council. </span></em></p>Some animals appear to use a ‘parliament’ of genes to determine sex. But a closer look reveals these are the exception rather than the rule.Jenny Graves, Distinguished Professor of Genetics and Vice Chancellor's Fellow, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1864452022-07-19T12:25:44Z2022-07-19T12:25:44ZCells become zombies when the ends of their chromosomes are damaged – a tactic both helpful and harmful for health<figure><img src="https://images.theconversation.com/files/473984/original/file-20220713-9184-rhhs18.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3000%2C2213&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Telomeres (red) at the ends of chromosomes protect your DNA from damage.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/JUr1Ay">Thomas Ried/NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>Damage to the ends of your chromosomes can create “zombie cells” that are still alive but can’t function, according to our recently published study in <a href="https://doi.org/10.1038/s41594-022-00790-y">Nature Structural and Molecular Biology</a>.</p>
<p>When cells prepare to divide, their DNA is tightly wound around proteins to form chromosomes that provide structure and support for genetic material. At the ends of these chromosomes are repetitive stretches of DNA called <a href="https://www.genome.gov/genetics-glossary/Telomere">telomeres</a> that form a protective cap to prevent damage to the genetic material. However, telomeres shorten each time a cell divides. This means that as cells divide more and more as you age, your telomeres become increasingly shorter and more likely to lose their ability to protect your DNA.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting chromosomes in the nucleus, highlighting the telomeres at the ends of each DNA-containing arm." src="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=381&fit=crop&dpr=1 600w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=381&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=381&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=479&fit=crop&dpr=1 754w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=479&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/474165/original/file-20220714-32290-qampef.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=479&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 serve as protective caps at the ends of each chromosome.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/telomere-chromosome-and-dna-royalty-free-illustration/961320764">FancyTapis/iStock via Getty Images</a></span>
</figcaption>
</figure>
<p>Damage to genetic material can lead to mutations that cause cells to divide uncontrollably, resulting in cancer. Cells avoid becoming cancerous when their telomeres become too short after dividing too many times and potentially accruing damage along the way, however, by entering a zombielike state that stops cells from from dividing through a process called <a href="https://doi.org/10.7554/eLife.72449">cellular senescence</a>.</p>
<p>Because they are resistant to death, senescent – or “zombie” – cells accumulate with age. They can be beneficial to health by promoting senescence in nearby cells at risk of becoming cancerous and attracting immune cells to clear out cancer cells. But they can also contribute to disease by impairing tissue healing and immune function, and by secreting chemicals that promote inflammation and tumor growth.</p>
<p>We wanted to know if direct damage to telomeres can be sufficient to trigger senescence and make zombie cells. In order to figure this out, we needed to confine damage just to the telomeres. So we attached a protein to the telomeres of human cells grown in the lab. Then we added a dye to the protein that makes it sensitive to light. Shining a far-red light (or light with a wavelength slightly shorter than infrared light) on the cells induces the protein to produce oxygen <a href="https://www.verywellhealth.com/information-about-free-radicals-2249103">free radicals</a> – highly reactive molecules that can damage DNA – right at the telomeres, sparing the rest of the chromosome and the cell.</p>
<p>We found that direct damage to the telomeres was sufficient to turn cells into zombies, even when these protective caps weren’t shortened. The reason for this, we discovered, was likely a result of <a href="https://doi.org/10.1038%2Fncb2897">disrupted DNA replication</a> at the telomeres that leaves chromosomes even more susceptible to damage or mutations. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of chromosomes with telomeres damaged by oxidation" src="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=348&fit=crop&dpr=1 600w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=348&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=348&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=437&fit=crop&dpr=1 754w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=437&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/473987/original/file-20220713-13035-8w2uvc.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=437&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The telomeres (green) at the tips of chromosomes (blue) damaged by free radicals become fragile (green arrows) and trigger senescence.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41594-022-00790-y">Ryan Barnes/Opresko Lab</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>Telomeres naturally shorten with age. They limit how many times a cell can divide by signaling cells to become zombies when they reach a certain length. But an excess of free radicals produced from both normal bodily processes as well as exposure to harmful chemicals like air pollution and tobacco smoke can lead to a condition called <a href="https://doi.org/10.1016/j.mad.2018.03.013">oxidative stress</a> that can accelerate telomere shortening. This can prematurely trigger senescence and contribute to age-related diseases, including <a href="https://doi.org/10.1172/jci120216">immunodeficiency</a>, <a href="https://doi.org/10.1038%2Fs41556-022-00842-x">cardiovascular disease</a>, <a href="https://doi.org/10.1038/nrg3246">metabolic disease</a> and <a href="https://doi.org/10.1016%2Fj.cell.2020.12.028">cancer</a>.</p>
<p>Our study reveals that telomeres not only serve as alarm clocks that indicate a cell divided too many times, but also as warning bells for harmful levels of oxidative stress. Age-related shortening of telomeres isn’t the only thing that triggers senescence; telomere damage is also sufficient to turn a cell into a zombie.</p>
<h2>What other research is being done</h2>
<p>Researchers are studying treatments and interventions that can protect telomeres from damage and prevent zombie cell accumulation. A number of studies in mice have found that removing zombie cells can promote healthy aging by improving <a href="https://doi.org/10.1111/acel.13296">cognitive function</a>, <a href="https://doi.org/10.1038/nature10600">muscle mass and function</a> and recovery from <a href="https://doi.org/10.1126/science.abe4832">viral infections</a>. </p>
<p>Researchers are also developing drugs called <a href="https://doi.org/10.1146/annurev-pharmtox-050120-105018">senolytics</a> that can either kill zombie cells or prevent them from developing in the first place.</p>
<h2>What’s next</h2>
<p>This study focuses on the consequences of telomere damage in actively dividing cells, like kidney and skin cells. We’re now looking at how this damage will play out in cells that don’t divide, like neurons or heart muscle cells. While researchers have shown that the telomeres of nondividing cells and tissues <a href="https://doi.org/10.1038/s41556-022-00842-x">become more dysfunctional with age</a>, it’s unclear why this happens when these telomeres should not be shortening in the first place.</p><img src="https://counter.theconversation.com/content/186445/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Patricia Opresko receives funding from the National Institutes of Health and has received funding from the Glenn Foundation for Medical Research. </span></em></p><p class="fine-print"><em><span>Ryan Barnes receives funding from:
NIA F32AG067710-01
NIEHS K99ES033771</span></em></p>The protective caps at the ends of chromosomes naturally shorten over time. Researchers found that direct damage can prematurely trigger senescence and contribute to age-related diseases like cancer.Patricia Opresko, Professor of Environmental and Occupational Health, University of PittsburghRyan Barnes, Postdoctoral Researcher in Environmental and Occupational Health, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1722932022-02-04T13:09:35Z2022-02-04T13:09:35ZNot everyone is male or female – the growing controversy over sex designation<figure><img src="https://images.theconversation.com/files/441210/original/file-20220118-13-l32vzy.jpg?ixlib=rb-1.1.0&rect=0%2C26%2C5906%2C3904&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Although the medical establishment is now recognizing that sex is not binary, society as a whole has been slow to embrace the concept.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/small-beautiful-child-lies-on-the-bed-on-his-royalty-free-image/1300384940?adppopup=true">Vera Livchak/Moment via Getty Images</a></span></figcaption></figure><p>Check out your birth certificate and surely you’ll see a designation for sex. When you were born, a doctor or clinician assigned you the “male” or “female” label based on a look at your genitalia. In the U.S., this has been <a href="https://doi.org/10.1056/nejmp2025974">standard practice for more than a century</a>. </p>
<p>But sex designation is not as simple as a glance and then a check of one box or another. Instead, the overwhelming evidence shows that <a href="https://doi.org/10.1002/ase.2002">sex is not binary</a>. To put it another way, the terms “male” and “female” don’t fully capture the complex biological, anatomical and chromosomal variations that occur in the human body. </p>
<p>That’s why calls are growing to remove sex designation from birth certificates, including <a href="https://thehill.com/changing-america/respect/equality/566767-ama-doctors-experts-recommend-removing-sex-designation-from">a recent recommendation</a> from the American Medical Association. </p>
<p>I am a <a href="https://www.bumc.bu.edu/busm/profile/carl-streed/">professor of medicine</a> who has worked extensively <a href="https://scholar.google.com.au/citations?user=Rv-dZJ4AAAAJ&hl=en">on lesbian, gay, bisexual, transgender, queer, intersex and asexual (LGBTQIA+) issues</a>. My co-author is a <a href="https://www.childrenshospital.org/directory/physicians/g/frances-grimstad">professor of gynecology</a> who is deeply involved in the health of people who are trans and intersex. </p>
<p>Our research and clinical experience show that sex designation is not something to take for granted. For those who don’t fit neatly into one of two categories – <a href="https://doi.org/10.1002/(sici)1520-6300(200003/04)12:2%3C151::aid-ajhb1%3E3.0.co;2-f">and there are millions</a> – an inappropriate classification on a birth certificate can have consequences that last a lifetime.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/n_5l2fwWGco?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">What does intersex mean?</span></figcaption>
</figure>
<h2>The problems with sex designation</h2>
<p>Variations in genital anatomy happen more frequently than you might think; <a href="https://doi.org/10.1002/(sici)1520-6300(200003/04)12:2%3C151::aid-ajhb1%3E3.0.co;2-f">they occur in 0.1 to 0.2% of births annually</a>. In the U.S., that’s about 4,000 to 8,000 babies each year. </p>
<p>Other sex traits don’t necessarily help either. Doctors examining the reproductive organs <a href="https://doi.org/10.1038/518288a">can find people</a> born with both a vagina and testes, and also those born without any gonads. And when evaluating an individual’s estrogen and testosterone hormone levels, long defined as key determinants of female and male bodies, doctors find some people with vaginas still produce <a href="https://doi.org/10.1016/S0140-6736(12)60071-3">significant amounts of testosterone</a>. Because of this, testosterone is not a great indicator for defining sex; higher amounts of testosterone do not necessarily make someone male. </p>
<p>Even karyotyping – a laboratory procedure used since the 1950s to evaluate an individual’s number and type of chromosomes – doesn’t tell the whole story. While we typically expect people to either have XX or XY pairs of sex chromosomes, <a href="https://doi.org/10.1038/518288a">many people have variations</a> that <a href="https://dx.doi.org/10.1159%2F000499274">do not fit either category</a>. These include <a href="https://www.mayoclinic.org/diseases-conditions/turner-syndrome/symptoms-causes/syc-20360782#">Turner syndrome</a>, in which a person is born with a single X chromosome, and <a href="https://www.mayoclinic.org/diseases-conditions/klinefelter-syndrome/symptoms-causes/syc-20353949#">Kleinfelter syndrome</a>, which occurs when a person is born with a combination of XXY chromosomes. </p>
<p>In short, human diversity has demonstrated that the binary categories of male and female are incomplete and inaccurate. Sex designation, rather than “two sizes fit all,” <a href="https://doi.org/10.1089/lgbt.2021.0018">is on a spectrum</a>. Up to 1.7% of the U.S. population – that’s more than 5 million Americans – have an anatomy and physiology that present intersex traits.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/cAUDKEI4QKI?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">What it’s like to be intersex.</span></figcaption>
</figure>
<h2>Binary designations can be damaging</h2>
<p>Those with intersex traits who <a href="https://doi.org/10.1371/journal.pone.0240088">are assigned at birth</a> to be female or male can <a href="https://www.amnesty.org/en/latest/campaigns/2017/05/intersex-rights/">experience medical care that harms them</a>, both physically and psychologically. </p>
<p>Sometimes physicians perform surgeries to align bodies into binary categories. For example, those born with a larger than typical clitoris <a href="https://doi.org/10.1089/lgbt.2021.0018">may have it reduced in size</a>. But some who have this childhood surgery suffer as adults from pain and difficulty having sex.</p>
<p>[<em><a href="https://memberservices.theconversation.com/newsletters?nl=science&source=inline-science-corona-important">Get The Conversation’s most important coronavirus headlines, weekly in a science newsletter</a></em>]</p>
<p>Additionally, governments sometimes limit those with intersex traits from fully participating in society. For instance, in Australia, <a href="https://ihra.org.au/16808/annulment-marriage-due-intersex-marriage-falsely-called/">marriages have been annulled</a> because governments have previously ruled that an intersex person – someone not seen to be “100% man” or “100% woman” – cannot be legally married.</p>
<p><a href="https://stillmed.olympics.com/media/Documents/News/2021/11/IOC-Framework-Fairness-Inclusion-Non-discrimination-2021.pdf">Private entities</a> often do the same. The International Olympics Committee uses <a href="https://www.wired.com/story/caster-semenya-and-the-twisted-politics-of-testosterone/">cutoffs of hormone levels</a> to determine who plays in women’s sports. As a result, some athletes have been barred from participation. </p>
<p>And for those with a gender identity that differs from the sex designation on a government document, <a href="https://transequality.org/sites/default/files/docs/usts/USTS-Full-Report-Dec17.pdf">discrimination, harassment or violence</a> can result. </p>
<p>State governments have begun to acknowledge sex diversity. Some let gender-diverse people change their designation on birth certificates, <a href="https://www.lgbtmap.org/equality-maps/identity_document_laws/birth_certificate">although there are restrictions</a>. Medicine too <a href="https://doi.org/10.1089/lgbt.2021.0018">is changing</a>. For example, some pediatric centers have stopped performing surgeries on newborns with <a href="https://protect-us.mimecast.com/s/jNAuCVOrlMC8Dq3vuQEnoR?domain=them.us">differences in sex development</a>. Still, society at large <a href="https://www.cnn.com/2017/09/20/health/geas-gender-stereotypes-study/index.html">has been much slower to move beyond</a> the use of strictly binary categories. </p>
<p>As clinicians, we strive to be accurate. The evidence shows that using male and female as the only options on birth certificates is not consistent with scientific reality. Evidence shows that removing this designation will tell new parents that it’s not sex assignment that’s most important at birth but rather the celebration of a healthy and happy baby.</p><img src="https://counter.theconversation.com/content/172293/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Carl Streed receives funding from the National Heart, Lung, and Blood Institute and the American Heart Association. He is affiliated with the US Professional Association for Transgender Health and the American Medical Association. </span></em></p><p class="fine-print"><em><span>Frances Grimstad 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>Millions of people do not fit neatly into male or female sex designations at birth, and wrong identification can set them up for a lifetime of physical and mental harm.Carl Streed Jr, Assistant Professor of Medicine, Boston UniversityFrances Grimstad, Assistant Professor of Gynecology, Harvard UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1687842021-11-02T22:44:33Z2021-11-02T22:44:33ZSpecks of dust on the microscope slide? No, we are looking at the building blocks of our genome<figure><img src="https://images.theconversation.com/files/426362/original/file-20211014-15-ect8po.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C5605%2C4902&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The genome of the spiny-tailed monitor is divided up into 8 big macochromosomes and 10 tiny microchromosomes huddled in the middle.</span> <span class="attribution"><span class="source">Jason Dobry</span>, <span class="license">Author provided</span></span></figcaption></figure><p>If you look at cells from a human or other mammal under a microscope, you’ll see big fat molecular complexes called chromosomes that contain our DNA. If the cells are from a bird or reptile, you’ll see a few of these chunky chromosomes but also a flotilla of tiny specks that look like broken-down pieces of chromosomes or even specks of dust.</p>
<p>Those specks turned out to be tiny chromosomes, but their significance has been a mystery for decades. I assembled a talented team of young genome scientists to show that <a href="https://www.pnas.org/content/118/45/e2112494118%20in%20all%20birds%20and%20reptiles">these “microchromosomes” are almost identical</a>, and they represent the ancient chromosomes of a spineless animal ancestor that lived 684 million years ago.</p>
<h2>The human genome and human chromosomes</h2>
<p>The human genome comprises about 3 billion base pairs of DNA, each one like a rung on a long, twisted ladder. If you stretched the whole genome out, it would be about 1 metre long. It contains about 20,000 genes and a lots of repetitive sequences of DNA with few known functions. </p>
<p>Our genome is broken up into 23 bits. We can see these bits when a cell divides into two, because during this process the DNA condenses with proteins into chromosomes (literally “staining bodies”) which we can see under the microscope. We have two copies of the genome in each of our cells (one from our mum and one from our dad), so we see 46 chromosomes in each cell.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/did-sex-drive-mammal-evolution-how-one-species-can-become-two-62535">Did sex drive mammal evolution? How one species can become two</a>
</strong>
</em>
</p>
<hr>
<p>Other mammals have pretty much the same set of genes on a similar length of DNA, but it is broken up differently. Some animals have lots of small chromosomes (there is a South American rat with 51) and others have a few big ones (the swamp wallaby has only 5).</p>
<p>Surprisingly, other higher vertebrates (birds and reptiles), though they have somewhat smaller genomes (1 or 2 billion base pairs) have pretty much the same sets of genes – as do frogs and even fish. The genomes of all vertebrates are amazingly similar.</p>
<h2>The story of microchromosomes</h2>
<p>When we look at the <em>chromosomes</em> of birds, turtles and squamates (snakes and lizards), however, we see big differences from those of mammals. They have between six and nine normal-looking chromosome pairs, but also lots of tiny elements that at first were thought to be degraded bits of chromosome or even dust on the microscope slide.</p>
<p>However, it proved that these elements were present in a constant – and even – number. Most birds have 62, representing 31 pairs of tiny “microchromosomes”.</p>
<p>Although microchromosomes are tiny, they have the same ends (telomeres) and attachment points (centromeres) as larger chromosomes. Curiously, they seem to hang out together in the centre of the cell. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/tick-tock-how-stress-speeds-up-your-chromosomes-ageing-clock-127728">Tick, tock... how stress speeds up your chromosomes' ageing clock</a>
</strong>
</em>
</p>
<hr>
<p>The real surprise came when it became possible to sequence bits of chicken microchromosome DNA and check out the genes they contained. It turned out that chick microchromosomes carry <a href="https://genome.cshlp.org/content/8/6/621">a big share of the genes</a> and contain far fewer repetitive sequences than the large “macrochromosomes”. In fact, about half the chicken genes lie on microchromosomes. This implied that <a href="https://doi.org/10.1159/000063018">microchromosomes are important parts of the bird genome</a>.</p>
<p>But the mystery remained. Why are there two such distinct size classes of chromosomes in birds and other reptiles? And why do you always see microchromosomes huddled together in the centre of the cell?</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=602&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=602&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=602&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=756&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=756&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426874/original/file-20211018-25-1ksq249.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=756&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">About half the genes of a chicken are carried in microchromosomes.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Chicken#/media/File:Brown_Leghorn_rooster_in_Australia.jpg">Fernando de Sousa</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Microchromosomes are highly conserved across birds and reptiles</h2>
<p>Thanks to huge improvements in DNA sequencing technology, there are now well-assembled end-to-end or “<a href="https://www.nature.com/articles/d42859-020-00117-1">telomere-to-telomere</a>” sequences of many birds and reptiles.</p>
<p>In <a href="https://www.pnas.org/content/118/45/e2112494118">our new work</a>, we have lined up DNA sequences of macro- and microchromosomes between several birds, turtles and squamates. We see startling similarities in the sequences.</p>
<p>Emus and pigeons are only distantly related to chickens, as birds go, but they have virtually the same chromosomes. Turtles and squamates have fewer microchromosomes than birds, but the ones they do have are very similar within each group. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426875/original/file-20211018-25-vhkj3c.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">Turtles have fewer microchromomes than birds.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Turtle#/media/File:Green_Sea_Turtle_swimming.jpg">Roberto Costa Pinto</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>When we compared sequences between emus, turtles and squamates, we saw a high degree of homology in microchromosome DNA sequences stretching over the nearly 300 million years since these species last shared a common ancestor. Turtles and squamates each carry different subsets of emu microchromosomes. We could see the lost microchromosomes; they had fused with each other or with macrochromosomes. </p>
<p>This suggested that 31 bird microchromosomes was present in the genome of a common ancestor of birds and reptiles about 300 million years ago, and turtles and squamates independently lost different subsets of these. </p>
<p>We used <a href="https://epigenie.com/epigenetics-research-methods-and-technology/chromatin-analysis/chromatin-conformation-analysis-3c-techniques/">new techniques</a> to reveal which bits of DNA are physically closest to which in the DNA tangle of a non-dividing cell. This showed that microchromosomes play tag with each other, and not with macrochromosomes. </p>
<p>This gives molecular reality to the old observations that microchromosomes lie close together in bird and reptile cells. It looks like microchromosomes form a compartment in the cell that might help the genes work together.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=475&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=475&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=475&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=597&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=597&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426870/original/file-20211018-25-190rjm4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=597&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The tiny chromosomes of the amphioxus or lancelet are the building blocks of the genomes of modern vertebrates.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Lancelet#/media/File:Branchiostoma_lanceolatum.jpg">Hans Hillewaert</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>Microchromosomes are ancient genetic elements</h2>
<p>As it turns out, microchromosomes go back far, far further than the ancestral reptile: all the way to the tiny chromosomes of a very distantly related animal called the amphioxus or lancelet. Lancelets are small fish-like invertebrates that last shared a common ancestor with vertebrates 684 million years ago, long before the spine evolved.</p>
<p>Lancelets have a very small genome (520 million base pairs) cut up into 19 tiny, gene-dense chromosomes. This genome was duplicated twice during the evolution of the fish that gave rise to animals with four limbs (tetrapods).</p>
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Read more:
<a href="https://theconversation.com/it-looks-like-an-anchovy-fillet-but-this-ancient-creature-helps-us-understand-how-dna-works-107353">It looks like an anchovy fillet but this ancient creature helps us understand how DNA works</a>
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<p>We found that most emu microchromosomes aligned with a single lancelet chromosome, or sometimes with two. So the tiny lancelet chromosomes have survived almost unchanged as bird and reptile microchromosomes. The rest of the vertebrate genome is made up of copies of these chromosomes, diluted with enormous amounts of repetitive DNA.</p>
<p>This means that the tiny lancelet chromosomes, represented today by bird and reptile microchromosomes, were the original building blocks of vertebrate genomes.</p>
<h2>Mammal genomes have gone mad</h2>
<p>Some reptile and bird groups seem to have lost all or most of their microchromosomes. We show that, in these exceptional genomes, microchromosomes fused with each other (as in crocodiles) or with macrochromosomes (as in eagles and their relatives).</p>
<p>But mammals are the real exceptions. They have no microchromosomes. When we lined up emu sequence against the human and koala genomes (representing the marsupial and placental branches of the mammal family tree), we could find only small patches of homology with microchromosomes, scattered all over the genome. </p>
<p>However, in monotremes (egg-laying mammals that represent a third, and the oldest, branch of mammals), we saw that four platypus chromosomes are composed entirely of fused microchromosomes.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=338&fit=crop&dpr=1 600w, https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=338&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=338&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=424&fit=crop&dpr=1 754w, https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=424&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/427689/original/file-20211021-19-b4d0l5.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=424&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Genomes of lizards and snakes, birds, turtles and mammals (vertical lines show genome size) with DNA sequences lined up between chromosomes (coloured by size, microchromosomes in blue/green). Chromosomes have stayed the same in birds and reptiles but gone mad in mammals. Genome array by Hardip Patel, Paul Waters, Nick Lister.</span>
<span class="attribution"><span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>This implies that microchromosomes fused together into large blocks in a reptile-like mammal ancestor more than 200 million years ago. The chromosomes stayed that way in monotremes. But in our own lineage (therian mammals that diverged into marsupials and placental mammals), blocks of micro- and macrochromosomes were rearranged, obliterating their origins.</p>
<p>After this rearrangement, marsupial chromosomes stayed quite conserved, 19 large blocks of genes being shifted around in simple ways. However, the chromosomes of placental mammals have gone quite mad, rearranging multiple times in many lineages. Such dizzying chromosome variation is unusual in vertebrates.</p>
<p>So the tiny microchromosomes of birds and reptiles are really the “normal” chromosomes rather than our big, fat mammal chromosomes that are scrambled and inflated by repetitive DNA sequences.</p><img src="https://counter.theconversation.com/content/168784/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council. </span></em></p>Our genomes are built from the tiny chromosomes of a small spineless creature that lived 684 million years ago.Jenny Graves, Distinguished Professor of Genetics and Vice Chancellor's Fellow, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1598942021-05-05T20:16:47Z2021-05-05T20:16:47ZWhat causes miscarriages? A doctor explains why women shouldn’t blame themselves<figure><img src="https://images.theconversation.com/files/399047/original/file-20210505-19-9ynagk.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C6364%2C4246&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Feelings of guilt often compound the grief that follows miscarriage.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/unhappy-biracial-woman-look-in-distance-feeling-royalty-free-image/1210820291?adppopup=true">fizkes/iStock via Getty Images Plus</a></span></figcaption></figure><p>As many as <a href="https://doi.org/10.1016/j.fertnstert.2012.06.048">one in four recognized pregnancies result in miscarriage</a>, and the would-be mothers often have feelings of sadness, anger, isolation and guilt. Often, <a href="https://www.nytimes.com/2019/10/02/parenting/after-a-miscarriage-grief-anger-envy-relief-and-guilt.html">women blame themselves</a> for the pregnancy loss, which may lead to feelings of hopelessness and depression, on top of the physical toll. Mother’s Day is a happy day for millions, but for those who have experienced a miscarriage, the day can be devastating. As many as <a href="https://doi.org/10.1016/j.fertnstert.2012.06.048">one in four recognized pregnancies result in miscarriage</a>. </p>
<p>Pregnancy loss can be mentally and physically taxing. Women often have feelings of sadness, anger, isolation and guilt. Often, <a href="https://www.nytimes.com/2019/10/02/parenting/after-a-miscarriage-grief-anger-envy-relief-and-guilt.html">women blame themselves</a> for the loss, which may lead to feelings of hopelessness and depression. </p>
<p>I am a <a href="https://med.virginia.edu/obgyn/education/maternal-fetal-medicine-fellowship/meet-our-fellows/rochanda-mitchell-do/">fellow in maternal-fetal medicine</a>, and I have seen firsthand the emotional upheaval that many women experience after miscarriage. Caregivers and loved ones can help by understanding a woman’s feelings and helping her know that this loss was not her fault. I know that having honest dialogue about the incidence and cause of early pregnancy loss may foster a community of support and make the topic of pregnancy loss less taboo.</p>
<h2>Why miscarriage is not the woman’s fault</h2>
<p>About <a href="https://doi.org/10.1016/j.fertnstert.2012.06.048">15% to 25% of all clinically recognized pregnancies</a> result in pregnancy loss. Some miscarriages occur before a woman is aware, thus accounting for the wide variation in the incidence of pregnancy loss. </p>
<p>About 80% of all pregnancy losses occur within the first trimester and are often caused by having missing or extra chromosomes, called <a href="https://www.acog.org/womens-health/faqs/genetic-disorders">aneuploidy</a>. Sporadic errors during chromosomal division and duplication cause aneuploidy. Many of the abnormal chromosomes are incompatible with life and result in miscarriage. These genetic errors are considered sporadic because they’re due to chance and weren’t passed down as an inheritable trait from the parents.</p>
<p>When an extra chromosome occurs, the result is called <a href="https://medlineplus.gov/genetics/condition/trisomy-13/">trisomy</a>. The most common chromosomal abnormality found in first trimester loss is trisomy 16. The term trisomy 16 indicates that there are three copies of chromosome 16, instead of the normal two copies of the chromosome. This almost always results in pregnancy loss.</p>
<p>About <a href="https://doi.org/10.1016/j.fertnstert.2012.06.048">5% of women will experience two consecutive</a> pregnancy losses, and 1% will experience three or more consecutive pregnancy losses. Consecutive pregnancy loss is known as recurrent pregnancy loss. Women who experience this should discuss it with their obstetrician/gynecologist and schedule a clinical workup.</p>
<h2>What doctors know about pregnancy loss</h2>
<p>The cause of pregnancy loss is often beyond a woman’s control. It can be related to genetics, <a href="https://doi.org/%2010.1097/OGX.0000000000000408">abnormalities in the uterus</a>, autoimmunity, infections and metabolic disorders. Lifestyle choices, such as avoiding tobacco and drugs, are a few of the things that can lower the risk of miscarriage.</p>
<figure class="align-center ">
<img alt="Empty crib with a stuffed animal lying beside it." src="https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=386&fit=crop&dpr=1 600w, https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=386&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=386&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=485&fit=crop&dpr=1 754w, https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=485&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/399052/original/file-20210505-19-8i7iou.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=485&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Miscarriage can be caused by a variety of factors.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/empty-cot-royalty-free-image/171743189?adppopup=true">Peter Dazeley/The Image Bank via Getty Images</a></span>
</figcaption>
</figure>
<p>Miscarriages caused by uterine abnormalities happen most often in the second trimester. Something called a <a href="https://www.verywellfamily.com/how-septate-uterus-affects-miscarriage-pregnancy-loss-risk-2371692">septate uterus</a> is the most common of the malformations, occurring when a fibrous or muscular membrane, or septum, develops inside of the uterus and divides it. This typically happened when the woman herself was a developing fetus in her own mother’s womb. Unless it has been diagnosed by a doctor, a woman would not even know she has this condition. </p>
<p>Septate uterus can be surgically corrected and improve pregnancy outcomes, but there are no known surgical corrective options for other types of abnormalities. </p>
<h2>Causes of miscarriages</h2>
<p>A clotting disorder known an <a href="https://www.mayoclinic.org/diseases-conditions/antiphospholipid-syndrome/symptoms-causes/syc-20355831">antiphospholipid syndrome</a> also is associated with pregnancy loss. This condition causes the placenta to develop and implant abnormally. About 5% to 20% of patients with recurrent pregnancy loss will be positive for antiphospholipid antibodies, but women are not routinely screened for this condition. If a women has a history of recurrent pregnancy loss, however, she and her physician should consider testing for this syndrome. Treatment with low-dose aspirin and heparin has been shown to improve live-born rate.</p>
<p>Women can and should do everything they can to take good care of themselves, pregnant or not. When pregnant, however, it is especially important to manage chronic diseases such as diabetes. Also, doctors who treat pregnant women who smoke, drink alcohol or use other drugs can and should help them get treatment to help them stop. Ceasing the use of tobacco, alcohol and other substances has been associated with a decreased risk of miscarriage.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Zeub1U8Ah14?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Chrissy Tiegen talks about the sadness she experienced after miscarriage.</span></figcaption>
</figure>
<h2>Grief and guilt abound</h2>
<h2>JA: Miscarriage leads to grief and guilt</h2>
<p>There is often a grief response associated with pregnancy loss. The psychological burden of miscarriage may negatively affect a couple’s relationship. Increased awareness and sensitivity to the issues associated with pregnancy loss are essential to eliminating the stigma some women experience. And, many women feel guilty when they experience a miscarriage, which may compound the grief.</p>
<p>Having more open dialogue regarding pregnancy loss may reveal just how common miscarriage is. Fostering a community of support is important in helping women move through this difficult process. During this Mother’s Day celebration, let us celebrate mothers with living children and honor those who have had the unfortunate experience of pregnancy loss.</p><img src="https://counter.theconversation.com/content/159894/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Rochanda Mitchell 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>Miscarriage occurs in 15% to 25% of diagnosed pregnancies, bringing heartache to millions of women, many of whom blame themselves. In most cases, however, miscarriage is due to random genetic errors.Rochanda Mitchell, Fellow in Maternal-Fetal Medicine, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1572102021-04-15T12:39:17Z2021-04-15T12:39:17ZScientists are on a path to sequencing 1 million human genomes and use big data to unlock genetic secrets<figure><img src="https://images.theconversation.com/files/395117/original/file-20210414-20-1od1b13.png?ixlib=rb-1.1.0&rect=32%2C64%2C3047%2C2349&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A complete human genome, seen here in pairs of chromosomes, offers a wealth of information, but it is hard connect genetics to traits or disease.</span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:UCSC_human_chromosome_colours.png#/media/File:UCSC_human_chromosome_colours.png">HYanWong/Wikimedia Comons</a></span></figcaption></figure><p>The first draft of the human genome was <a href="https://www.washingtonpost.com/archive/politics/2000/06/27/teams-finish-mapping-human-dna/3af9bfcf-e7b6-4ac1-bcdb-f4fc117c19bd/">published 20 years ago</a> in <a href="https://www.genome.gov/25520483/online-education-kit-2001-first-draft-of-the-human-genome-sequence-released">2001</a>, took nearly three years and cost <a href="https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost">between US$500 million and $1 billion</a>. The <a href="https://www.genome.gov/human-genome-project">Human Genome Project</a> has allowed scientists to read, almost end to end, the 3 billion pairs of DNA bases – or “letters” – that biologically define a human being. </p>
<p>That project has allowed a new generation of <a href="https://scholar.google.com/citations?user=Yy8gde8AAAAJ&hl=en&oi=ao">researchers like me</a>, currently a postdoctoral fellow at the National Cancer Institute, to identify <a href="https://doi.org/10.1038/s41586-020-2099-x">novel targets for cancer treatments</a>, engineer <a href="https://doi.org/10.1038/s41590-019-0416-z">mice with human immune systems</a> and even build a <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr14%3A95086244%2D95158010&hgsid=1066518897_QJL7hsBNGEhTnw6DgqcZaMG4YFB2">webpage where anyone can navigate the entire human genome</a> with the same ease with which you use Google Maps.</p>
<p>The first complete genome was generated from a handful of anonymous donors to try to produce a reference genome that represented more than just one single individual. But this fell far short of encompassing <a href="https://doi.org/10.1038/nature18964">the wide diversity of human populations in the world</a>. No two people are the same and no two genomes are the same, either. If researchers wanted to understand humanity in all its diversity, it would take sequencing thousands or millions of complete genomes. Now, a project like that is underway. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diverse group of people." src="https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=493&fit=crop&dpr=1 600w, https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=493&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=493&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=619&fit=crop&dpr=1 754w, https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=619&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/395378/original/file-20210415-18-fmgye7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=619&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">There is a huge amount of genetic variation between people around the globe.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/group-portrait-of-people-smiling-royalty-free-image/560447233?adppopup=true">Flashpop/DigitalVision via Getty Images</a></span>
</figcaption>
</figure>
<h2>Understanding genetic diversity</h2>
<p>The wealth of genetic variation among people is what makes each person unique. But genetic changes also cause many disorders and make some groups of people more susceptible to certain diseases than others.</p>
<p>Around the time of the Human Genome Project, researchers were also sequencing the complete genomes of organisms such as <a href="https://doi.org/10.1038/nature01262">mice</a>, <a href="https://doi.org/10.1126/science.287.5461.2185">fruit flies</a>, <a href="https://doi.org/10.1126/science.274.5287.546">yeasts</a> and <a href="https://doi.org/10.1038/35048692">some plants</a>. The huge effort made to generate these first genomes led to a revolution in the technology required to read genomes. Thanks to these advances, instead of taking years and costing hundreds of millions of dollars to sequence a whole human genome, it now takes <a href="https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost">a few days and costs merely a thousand dollars</a>. Genome sequencing is very different from genotyping services like 23 and Me or Ancestry, which look at only a tiny fraction of locations in a person’s genome.</p>
<p>Advances in technology have allowed scientists to sequence the complete genomes of thousands of individuals from around the world. Initiatives such as the <a href="https://gnomad.broadinstitute.org/">Genome Aggregation Consortia</a> are currently making efforts to collect and organize this scattered data. So far, that group has been able to gather nearly <a href="https://doi.org/10.1038/s41586-020-03174-8">150,000 genomes</a> that show an incredible amount of human genetic diversity. Within that set, researchers have found more than 241 million differences in people’s genomes, <a href="https://doi.org/10.1038/nature19057">with an average of one variant for every eight base pairs</a>.</p>
<p>Most of these variations are very rare and will have no effect on a person. However, hidden among them are variants with important physiological and medical consequences. For example, certain variants in the BRCA1 gene predispose some groups of woman, like Ashkenazi Jews, to <a href="https://doi.org/10.1038/s41586-018-0461-z">ovarian and breast cancer</a>. Other variants in that gene lead some <a href="https://doi.org/10.1038/s41467-018-06616-0">Nigerian women to experience higher-than-normal mortality</a> from breast cancer. </p>
<p>The best way researchers can identify these types of population-level variants is through <a href="https://www.ebi.ac.uk/gwas/">genomewide association studies</a> that compare the genomes of large groups of people with a control group. But diseases are complicated. An individual’s lifestyle, symptoms and time of onset can vary greatly, and the effect of genetics on many diseases is hard to distinguish. The predictive power of current genomic research is too low to tease out many of these effects because <a href="https://doi.org/10.1038/s41588-018-0313-7">there isn’t enough genomic data</a>.</p>
<p>Understanding the genetics of complex diseases, especially those related to the genetic differences among ethnic groups, is essentially a big data problem. And researchers need more data.</p>
<h2>1,000,000 genomes</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="The double helix DNA structure." src="https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1038&fit=crop&dpr=1 600w, https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1038&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1038&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1304&fit=crop&dpr=1 754w, https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1304&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/395116/original/file-20210414-16-rrcqz1.gif?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1304&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The link between genetics and disease is nuanced, but the more genomes you can study, the easier it is to find those links.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:DNA_animation.gif#/media/File:DNA_animation.gif">brian0918/Wikimedia Commons</a></span>
</figcaption>
</figure>
<p>To address the need for more data, the National Institutes of Health has started a program called <a href="https://allofus.nih.gov/">All of Us</a>. The project aims to collect genetic information, medical records and health habits from surveys and wearables of more than a million people in the U.S. over the course of 10 years. It also has a goal of gathering more data from underrepresented minority groups to facilitate the study of health disparities. The <a href="https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act">All of Us project</a> opened to public enrollment in 2018, and more than 270,000 people have contributed samples since. The project is continuing to recruit participants from all 50 states. Participating in this effort are many academic laboratories and private companies.</p>
<p>This effort could benefit scientists from a wide range of fields. For instance, a neuroscientist could look for genetic variations associated with depression while taking into account exercise levels. An oncologist could search for variants that correlate with reduced risk of skin cancer while exploring the influence of ethnic background.</p>
<p>A million genomes and the accompanying health and lifestyle information will provide an extraordinary wealth of data that should allow researchers to discover the effects of genetic variation on diseases, not only for individuals, but also within different groups of people.</p>
<p>[<em>Understand new developments in science, health and technology, each week.</em> <a href="https://theconversation.com/us/newsletters/science-editors-picks-71/?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=science-understand">Subscribe to The Conversation’s science newsletter</a>.]</p>
<h2>The dark matter of the human genome</h2>
<p>Another benefit of this project is that it will allow scientists to learn about parts of the human genome that are currently very hard to study. Most genetic research has been on the parts of the genome that encode for proteins. However, these represent only <a href="https://dx.doi.org/10.1038%2Fnrd.2018.93">1.5% of the human genome</a>.</p>
<p>My research focuses on RNA – a molecule that turns the messages encoded in a person’s DNA into proteins. However, RNAs that come from the 98.5% of the human genome that doesn’t make proteins have a myriad of functions by themselves. Some of these noncoding RNAs are involved in processes such as <a href="https://doi.org/10.1038/nature08975">how cancer spreads</a>, <a href="https://doi.org/10.1242/dev.146613">embryonic development</a> or <a href="https://doi.org/10.1038/35047580">controlling the X chromosome in females</a>. In particular, I study how genetic variations can influence the intricate folding that allows noncoding RNAs to do their jobs. Since the All of Us project includes all coding and noncoding parts of the genome, it is going to be by far the largest dataset relevant to my work and will hopefully shed light on these mysterious RNAs.</p>
<p>The first human genome sparked 20 years of incredible scientific progress. I think it is almost certain that a huge dataset of genomic variations will unlock clues about complex diseases. Thanks to large-scale population studies and big-data projects such as All of Us, researchers are paving the way to answering, in the next decade, how our individual genetics shape our health.</p>
<p><em>A photo in this story was updated to better represent our editorial guidelines.</em></p><img src="https://counter.theconversation.com/content/157210/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Xavier Bofill De Ros receives funding from the National Institutes of Health (NIH). He is affiliated with ECUSA, an association of Spanish scientists in the USA.</span></em></p>The first full human genome was sequenced 20 years ago. Now, a project is underway to sequence 1 million genomes to better understand the complex relationship between genetics, diversity and disease.Xavier Bofill De Ros, Research Fellow in RNA biology, National Institutes of HealthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1549982021-02-18T21:11:35Z2021-02-18T21:11:35ZCryptic sex: How female and unisexual animals reproduce ‘asexually’ — without males<figure><img src="https://images.theconversation.com/files/383398/original/file-20210209-17-1ig7ur9.jpg?ixlib=rb-1.1.0&rect=38%2C19%2C6451%2C3970&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Asexual reproduction can — through cell division, or meiosis — take place without the need for sperm.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Not all species need sperm to fertilize an egg for sexual reproduction. Some species need sperm in order to induce completion of egg nucleus development, but then never use the sperm’s DNA. I describe how this self-sexual reproduction occurs in many animals, including some insects, molluscs, fish, amphibians and reptiles, but not mammals.</p>
<p>People have long understood that ejaculate is needed for human pregnancy, but did not understand much more. In the late 1600s, the Dutch scientist Antonie van Leeuwenhoek, who was one of the first microbiologists, thought <a href="https://www.smithsonianmag.com/science-nature/scientists-finally-unravel-mysteries-sperm-180963578/">his own sperm were parasites</a>.</p>
<p>For most of the 1700s and 1800s, <a href="https://www.jstor.org/stable/30053946">people thought that sperm contributed nothing more than a spark</a> to start development of an egg, although eventually decided — in a sexist fashion — that sperm contributed all the information and developmental instructions, while eggs merely provided a nutrient-rich vessel for the developing fertilized egg — zygote — and fetus.</p>
<p>In 1890, after chromosomes were seen under improved microscopes, German biologist Oscar Hertwig realized that <a href="https://embryo.asu.edu/pages/wilhelm-august-oscar-hertwig-1849-1922">egg and sperm each contributed half the normal number of chromosomes to a zygote</a>.</p>
<p>Therefore sexual reproduction has two parts: halving the normal number of chromosomes per cell nucleus, which is called meiosis, and restoring the normal number of chromosomes per nucleus, usually by combining chromosomes from an egg nucleus and a sperm nucleus, which is called fertilization.</p>
<p>But, as we will see, in many species, only meiosis is needed.</p>
<h2>Some form of sex</h2>
<p>It seems that all animals eventually need to engage in some form of sex. Human cells contain a nucleus with 46 chromosomes. When it goes through meiosis, the cells — and all its intracellular components, including the nucleus — multiply and then split, so that one cell with one nucleus and 46 chromosomes becomes four cells with four nuclei and 23 chromosomes.</p>
<p>Meiosis in all animals proceeds the same way. It starts with a duplication of all chromosomes in a cell nucleus that has the normal number of chromosomes (46 in humans) — all nuclear divisions start with a chromosomal duplication. Cryptic sex is <a href="https://doi.org/10.1002/evl3.216">how biologists refer to undetected meiosis</a>.</p>
<p>Not only do our bodies degrade as we age, but so do our chromosomes, which tatter at the edges. As far as we know, the only things that rejuvenate chromosomes and cell lineages is sex vis-à-vis meiosis or fertilization.</p>
<p>Next, <a href="http://doi.org/10.4033/iee.2011.4.3.n">this nucleus with twice the normal number of chromosomes divides those equally between two nuclei, and then divides each of these equally again, to form four nuclei</a>, each with half the normal number of chromosomes. Thus, either four egg or four sperm nuclei are formed. Egg cells contain four egg nuclei plus as many sperm nuclei as manage to get inside the egg cell. This is where things get interesting.</p>
<h2>No sperm required</h2>
<p>We often only consider one egg nucleus fusing with one sperm nucleus to form a zygote nucleus and the other nuclei are discarded. But two egg nuclei can fuse to form the zygote nucleus, with all other egg and sperm nuclei ejected or discarded, <a href="https://doi.org/10.1111/j.1095-8312.2009.01334.x">a process called gynogenesis</a>.</p>
<p>Meiosis of animal eggs usually requires a sperm cell to finish egg meiosis, but with gynogenesis, no sperm chromosomes are used in the zygote and both egg nuclei were from the same meiosis. Gynogenesis occurs in many different animals, including lots of fish, amphibians and reptiles, but not in mammals.</p>
<p>Gynogenesis can occur in other ways. With four egg nuclei per egg cell, each with half the normal number of chromosomes, and this time with no sperm, two of the four egg nuclei can fuse with one another to form a zygote. The remaining two nuclei are ejected or degraded. Alternatively, one of the four egg nuclei could spontaneously duplicate all of its chromosomes to form a viable zygote without fertilization, as <a href="https://doi.org/10.1007/s10577-018-9581-4">occurs in some fish</a> and <a href="https://doi.org/10.1159/000109628">salamanders</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="One yellow-dotted black salamander and one blue-dotted black salamander chilling on a log" src="https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/383821/original/file-20210211-17-rj0z7p.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">Some salamanders that have only one biological sex reproduce asexually.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>As another alternative, a spontaneous doubling of all chromosomes can occur just before meiosis, in which case the four egg nuclei at the end of meiosis will have the normal number of chromosomes and therefore one of them can form a zygote without fertilization. I would consider any of these gynogenetic scenarios to be cryptically self-sexual because they involve meiosis, but this is often called asexual reproduction.</p>
<p>With four egg nuclei and any number of sperm nuclei per mature egg cell, each with half the normal number of chromosomes, there are other ways to get self-sexual reproduction. Two sperm nuclei can fuse to form a normal zygote or one sperm nucleus can spontaneously duplicate all its chromosomes to form a normal zygote, with processes called androgenesis.</p>
<p>With androgenesis, all four egg nuclei are ejected or degraded, with the egg just providing a large nutritious cell to support the sperm nuclei. That resembles conceptualizations of sex from the 1800s! Compared with gynogenesis, androgenesis is extremely rare, only known from a <a href="https://doi.org/10.2307/2409646">few insects</a> and <a href="https://doi.org/10.1007/s004270050152">molluscs</a>.</p>
<p>The bottom line is that, except for mammals, asexual reproduction is quite common, but is often really self-sexual reproduction.</p><img src="https://counter.theconversation.com/content/154998/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Root Gorelick 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>Perceptions about the role of sperm have changed over time, but asexual reproduction doesn’t need sperm for fertilization.Root Gorelick, Professor, Biology, Carleton UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1307392020-01-29T15:39:58Z2020-01-29T15:39:58ZDown’s syndrome: specific genes in chromosome 21 found to be the cause of learning and memory problems<figure><img src="https://images.theconversation.com/files/312485/original/file-20200129-92959-77k5b3.jpg?ixlib=rb-1.1.0&rect=17%2C11%2C3976%2C2976&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It was previously thought cognitive impairments were caused by more copies of single genes from chromosome 21.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/cute-kid-downs-syndrome-playing-kindergarten-528036100">Olesia Bilkei/ Shutterstock</a></span></figcaption></figure><p>Down’s syndrome is a genetic disorder that occurs in about <a href="https://www.ncbi.nlm.nih.gov/pubmed/25822844">1 in 800 births</a>. It’s caused by having three copies of genes – rather than the usual two – on <a href="https://ghr.nlm.nih.gov/condition/down-syndrome">human chromosome 21</a>. Down’s syndrome is associated with physical growth delays, and people with the condition might face <a href="https://www.ncbi.nlm.nih.gov/pubmed/25989505">problems in memory function</a>, planning, and decision-making.</p>
<p>Although we know Down’s syndrome is caused by genes on human chromosome 21, we don’t know which genes cause learning disability when they are present in the three chromosomal copies – which is what our team of researchers <a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31722-X">wanted to find out</a>. Our study found out that multiple different genes on chromosome 21 contribute to learning and memory problems in people with Down’s syndrome. </p>
<p>We used mouse models to conduct our study, as groups of genes found on three different chromosomes in mice are comparable to those on human chromosome 21. We worked with mice that had duplicated genes from mouse chromosomes 10, 16, and 17 to replicate features of Down’s syndrome in these mice. This allowed us to ask three key questions:</p>
<ol>
<li>Do all of these mice have intellectual disabilities (cognitive impairments)?</li>
<li>Are the cognitive impairments that occur in each of these mice the same?</li>
<li>What is the abnormality in brain function that results in this disability?</li>
</ol>
<p>If we found any impairments, we would then need to find out which genes are present in the three individual chromosomes in the mice – and which genes caused the impairment. </p>
<p>Our study used a very simple task to determine cognitive impairments in the mice, called an <a href="https://www.ncbi.nlm.nih.gov/pubmed/17406205">alternating T maze</a>. When at a T junction, mice will first explore one arm of the maze before the other. When the task is repeated, they naturally explore the other arm first. To successfully complete this task, the mouse has to remember which arm it had explored previously and – when it gets to the T junction – it has to decide to go the opposite way.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=432&fit=crop&dpr=1 600w, https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=432&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=432&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=543&fit=crop&dpr=1 754w, https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=543&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/312486/original/file-20200129-93030-yivafq.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=543&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The T maze tested a mouse’s memory and decision-making.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/white-experimental-mouse-ymaze-study-cognitive-793031041">unoL/ Shutterstock</a></span>
</figcaption>
</figure>
<p>Tracking the number of times a mouse chooses the alternate arm gives us a measure of memory. The amount of time the mouse takes to make its choice at the T junction gives us a measure of decision-making. While the mice performed the task, we also recorded their brain activity using implanted electrodes and a wireless system. We simultaneously measured the <a href="https://www.nature.com/articles/nrn2335">activity in the hippocampus</a> (an area of the brain critical for memory function) and the <a href="https://www.ncbi.nlm.nih.gov/pubmed/23259943">prefrontal cortex</a> (an area of the brain critical for decision-making).</p>
<p>The results were unexpected. Only two of the mice strains, those with duplicated genes on chromosome 16, and those with duplicated genes on chromosome 10, had measurable cognitive impairments – meaning that the duplicated genes from these two regions must cause intellectual disability. More surprising was that these two mouse strains had completely different cognitive problems. The chromosome 16 mice had normal memory but very delayed decision-making, while the chromosome 10 mice had normal decision-making but poor memory. The mice with duplications of genes from chromosome 17 had no differences at all – indicating that the genes in this region don’t cause intellectual disability. </p>
<p>These findings show that cognitive impairments aren’t caused by more copies of single genes from chromosome 21. Rather, extra copies of some genes cause memory impairments, while extra copies of completely different genes lead to problems with decision-making. Moreover, this study showed that one of the main genes, called “<a href="https://ghr.nlm.nih.gov/gene/DYRK1A">Dyrk1A</a>” – which was previously thought to cause intellectual disability in Down’s syndrome – was actually found not to cause any cognitive problems in our tests.</p>
<p>Measures of the electrical activity in the hippocampus and prefrontal cortex of these mice in the T maze also differed in each different mice strain. The chromosome 17 mice – which had not shown any learning and memory deficits – had normal electrical activity. The chromosome 10 mice, which had memory problems, were found to have distinct abnormalities in the brain’s hippocampus, which is critical for memory.</p>
<p>The chromosome 16 mice also had some abnormality in their hippocampus’s function. But most notably, they had abnormalities in the communication that takes place between the hippocampus and the prefrontal cortex – suggesting that the problem is not just to do with abnormal function in specific brain areas, but with the communication between those brain areas. As such, the different cognitive problems in Down’s syndrome are likely due to different brain and circuitry dysfunctions. </p>
<p>Because groups of genes on the mouse chromosomes, 16, 17, and 10 are the same as those on human chromosome 21, this now gives us a way of identifying which genes are important in learning and memory in people with Down’s syndrome, by looking at the same genes in mice. Our results suggest that specific learning and memory problems associated with Down’s syndrome are caused by different underlying genetic, brain region and brain connectivity abnormalities. Knowing this will help us further understand these cognitive deficits, and might help improve therapies. Further research will now need to focus on honing in on the particular sets of responsible genes.</p><img src="https://counter.theconversation.com/content/130739/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Matthew Walker receives funding from UK medical research council, Epilepsy Research UK and the National Institute for Health Research University College London Hospitals Biomedical Research Centre.</span></em></p><p class="fine-print"><em><span>Elizabeth Fisher receives funding from Wellcome Trust, Medical Research Council, Rosetrees Foundation.</span></em></p>This new research shows that cognitive impairments are actually caused by extra copies of some genes on chromosome 21.Matthew Walker, Professor of Neurology, UCLElizabeth Fisher, Professor of Molecular Genetics, UCLLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1268392019-11-25T01:12:12Z2019-11-25T01:12:12ZGenetic testing IVF embryos doesn’t improve the chance of a baby<figure><img src="https://images.theconversation.com/files/302547/original/file-20191119-111663-1cc8lwc.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Genetic testing costs around A$700 per embryo.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/new-born-baby-boy-resting-mothers-663728050">KieferPix</a></span></figcaption></figure><p>If you’re going through IVF, you may be offered a test to look at your embryos’ chromosomes. </p>
<p><a href="https://www.fertstert.org/article/S0015-0282(19)32454-9/fulltext">Pre-implantation genetic testing</a> for aneuploidy (chromosome abnormalities), known as PGT-A, is an “add on” used to help choose embryos with the right number of chromosomes. It’s promoted by IVF clinics as a way to increase the chance of success, especially for women over 35. </p>
<p>But the <a href="https://www.ncbi.nlm.nih.gov/pubmed/30085138">evidence shows</a> that in most cases, PGT-A doesn’t improve the chance of a baby.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-business-of-ivf-how-human-eggs-went-from-simple-cells-to-a-valuable-commodity-119168">The business of IVF: how human eggs went from simple cells to a valuable commodity</a>
</strong>
</em>
</p>
<hr>
<h2>What is aneuploidy?</h2>
<p>Human cells usually contain 46 chromosomes. Aneuploidy is a term that describes a chromosome number that is different from 46 – either too many or too few chromosomes. </p>
<p>In human embryos, most aneuploidies are lethal, resulting in miscarriage, or do not result in pregnancy at all. </p>
<p>The chance of aneuploidy increases with the age of the woman; by the time a woman reaches age 40, <a href="https://journals.sagepub.com/doi/full/10.1177/2058915816653277">approximately 80%</a> of her embryos are aneuploid. </p>
<h2>What is PGT-A?</h2>
<p>All couples produce some aneuploid embryos, whether they conceive naturally or with IVF. The idea behind PGT-A is that if the aneuploid embryos can be identified they can be discarded, so that only embryos capable of producing a healthy pregnancy are used. </p>
<p>PGT-A involves the woman having fertility drugs to produce several eggs. When they are mature, they are retrieved and mixed with sperm to create embryos. </p>
<p>Embryos are grown in the laboratory for five to six days. At this time, two types of cells are distinguishable: the cells that will develop into the placenta and the cells that will become the baby. </p>
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Read more:
<a href="https://theconversation.com/considering-using-ivf-to-have-a-baby-heres-what-you-need-to-know-108910">Considering using IVF to have a baby? Here's what you need to know</a>
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<p>A few cells are removed from the future placenta for testing and the embryos are frozen until test results are available. </p>
<p>If the test shows there are normal embryos, one is thawed and transferred to the woman’s uterus. Any remaining normal embryos will be kept frozen for transfer later if the first transfer is unsuccessful. </p>
<p>Importantly, PGT-A doesn’t “correct” chromosomally abnormal embryos, it simply allows couples to avoid transferring them.</p>
<h2>Who might be offered PGT-A?</h2>
<p>Many clinics recommend PGT-A for women over 35 (<a href="https://npesu.unsw.edu.au/sites/default/files/npesu/data_collection/Assisted%20Reproductive%20Technology%20in%20Australia%20and%20New%20Zealand%202017.pdf">more than half of women who have IVF</a>) and those who have had repeated miscarriages or failed IVF treatments. This is because women over 35 and women with previous losses are more likely to produce aneuploid embryos. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302799/original/file-20191121-502-z5l5id.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">Women over 35 are more likely to have embryos with chromosomal abnormalities than younger women.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/510591736?src=f8b1f75f-c3ae-4a42-8efa-9e5cf579abc3-1-20&size=huge_jpg">Natalia Lebedinskaia/Shutterstock</a></span>
</figcaption>
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<h2>Does PGT-A work?</h2>
<p>While the theory behind PFT-A makes sense, randomised controlled trials (the gold standard evidence to tell us if an intervention makes a difference) have not demonstrated a clear benefit. </p>
<p>Of the two <a href="https://www.ncbi.nlm.nih.gov/pubmed/30085138">most recent trials</a> of PGT-A, one reported fewer embryo transfers and fewer miscarriages in the PGT-A group but <a href="https://www.ncbi.nlm.nih.gov/pubmed/31551155">neither showed benefits</a> in terms of improving the live-birth rate. </p>
<h2>The pitfalls of PGT-A</h2>
<p>PGT-A actually has the potential to <em>reduce</em> <a href="https://doi.org/10.1111/ajo.12960">the chance of a baby</a>. It can do this in two ways. </p>
<p>First, <a href="https://doi.org/10.1111/ajo.12960">PGT-A is not 100% accurate</a>. This means that inevitably, some embryos that have the capacity to form a healthy baby will be discarded. </p>
<p>The most common reason for these “false positive” results is that a proportion of embryos are “mosaic” – they have a mix of normal and abnormal cells. Surprisingly, mosaic chromosome abnormalities are <a href="https://www.rbmojournal.com/article/S1472-6483(19)30599-1/fulltext">quite common</a> in early human embryos, and do not seem to prevent the embryo developing into a healthy baby. </p>
<p>However, if abnormal cells are removed and tested, the embryo will be misclassified as abnormal and discarded – a lost opportunity for a healthy pregnancy. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/fertility-miracle-or-fake-news-understanding-which-ivf-add-ons-really-work-118585">Fertility miracle or fake news? Understanding which IVF 'add-ons' really work</a>
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<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/31236830">Many healthy babies have been born</a> to people who have elected to have mosaic embryos transferred because they were the only embryos they had. </p>
<p>In a <a href="https://doi.org/10.1016/j.fertnstert.2018.10.001">recent study of 98 women</a> who had mosaic embryos, 32 (33%) elected to have at least one transferred. Of these, 11 (34%) had a successful pregnancy with apparently healthy babies born.</p>
<p>Second, while the <a href="https://www.fertstert.org/article/S0015-0282(18)30002-5/fulltext">risk is small</a>, embryos can be damaged in the biopsy procedure and some embryos don’t survive the freezing and thawing process. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=407&fit=crop&dpr=1 600w, https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=407&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=407&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=512&fit=crop&dpr=1 754w, https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=512&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/302800/original/file-20191121-474-1o2hsdf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=512&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">Some women elect to have mosaic embryos transferred.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/749056846?src=ea47bcd4-7675-4022-927d-8b4cff73b144-1-14&size=huge_jpg">Rawpixel.com/Shutterstock</a></span>
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<h2>To have or not to have PGT-A?</h2>
<p>PGT-A costs around A$700 per embryo which adds up to A$2,800 if there are four embryos to test.</p>
<p>While doctors likely offer their patients detailed and individualised information about different treatment options, information about the possible benefits of PGT-A on clinic websites can be difficult to interpret. </p>
<p>That’s why independent information about the pros and cons of PGT-A is needed to help people make informed decisions. The Victorian Assisted Reproductive Treatment Authority (VARTA) has developed a <a href="https://www.varta.org.au/resources/publications/pros-and-cons-pre-implantation-genetic-testing-aneuploidy-pgt">downloadable resource</a> about the current state of knowledge about PGT-A. </p>
<p>Some clinics are now offering a less invasive technique where, rather than removing cells from the embryo, they test the fluid that the embryo is grown in to <a href="https://www.pnas.org/content/116/28/14105.short">determine if the embryo has the right number of chromosomes</a>. Time will tell of this will improve the chance of having a baby with IVF. </p>
<p>In the meantime, it may help to ask the five questions recommended by <a href="http://www.choosingwisely.org.au/resources/consumers/5-questions-to-ask-your-doctor">Choosing Wisely</a>: </p>
<ul>
<li>do I really need this test?</li>
<li>what are the risks?</li>
<li>are there safer, simpler options?</li>
<li>what happens if I don’t do anything?</li>
<li>what are the costs?</li>
</ul>
<p>And in the case of IVF: how will this improve my chance of a live birth?</p>
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<p>
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<strong>
Read more:
<a href="https://theconversation.com/your-questions-answered-on-donor-conception-and-ivf-45715">Your questions answered on donor conception and IVF</a>
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<img src="https://counter.theconversation.com/content/126839/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Karin Hammarberg is affiliated with the Victorian Assisted Reproductive Treatment Authority.</span></em></p><p class="fine-print"><em><span>David Amor 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>Women aged over 35 are sometimes offered genetic testing of their IVF embryos to rule out abnormalities. But it’s expensive and doesn’t increase their chance of a baby. In fact, it could reduce it.Karin Hammarberg, Senior Research Fellow, Global and Women's Health, School of Public Health & Preventive Medicine, Monash UniversityDavid Amor, Lorenzo and Pamela Galli Chair in Developmental Medicine, Murdoch Children's Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1217642019-08-13T20:01:25Z2019-08-13T20:01:25ZThe sex gene SRY and Parkinson’s disease: how genes act differently in male and female brains<figure><img src="https://images.theconversation.com/files/287796/original/file-20190813-9419-chhweo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Male and female brains are different at every level. Science is continuing to uncover how these differences affect health and disease.</span> <span class="attribution"><span class="source">From shutterstock.com</span></span></figcaption></figure><p>Parkinson’s disease, a debilitating neurodegenerative disease common in elderly people, is <a href="https://www.sciencedaily.com/releases/2000/11/001120072645.htm">twice as prevalent</a> in men than in women.</p>
<p>A new study <a href="https://www.pnas.org/content/early/2019/07/31/1900406116">published this month</a> suggests the sex gene (SRY on the male-specific Y chromosome) plays a role in the loss of dopamine-making neurons that underlies this disease. </p>
<p>As well as providing a spectacular example of how genes act differently in male and female brains, this discovery may lead to a new treatment option for men suffering from Parkinson’s disease.</p>
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<strong>
Read more:
<a href="https://theconversation.com/not-just-about-sex-throughout-our-bodies-thousands-of-genes-act-differently-in-men-and-women-86613">Not just about sex: throughout our bodies, thousands of genes act differently in men and women</a>
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<h2>Sex and disease</h2>
<p>Many diseases are more common in one sex than the other. For example, multiple sclerosis and other immune disorders are more common in women than men. Parkinson’s disease, and several mental health conditions such as schizophrenia and autism, are more common in men than women.</p>
<p>Treatments, too, may be differently effective in men and women because of <a href="https://www.ncbi.nlm.nih.gov/pubmed/27267697">differences in expression of genes</a> important for drug metabolism.</p>
<p>The bases of these sex differences are often unclear. Is it a hormonal difference that makes men and women differently susceptible to diseases, and differently amenable to treatment? For instance, the sex difference in Parkinson’s disease was previously attributed solely to the protective effect of the hormone oestrogen in female brains. </p>
<p>But as well as hormonal differences, we now have reason to believe genes on sex chromosomes may directly affect the brain.</p>
<h2>Parkinson’s disease</h2>
<p>Parkinson’s disease is a growing problem, particularly with an ageing population. Nearly <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/parkinsons-disease">one in 300</a> Australians live with Parkinson’s disease. It usually appears in later life as problems in starting and maintaining voluntary movements, and may be accompanied by severe tremor.</p>
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<strong>
Read more:
<a href="https://theconversation.com/what-causes-parkinsons-disease-what-we-know-dont-know-and-suspect-57579">What causes Parkinson's disease? What we know, don't know and suspect</a>
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<p>Parkinson’s disease is caused by a loss of neurons responsible for making dopamine, a hormone and neurotransmitter that sends messages to other nerve cells. Symptoms appear when <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/parkinsons-disease">70% of these dopamine-synthesising cells</a> have been depleted.
We don’t understand how these neurons are lost, but expect the effect of loss on motor function is due to the curtailed dopamine production. </p>
<p>Parkinson’s disease is progressive and incurable, but the symptoms may be ameliorated and delayed by medications that boost dopamine or substitute for it.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/287798/original/file-20190813-9425-dc93zl.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">A lack of the neurotransmitter dopamine is known to be associated with Parkinson’s disease.</span>
<span class="attribution"><span class="source">From shutterstock.com</span></span>
</figcaption>
</figure>
<h2>SRY and Parkinson’s disease</h2>
<p>In humans and other mammals, females have two X chromosomes (XX), and males a single X and a male-specific Y chromosome (XY). SRY is <a href="https://www.ncbi.nlm.nih.gov/pubmed/1695712">the master gene</a> on the Y chromosome that determines the male sex of a baby in the embryo. </p>
<p>But research has found SRY seems to be active in other parts of the body, too. In mice and rats, SRY is active in the brain, and in humans it’s expressed <a href="https://www.ncbi.nlm.nih.gov/pubmed/8111368">in several tissues and organs</a>, including the brain.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
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<p>SRY has been found to be expressed at <a href="https://www.sciencedaily.com/releases/2006/02/060222093758.htm">abnormally high levels</a> in the brains of mice and rats mutated to have symptoms of Parkinson’s disease, and in animals where the disease was induced by chemical treatment. </p>
<p>Previous work showed overactivity of the SRY gene destroys neurons that synthesise dopamine. We’re not entirely sure how this happens, but given the link between dopamine production and Parkinson’s disease, it might partly explain why Parkinson’s disease affects males more commonly than females.</p>
<p>This <a href="https://www.pnas.org/content/early/2019/07/31/1900406116">new study</a> now shows that interfering with SRY expression in the brains of rodents with Parkinson’s disease ameliorates the severity of symptoms. Vince Harley and Joohyung Lee from the Hudson Institute in Melbourne found that quashing SRY action prevented or mitigated the reduced mobility of male animals with Parkinson’s disease.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/287800/original/file-20190813-9425-1e5k2st.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">For every woman who has Parkinson’s disease, two men have it.</span>
<span class="attribution"><span class="source">From shutterstock.com</span></span>
</figcaption>
</figure>
<p>So, suppressing the activity of SRY in neurons of Parkinson’s disease patients could <a href="https://hudson.org.au/research.../sry-a-risk-factor-for-parkinsons-disease-in-males/">ameliorate their symptoms</a>. </p>
<p>This sort of a cure may be many years away, but it would have a huge impact on the quality of life of thousands of men in Australia living with Parkinson’s disease.</p>
<h2>Sex and the brain</h2>
<p>Male and female brains really are different at every level; molecular, cellular, and behavioural. For 60 years this has been attributed to sex hormones. But we’re beginning to find that genes may also have direct effects. </p>
<p>A recent analysis of the activity of most of the 20,000-odd genes in the bodies of hundreds of men and women showed that <a href="https://theconversation.com/not-just-about-sex-throughout-our-bodies-thousands-of-genes-act-differently-in-men-and-women-86613">more than one-third</a> were expressed much more highly in one sex than the other. This sex bias was not limited to sex organs, but was obvious at many other sites, including the brain.</p>
<p>The effect of SRY in the brain is a strong demonstration that male and female brains are genetically different in health and disease, and a reminder we must take account of sex differences in diagnosing and treating disease in men and women.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/differences-between-men-and-women-are-more-than-the-sum-of-their-genes-39490">Differences between men and women are more than the sum of their genes</a>
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<img src="https://counter.theconversation.com/content/121764/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives research grants from the Australian Research Council</span></em></p>Parkinson’s disease is twice as common in men than in women. A sex gene called SRY, found only in men, could go some way to explaining this – and might pave the way for potential treatments.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1164482019-05-09T20:07:52Z2019-05-09T20:07:52ZTen ethical flaws in the Caster Semenya decision on intersex in sport<figure><img src="https://images.theconversation.com/files/273417/original/file-20190508-183103-1eva5jd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Caster Semenya is legally female, was from birth raised as female and identifies as a female.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/ciamabue/7968832970/in/photolist-d9bmpU-6WYxJP-gbWqNq-faB1Ei-d2L35o-QYHomP-aciLfF-X6bjAG-27BHwNd-doMJTN-cT2bCb-RNztaz-cTaov7-74mBHV-cUT2rq-dXYK7q-cRCJDY-cQ9hZQ-RoFRBk-24xxRw2-8RuT7h-cUSVzh-dyUu74-dyUuRP-o4j6Zs-d6XYyN-74qwom-cUT6A5-d6XYpL-dyZXuN-6Rdv6M-d6XYw5-a9coyA-6YGtw4-dyZZsS-dyUuyt-d6XYdN-dyUuKK-25Xb6zb-dyZXsq-dyUuWM-25Xb5Zd-dyZXKL-dyZY9s-dyZXvw-dyZYfL-dyZXES-dyUtKa-dyZXq7-dyZXLW">Jon Connell on flickr </a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p><em>This essay is part of our occasional series <a href="https://theconversation.com/au/topics/zoom-out-51632">Zoom Out</a>, where authors explore key ideas in science and technology in the broader context of society and humanity.</em></p>
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<p>Middle-distance runner Caster Semenya will need to take hormone-lowering agents, or have surgery, if she wishes to continue her career in her chosen athletic events.</p>
<p>The Court of Arbitration in Sport (<a href="https://www.tas-cas.org/en/index.html">CAS</a>) <a href="https://www.tas-cas.org/en/general-information/news-detail/article/semenya-asa-and-iaaf-executive-summary.html">decided last week</a> to uphold a rule requiring athletes with certain forms of what they call “disorders of sex development” (DSD) – more commonly called “intersex” conditions – to lower their testosterone levels in order to still be eligible to compete as women in certain elite races. </p>
<p>The case was brought to CAS by Semenya, as <a href="https://theconversation.com/caster-semenyas-impossible-situation-testosterone-gets-special-scrutiny-but-doesnt-necessarily-make-her-faster-116407">she argued discrimination</a> linked to a 2018 decision preventing some women, including herself, from competing in some female events. </p>
<p>This ruling is flawed. On the basis of <a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">science and ethical reasoning</a>, there are ten reasons CAS’s decision does not stand up. </p>
<p>But first let’s take a quick look at the biology involved.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/caster-semenya-how-much-testosterone-is-too-much-for-a-female-athlete-116391">Caster Semenya: how much testosterone is too much for a female athlete?</a>
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<p><a href="https://www.bbc.co.uk/sport/athletics/48128682">Semenya underwent medical testing in 2009</a>: at the time she was told it was a doping test. The results are confidential, but it has been widely reported that she does have an intersex condition. It seems reasonable to assume she has XY chromosomes, as she is covered by the CAS ruling. Her testosterone levels have not been disclosed, but since the ruling applies to her, they must almost certainly be in what they classify as the “male range”.</p>
<p>According to CAS, the DSD regulations require athletes who want to compete in some female events, who have XY chromosomes and in whom testosterone has a biological effect to reduce their natural testosterone levels to an agreed concentration (below 5 nmol/L). </p>
<p>In women referred to as “46 XY DSD” – the most common intersex condition among female athletes – the presence of a Y chromosome causes the development of testes. These do not descend from the abdomen but do produce testosterone. However the receptors for testosterone are abnormal, with the result that the individual develops as female with a vagina, but no ovaries or uterus. Circulating testosterone may have no biological effect in the case of complete androgen insensitivity syndrome (AIS), or some effect in partial AIS.</p>
<p>Now let’s consider what’s wrong with the ruling. </p>
<h2>1. It confuses sex with gender</h2>
<p>Sex refers to biology, and gender refers to social role or self-identification. In sport, the definition of male and female used to be based solely on sex. <a href="https://bjsm.bmj.com/content/39/10/695.info">This was assessed anatomically in the 1960s</a>, then by biological tests such as the presence of a structure called a “Barr body” in cells (found only in genetic females), or the gene for testicular development. </p>
<p>Sex determination was abandoned in the 1990s in favour of gender. From the 2000 Sydney Olympics forwards, <a href="https://bjsm.bmj.com/content/39/10/695.info">there were no tests of gender other than self-identification</a>. </p>
<p>Caster Semenya’s gender is uncontroversially female. She is legally female, was from birth raised as female and identifies as a female. So, on the current definition, Semenya is a female. Indeed, there has been no question of her gender.</p>
<p>Sex determination itself is not simple, with chromosomal, gonadal (presence of ovaries or testes), or secondary sex characteristics (physical) all possible definitions that would include or exclude different groups. </p>
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Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
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<p>The CAS decision relates to “XY females with disorders of sexual development.” XY denotes the male sex chromosomes. This reverts back to the old biological categories. Behind this ruling is the view that Semenya is really a man competing in the women’s category. This view is embodied beautifully in an article entitled “<a href="https://quillette.com/2019/05/03/a-victory-for-female-athletes-everywhere/">A victory for female athletes everywhere</a>.” </p>
<p>But Semenya is a female by the rules used by the International Association of Athletics Federations (<a href="https://www.iaaf.org/home">IAAF</a>) – so she should be allowed to compete to the best of her potential in her category.</p>
<p>An alternative is to retreat to the old sex-based definition based on the presence of a Y chromosome. But that carries its own questions on definitions, and also comes at great political and individual cost. It would imply that Semenya is a male with a disorder of sexual development. </p>
<h2>2. It discriminates against some forms of hyperandrogenism</h2>
<p>Hyperandrogenism is a term used to describe high levels of testosterone. </p>
<p>But the CAS decision does not cover all forms of hyperandrogenism. It only refers to women who have XY chromosomes, such as <a href="https://www.nhs.uk/conditions/androgen-insensitivity-syndrome/">partial androgen insensitivity syndrome (AIS)</a>. </p>
<p>It does not cover a condition called <a href="https://rarediseases.info.nih.gov/diseases/1467/congenital-adrenal-hyperplasia">congenital adrenal hyperplasia</a>, which can cause elevated levels of testosterone in women with XX chromosomes. </p>
<p>The implication is that XX females are real women, while those with XY chromosomes are not. </p>
<h2>3. It’s based on inadequate science</h2>
<p>The significant problem in partial AIS is that although testosterone is elevated in the blood, the receptors for testosterone do not respond to the hormone in the usual way. That is why these individuals have typical external female physical characteristics. </p>
<p>While the testosterone may have some impact on how the body works, it is impossible to quantify how much effect it is having. For example, the difference testosterone makes between males and females in all events is estimated to be <a href="https://sportsscientists.com/2019/05/on-dsds-the-theory-of-testosterone-performance-the-cas-ruling-on-caster-semenya/">up to 12% (all other items being equal)</a>. But Semenya’s best time is only <a href="https://shows.pippa.io/the-science-of-sport-podcast/episodes/the-caster-semenya-decision-explained">2% faster than her competitors</a>. It is not possible to determine how much of this 2% is due to testosterone, and how much due to other factors about her as an athlete, or her psychology.</p>
<p>The study on which the current decision is based contains only correlations and is flawed in several ways, with a call for its <a href="https://doi.org/10.1007/s40318-019-00143-w">retraction on scientific grounds</a>. It is a single study, conducted by the IAAF and the full data have not been released for independent replication. The sole ground for the claim that Semenya derives “material androgenizing effect” (that is, biological impact) appears to be the “statistical over-representation of female athletes with 46 XY DSD” in the relevant events, as documented in this single, poorly conducted study.</p>
<p>Even if Semenya’s times were to drop after the reduction of testosterone, this could be a side-effect of the drugs used to reduce testosterone, or a function of reductions in mental or physical functions which are themselves legitimate entitlements of the athlete. </p>
<p>Her body has grown up in the presence of a certain level of testosterone of uncertain function. Our bodies are complex, and still poorly understood. A change of this kind may lead to unexpected results. Some of these reductions in functions may be unjust. </p>
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Read more:
<a href="https://theconversation.com/testosterone-why-defining-a-normal-level-is-hard-to-do-113587">Testosterone: why defining a 'normal' level is hard to do</a>
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<p>No one has given a complete description of the role of testosterone in someone like Semenya, nor how much it ought to be reduced to achieve a supposedly fair outcome. The comparisons are only with XX chromosome women, who have a very different physiology and normal functioning testosterone receptors. </p>
<p>Put simply, a level of 5 nMol/L testosterone is meaningless in Semenya’s case because the receptors are not responding in the usual way. It does not achieve a “<a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">level hormonal playing field</a>”. </p>
<p>This is an example of “decimal point science smokescreen.” There is the impression of much greater confidence and sensitivity than the science warrants by appealing to figures with multiple decimal points. The science around testosterone in intersex conditions is poorly understood, let alone as it applies to individuals. This is a level chosen for convenience, not a level that will negate any perceived advantage, but go no further.</p>
<h2>4. It’s inconsistent with values of sport and human rights</h2>
<p>The self-professed values of sport include the <a href="https://www.wada-ama.org/sites/default/files/resources/files/wada_ethicspanel_setofnorms_oct2017_en.pdf">development of one’s own talent</a> . </p>
<p>Yet Semenya is asked to cobble her natural potential as a female competitor. She must take risky biological interventions to reduce her performance. </p>
<p>The United Nations Human Rights Council has stated that the regulations <a href="https://theconversation.com/its-not-clear-where-human-rights-fit-in-the-legal-ruling-on-athlete-caster-semenya-116417">contravene human rights</a> “including the right to equality and non-discrimination […] and full respect for the dignity, bodily integrity and bodily autonomy of the person”. </p>
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Read more:
<a href="https://theconversation.com/its-not-clear-where-human-rights-fit-in-the-legal-ruling-on-athlete-caster-semenya-116417">It's not clear where human rights fit in the legal ruling on athlete Caster Semenya</a>
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<h2>5. It’s inconsistent with treatment of other athletes</h2>
<p>Other women with disorders resulting in higher than expected levels of testosterone, such as congenital adrenal hyperplasia, are not required to reduce their biological advantage.</p>
<p>Competitors with genetic mutations causing increases in red blood cell mass, and who experience enhanced oxygen-carrying capacity as a result, are not required to reduce their biological levels. </p>
<p>The Finnish skier Eero Mäntyranta had a genetic mutation that boosted his red blood cell count by 25-50% (he produced more blood hormone erythropoetin, or EPO). He and won several Olympic medals with this <a href="https://bjsm.bmj.com/content/bjsports/37/3/192.full.pdf">natural form of doping</a>. </p>
<h2>6. It’s unjust</h2>
<p>The decision is unjust in several ways. </p>
<p>Firstly, it was the IAAF which moved from sex to gender definition of female in 1990s. Semenya has entered competition, trained and competed fairly under the rules. To change them now will be undermine her capacity to compete, work and live, after a lifetime of investment. </p>
<p>If the rules are to be changed, they should not affect athletes who agreed to the current rules, but future athletes. There should be a “grandmother clause” for current athletes, like Semenya or else they are unfairly burdened by the bungles of the IAAF. Even if these rules could be considered justified, they should apply to future athletes as soon as possible after puberty.</p>
<p>Secondly, justice is about giving priority to the worst off in our society – but this ruling adds disadvantage to the worst off. Those with intersex conditions are already stigmatised, discriminated against, in many cases cannot bear children even if they want to. They are the socially disadvantaged. This ruling adds further discrimination and disadvantage.</p>
<p>Thirdly, it sets back integration of intersex people, by stigmatising and marginalising them. We have told them: be yourself, society will accept you. But this sends the message: you are really male, we don’t accept you, you should be castrated.</p>
<h2>7. It is an inappropriate reaction to fear of a ‘slippery slope’</h2>
<p>At the heart of this decision is the fear of displacement of cisgender women on the podia by increasing debate over transgender athletes. <a href="https://quillette.com/2019/05/03/a-victory-for-female-athletes-everywhere/">The concern is</a> that if “XY females” are allowed to compete in the female category, formerly male transgender females will follow and rob cisgender women of their medals. </p>
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Read more:
<a href="https://theconversation.com/explainer-what-does-it-mean-to-be-cisgender-103159">Explainer: what does it mean to be 'cisgender'?</a>
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<p>This is a separate issue. Transgender athletes have normal testosterone receptors and would have grown up in the presence of male levels of testosterone acting on normal receptors. Intersex athletes have not grown up in this way and are typically raised as female.</p>
<p>The perceived problem of transgender domination of female sports can be dealt with by separate rules that do not disadvantage existing intersex athletes, though they will raise contentious issues of their own. </p>
<h2>8. It is disproportionate and unreasonable</h2>
<p>All methods of reducing testosterone involve some risk. For example, the administration of <a href="https://www.ncbi.nlm.nih.gov/pubmed/2960241">high-dose birth control medication</a> involves risk of clots, including fatal lung clots. </p>
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Read more:
<a href="https://theconversation.com/how-to-choose-the-right-contraceptive-pill-for-you-87614">How to choose the right contraceptive pill for you</a>
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<p>These interventions interfere with a normally functioning organism for highly uncertain benefits to other people. This is disproportionate and unreasonable.</p>
<h2>9. It can’t be implemented</h2>
<p>The World Medical Association has advised doctors <a href="https://www.wma.net/news-post/wma-reiterates-advice-to-physicians-not-to-implement-iaaf-rules-on-classifying-women-athletes/">not to administer</a> testosterone-lowering interventions, describing the regulation as “<a href="https://www.wma.net/news-post/wma-urges-physicians-not-to-implement-iaaf-rules-on-classifying-women-athletes/">contrary to international medical ethics and human rights standards</a>”. </p>
<p>Their use would be “off label” and is for purposes other than the athlete’s health. The rules involve “strict liability” which means the athlete is responsible for any failure to comply, even if unintentional and outside of the athlete’s control.</p>
<h2>10. There are fairer, safer alternatives</h2>
<p>I have argued athletes <a href="https://www.bmj.com/content/347/bmj.f6150">should be able take performance-enhancing substances</a> within the normal physiological range. This would mean cisgender female athletes could take testosterone up to 5 nMol/L. This would reduce any advantage Semenya may have.</p>
<p>It would also deal with the problem that <a href="https://link.springer.com/article/10.1007/s40279-014-0247-x">up to 40%</a> of elite athletes are currently doping anyway. Semenya received the <a href="https://www.olympic.org/london-2012/athletics/800m-women">London 2012 800m gold medal</a> after the <a href="https://www.reuters.com/article/us-doping-russia-savinova/savinova-stripped-of-london-games-800m-gold-for-doping-idUSKBN15P1EO">original winner was disqualified for doping</a>. It is highly likely that some of her current competitors are also doping.</p>
<p>No doubt part of the resistance to allowing Semenya to “naturally dope” is that it will encourage other athletes to engage in doping. But they already are, and a better approach to “de-enhancing” Semenya is to <a href="https://www.bmj.com/content/347/bmj.f6150">regulate and monitor the enhancement of other athletes</a>. </p>
<h2>Spectacular fail</h2>
<p>Rarely does a public policy fail so spectacularly on so many ethical grounds. </p>
<p><a href="https://www.tas-cas.org/fileadmin/user_upload/Media_Release_Semenya_ASA_IAAF_decision.pdf">CAS acknowledged</a> that its decision constituted discrimination: </p>
<p>“The panel found that the DSD Regulations are discriminatory but the majority of the panel found that, on the basis of the evidence submitted by the parties, such discrimination is a necessary, reasonable and proportionate means of achieving the IAAF’s aim of preserving the integrity of female athletics in the restricted events.”</p>
<p>The UNHRC <a href="https://documents-dds-ny.un.org/doc/UNDOC/LTD/G19/072/46/PDF/G1907246.pdf?OpenElement">has refuted this claim of proportionality</a>: “there is no clear relationship of proportionality between the aim of the regulations and the proposed measures and their impact”.</p>
<p>This ruling is neither necessary, reasonable nor proportionate. It is simply unjust discrimination.</p>
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<strong>
Read more:
<a href="https://theconversation.com/caster-semenyas-impossible-situation-testosterone-gets-special-scrutiny-but-doesnt-necessarily-make-her-faster-116407">Caster Semenya's impossible situation: Testosterone gets special scrutiny but doesn't necessarily make her faster</a>
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<p><em>Thanks to Michelle Telfer and Ken Pang for comments</em></p>
<p><em>This article builds on arguments presented in the paper <a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">Time to re-evaluate gender segregation in athletics?</a>.</em></p><img src="https://counter.theconversation.com/content/116448/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Julian Savulescu receives funding from Uehiro Foundation on Ethics and Education and the Wellcome Trust. </span></em></p>Athlete Caster Semenya will need to take hormone-lowering agents, or have surgery, if she wishes to continue her career in her chosen events. But the decision to ban her is flawed on many grounds.Julian Savulescu, Visiting Professor in Biomedical Ethics, Murdoch Children's Research Institute; Distinguished Visiting Professor in Law, University of Melbourne; Uehiro Chair in Practical Ethics, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1123262019-02-28T10:14:31Z2019-02-28T10:14:31Z16p11.2: rare genetic changes linked to autism now connected to higher chance of other psychiatric disorders<figure><img src="https://images.theconversation.com/files/261199/original/file-20190227-150688-e8d7t5.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/hand-scientist-replacing-dna-genetic-engineering-1022905567">andriano.cz/Shutterstock</a></span></figcaption></figure><p>In most of the trillion cells that make up our bodies, 23 pairs of chromosomes store the vital strands of DNA needed to make our bodies grow and function properly. But if the amount of genetic material within our cells is a bit too much or too little, then this can potentially interfere with normal development. It can also lead to syndromes such as Down Syndrome, 22q11.2 Deletion Syndrome – the <a href="https://theconversation.com/22q11-2-deletion-the-most-common-syndrome-you-have-never-heard-of-76124">second most common syndrome after Down</a> – and 16p11.2 deletion or duplication syndrome.</p>
<p>The name 16p11.2 explains where the missing or extra genetic parts (otherwise known as copy number variants or CNVs) are located in the DNA of people with these deletions or duplications. Those with 16p11.2 deletion have a tiny part of genetic material missing on one of their two number 16 chromosomes, while people with 16p11.2 duplication have an extra copy of this part. </p>
<p>Think of it as if DNA is a bookcase and the books are the chromosomes. Deletions are when a paragraph within a book is missing, and duplications are when they are repeated. p11.2 specifies the exact location – “p” indicates it is in the first half of the 16th book (chromosome 16) in this bookcase, “11” which chapter and “2” which paragraph has some text missing or extra. </p>
<p>Problems commonly associated with a 16p11.2 deletion or duplication include developmental delay, issues with gross and fine movements, and low muscle tone (known as hypotonia). Epilepsy and difficulties with speech and language development have also been reported.</p>
<p>Most people who are tested for 16p11.2 come to the attention of medical professionals due to <a href="https://www.ncbi.nlm.nih.gov/pubmed/25064419">developmental delay or autistic behaviour</a>. In fact, 16p11.2 deletion and duplication are among <a href="https://www.ncbi.nlm.nih.gov/pubmed/23054248">the strongest genetic risk factors</a> for autism. The prevalence rate of autism in 16p11.2 deletions and duplications is <a href="https://www.ncbi.nlm.nih.gov/pubmed/30664628">much higher</a> (15 to 26%) than in the general population <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Prevalence+of+Parent-Reported+ASD+and+ADHD+in+the+UK%3A+Findings+from+the+Millennium+Cohort+Study">(~1.7%)</a>. </p>
<p>16p11.2 duplication, but not deletion, is <a href="https://www.ncbi.nlm.nih.gov/pubmed/24311552">also related to</a> risk for another mental health condition: schizophrenia. It has been unclear, however, if 16p11.2 deletion and duplication are related to risk for other mental health conditions. </p>
<h2>Psychiatric disorders</h2>
<p>We have recently published the findings of <a href="https://doi.org/10.1038/s41398-018-0339-8">the largest study to date</a> which examined the kind and frequency of a range of psychiatric conditions in children with 16p11.2 deletion or duplication. With the help of families from the UK and US, we studied 217 children with the deletion and 77 of their siblings without the deletion, as well as 114 children with the duplication and 32 of their siblings without the duplication.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/261230/original/file-20190227-150708-gsfc2m.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">
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<span class="caption">In 16p11.2, part of the DNA on chromosome 16 is missing or repeated.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/dna-helix-break-replace-concept-genetic-1036880737?src=oNSVr-ZEMYsA5vMJnhgcvw-1-32">Anusorn Nakdee/Shutterstock</a></span>
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<p>This work, which was an international collaboration between the UK-based <a href="https://www.cardiff.ac.uk/mrc-centre-neuropsychiatric-genetics-genomics/research/themes/developmental-disorders/echo-study-cnv-research">Cardiff ECHO</a> and <a href="http://imagine-id.org/">IMAGINE ID</a> studies, the 16p11.2 European Consortium and the <a href="https://simonsvipconnect.org/">Simons VIP Consortium</a> in the US, builds on previous research into 16p11.2. Our new findings indicate that the mental health consequences of the deletion and duplication are broad, and include a high frequency of a range of mental health problems including attention deficit hyperactivity disorder (ADHD). </p>
<p>Our research shows that children with the deletion or duplication have a higher chance of having at least one psychiatric disorder than their siblings without the CNV. Particularly, risk of ADHD is higher in children with the deletion or duplication. In addition, we found that children with the deletion or duplication had similar frequency of autism, replicating previous findings. </p>
<p>Our findings also highlight that recognition of the fact that 16p11.2 deletion and duplication can lead to mental health problems is important, so that diagnosis and treatment early in development can be put in place. But it must be noted that not all children with 16p11.2 deletion or duplication in our study had psychiatric problems. Future research is needed to understand why some people with these deletions or duplications do develop mental health problems while others do not. This could help with the development of early intervention for mental health problems to reduce the risk of serious and engrained psychiatric disorders down the line. </p>
<h2>Further research</h2>
<p>16p11.2 CNVs are relatively rare. They occur in three out of every 10,000 people. It takes a lot of time and effort to build a study with sufficient numbers of people with these rare conditions and it isn’t easy for researchers to obtain funding for such projects. </p>
<p>But it is very important to have this information so that medical professionals know how these patients are affected, and how to best help them. Research like ours can also help people and their families interpret certain behaviours or symptoms associated with these syndromes and know when to seek help. In addition, families need this information to empower them. Because these conditions are so rare, their doctor may not be aware of 16p11.2.</p>
<p>We are keen to better understand how young people with 16p11.2 deletion and duplication develop into adolescence and adulthood, and hope to be able to see the children who took part in our study again to find out how they are doing. Our ECHO study is also interested in other rare genetic conditions, such as deletion or duplication on chromosomes 1, 3, 9, 15 and 22. By comparing these different CNVs we hope to better understand how things like learning and development and mental health present in similar ways for all groups, and how certain CNVs have specific outcomes. </p>
<p>To find out more about our studies of individuals with 16p11.2 deletion or duplication and other genetic conditions, please visit our <a href="https://www.cardiff.ac.uk/mrc-centre-neuropsychiatric-genetics-genomics/research/themes/developmental-disorders/echo-study-cnv-research">website</a>, or contact us directly at echo@cardiff.ac.uk or on +44 (0)29 2068 8038.</p><img src="https://counter.theconversation.com/content/112326/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Maria Niarchou receives funding from Wellcome Trust. This project received funding from the Medical Research Council, the Wellcome Trust and the Waterloo Foundation.
The investigators would like to thank all the children and families who have taken part and shared their experiences of living with 16p11.2 deletion and duplication conditions. We also thank NHS Medical Genetic clinics, Unique and the UK 16p11.2 network for their support.</span></em></p><p class="fine-print"><em><span>Marianne van den Bree has previously received funding from MRC, MRF, Wellcome Trust, National Institute for Mental Health, The Baily Thomas Charitable Trust, the Waterloo Foundation and European Cooperation in Science and Technology (COST).
</span></em></p>16p11.2 deletion or duplication syndrome occurs in three out of every 10,000 people.Maria Niarchou, Research Associate, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityMarianne van den Bree, Professor, Division of Psychological Medicine and Clinical Neurosciences, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/959892018-08-30T10:49:40Z2018-08-30T10:49:40ZMath shows how DNA twists, turns and unzips<figure><img src="https://images.theconversation.com/files/233904/original/file-20180828-86138-1y73dsr.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">DNA knot as seen under the electron microscope.</span> <span class="attribution"><span class="source">Javier Arsuaga</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>If you’ve ever seen a picture of a DNA molecule, you probably saw it in its famous B-form: two strands coiling around each other in a right-handed fashion to form a double helix. But did you know that DNA can change its shape?</p>
<p>DNA molecules, which carry the genetic code of an organism, have to be tightly packed to fit inside a cell. However, every few hours, the cell produces a faithful copy of its genome in preparation for cell division. This replication process puts tremendous stress on the DNA and can change its shape in lethal ways.</p>
<p>As a mathematician and a biologist, I am interested in how mathematics can describe the many shapes of DNA, as well as cellular processes like DNA replication. The answers to these questions inspire new mathematics and possibly a better understanding of the molecule of life.</p>
<h2>The shape of DNA</h2>
<p>To understand the mathematics of the shape of DNA, you need to consider both its geometry and its topology. These are related but distinct concepts. </p>
<p>Geometry describes an object at a particular moment in time – frozen rigid in space, like a sculpture. In the cell, the DNA helix coils upon itself, or “supercoils.” The way DNA folds and coils encodes valuable geometric information that can be crucial to <a href="https://doi.org/10.1093/hmg/ddy164">control the way genes are expressed</a>. </p>
<p>Topology describes how an object deforms smoothly, as if made out of clay without making new holes or breaks. For example, imagine a rubber band tumbling around in a whirlpool. As the water swirls, the rubber band twists, stretches and shrinks. All of the shapes adopted by the band as it moves are topologically identical, but geometrically different.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=205&fit=crop&dpr=1 600w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=205&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=205&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=258&fit=crop&dpr=1 754w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=258&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=258&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">These three objects have very different geometries, but are topologically the same – meaning that the objects can be bent or twisted from one shape into another.</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Merely copying DNA creates a large number of shape-related problems, but <a href="http://www.thoughtco.com/dna-replication-3981005">textbook images</a> rarely illustrate this topological conundrum. </p>
<p>During the cell cycle, each chromosome is replicated into two identical copies. In order for that to happen, the DNA helix must unwind, causing stress on the DNA. DNA responds to this stress by supercoiling, just like an old telephone cord. But the cell cannot tolerate too much supercoiling. If DNA contorts too much, the cell will suffer. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=281&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=281&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=281&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=353&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=353&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=353&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Sketch of a right handed DNA double helix (left). The opening of the helix, indicated by a triangle, causes the DNA to supercoil (right). A supercoil occurs when the axis of the helix, indicated in purple, coils upon itself.</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>A DNA molecule can be linear – as in the case of human chromosomes – or circular. Examples of circular DNA molecules include bacterial chromosomes and human mitochondrial DNA. If the DNA molecule is circular, then cellular processes such as replication may <a href="http://doi.org/10.1093/nar/gkx1137">tie DNA into knots</a> or <a href="http://doi.org/10.1098/rstb.2003.1363">links</a>, like rings in a keychain. DNA knots and links can <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC146338/?report=reader">cause cells to malfunction</a> or even die.</p>
<h2>Stabilizing DNA</h2>
<p>Consider the bacterium <em>E. coli</em>. Its genetic code is found in one single DNA chromosome. In <em>E. coli</em> and other bacteria, the DNA double helix closes into a circle, like a twisted rubber band. </p>
<p>Replication of the <em>E. coli</em> chromosome can happen in as short as 20 minutes in a test tube. But when a circular chromosome is replicated, the process yields two <a href="https://www.sciencedirect.com/science/article/pii/S0092867400817407">interlinked chromosomes</a>. That is, the new chromosomes form two rings linked through each other. The new chromosomes must unlink before the cell divides into two cells. Otherwise they would either break on the way to their target cell, or one cell would inherit two interlinked copies of one chromosome and the other one would be missing the chromosome altogether. </p>
<p>The cell recruits enzymes to unlink the DNA. Enzymes called topoisomerases and recombinases act as scissors and glue for DNA. They can change the geometry and topology of DNA, thus maintaining a stable genome. In <em>E. coli</em>, topoisomerases work tirelessly during and after replication to maintain healthy levels of supercoiling and to safely unlink the chromosomes.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=227&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=227&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=227&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=285&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=285&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=285&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Replication of a circular DNA molecule. The arrows show the direction of replication (left). The new molecules interlink in this process (right).</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>When topoisomerases don’t work</h2>
<p>When topoisomerases don’t work, the cell eventually dies. This makes them good targets for <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536865/">drug design</a>. But cells have different types of topoisomerases and other enzymes such as recombinases that may be able to come to the rescue. For example, <a href="http://emboj.embopress.org/content/26/19/4228.long">we showed</a> that, in <em>E. coli</em> cells where the topoisomerases in charge of unlinking have been disabled, other enzymes called site-specific recombinases can untie replication links. </p>
<p>Both topoisomerases and site-specific recombinases bind double stranded DNA and can change its shape by introducing breaks. Type II <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418509/">topoisomerases</a> introduce a break along the DNA molecule and transport another piece of DNA through the break before resealing it. <a href="https://www.annualreviews.org/doi/full/10.1146/annurev.biochem.73.011303.073908?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed">Site-specific recombinases</a> attach to two sites along the DNA, introduce one cut in each, then reconnect the ends. </p>
<p>My lab uses mathematics and computer simulations to understand how these enzymes unlink DNA molecules. While the local action is well understood on a biochemical level, how exactly enzymes simplify the topology of DNA is still a mystery. </p>
<p>In one of our studies, we focused on <a href="http://emboj.embopress.org/content/26/19/4228.long"><em>E. coli</em> cells where the topoisomerases don’t work</a>. <a href="http://www.pnas.org/content/110/52/20906.long">We showed</a> how to untie a replication link in the minimum number of steps. </p>
<p>In general, there can be many unlinking pathways. We use computer simulations to <a href="https://www.nature.com/articles/s41598-017-12172-2">assign probabilities</a> to each pathway. Our work indicates that, in the case of replication links, the simplest pathway is the one that enzymes most likely take.</p>
<p>Sophisticated mathematical methods can help explain how enzymes unlink DNA. Without mathematical modeling, researchers would be restricted to simplified models suggested by biological experiments.</p><img src="https://counter.theconversation.com/content/95989/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mariel Vazquez receives funding from the National Science Foundation (CAREER DMS 1519375, DMS 1716987 and DMS 1817156).</span></em></p>Mathematical models can describe the many shapes of DNA, as well as cellular processes like DNA replication.Mariel Vazquez, Professor of Mathematics, University of California, DavisLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/921942018-03-27T13:44:14Z2018-03-27T13:44:14ZWhy genes don’t hold all the answers for biologists<figure><img src="https://images.theconversation.com/files/209732/original/file-20180309-30954-yyfm87.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/embryonic-stem-cell-colony-cellular-therapy-512201353?src=zArM-TGfjOHpUr3eXMLYpQ-1-15">Shutterstock</a></span></figcaption></figure><p>It is still widely believed that the gene is the foundation of life – that its discovery has provided information about how all living beings are controlled by the genetic factors they inherit from their parents. </p>
<p>But scientists and philosophers are beginning to doubt the relevance of the gene for understanding biology. </p>
<p>Despite being central to the subject for over a century, there has never been a universally accepted, constant definition of what genes actually are. From the beginning, scientists have tried to link human characteristics to genes, but had limited success in establishing stable connections. </p>
<p>Instead, our understanding about genes and how they determine characteristics, including hereditary diseases, has been in continual flux. In our new book <a href="http://press.uchicago.edu/ucp/books/book/chicago/G/bo20952390.html">The Gene: From Genetics to Postgenomics</a>, we look back at this changing history of genetics. Most recently, technologies <a href="https://ghr.nlm.nih.gov/primer/genomicresearch/sequencing">have emerged</a> which allow the sequencing of whole genomes rapidly and cheaply, and the study of complex bio-molecular systems as they evolve. </p>
<p>As a consequence, the function of genes is now understood to depend on systems of <a href="http://www.cam.ac.uk/research/news/scientists-discover-how-epigenetic-information-could-be-inherited">epigenetic inheritance</a> and environmental signalling. Whether a gene is activated (or not) to produce a protein depends on how it is “packaged” into chromosomes, and information the organism <a href="https://theconversation.com/epigenetics-can-stress-really-change-your-genes-55898">receives from the environment</a>.</p>
<p>The most important insight associated with the <a href="https://www.dna-worldwide.com/resource/160/history-dna-timeline">discovery of the gene</a> in the early 20th century was that the order in which genes operate does not reflect the order in which the human (or plant or animal) body develops. One gene is not linked to one physical trait – many genes control many traits. Likewise, a single trait is often controlled by hundred of genes forming complex networks of interaction. </p>
<p>The study of genes has been complicated from the start. After years of detailed study in the mid-19th century, Austrian monk Gregor Mendel’s <a href="https://www.nature.com/scitable/topicpage/gregor-mendel-and-the-principles-of-inheritance-593">original laws</a>, which were rediscovered by three botanists in 1900, and are still taught in schools and universities around the world, were not really taken as a description of reality by early geneticists. </p>
<p>Instead, knowledge of what happened to traits if you crossed purebred organisms simply served as a starting point for mapping genes onto chromosomes – and for studying their interactions in increasingly complicated experiments. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/QmSJGhPTB5E?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
</figure>
<p>Using insects, bread mould, bacteria and viruses as their model organisms, scientists in the 1930s and 1940s began transferring genes, uncovering different reactions. Radiation was also used by some scientists in the early 1930s to measure their size. </p>
<p>With the subsequent identification of DNA as the hereditary material in 1953, it became possible to directly access and manipulate the genetic code. Even with this discovery, however, it turned out that genes are not well-defined stretches of DNA that translate directly into the structure of proteins. </p>
<p>Genes may consist of separate building blocks that are distributed over the genome and have different functions. They may overlap and be read in a variety of ways. Their products in turn, may be cut into pieces and then spliced together again in a variety of ways. All of these activities depend on a variety of signals – from within the cell, from other cells, or from the environment.</p>
<p>It is these insights into genetic mechanisms which made a single rigid definition of the gene impossible. Instead, experimental systems were developed in which genes were defined flexibly in order to track processes involved in the development and evolution of organisms. </p>
<h2>Gene variation</h2>
<p>What it is to be a gene varies widely, just as everything else does in biology, since genes are not so much autonomous units of life, but themselves a <a href="https://theconversation.com/what-makes-us-human-genetics-culture-or-both-14505">product of evolution</a>. </p>
<p>Biologists will of course continue to talk about genes in the future. But genes will no longer be seen as the blueprint for life, even if technological and medical applications of gene technology suggest this. Instead, they are increasingly seen as only one of the many resources that organisms make use of in adapting to challenges in their environments. </p>
<p>In order to address medical and environmental problems, scientists will therefore need to work as part of bigger and bigger teams, with computer scientists, physicists, biochemists and evolutionary biologists. This work will be time consuming and hard to explain. They will need to show the public more clearly that sometimes research is an exercise that does not produce a clear path to the future. </p>
<p>Knowing more about the gene will always involve surprises. The history of the gene, once believed to be one of the biggest triumphs of 20th century science, shows how messy and unpredictable science is.</p><img src="https://counter.theconversation.com/content/92194/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Staffan Müller-Wille has received funding from the British Council, British Academy, Wellcome Trust, Volkswagen Foundation and the Karl Schaedler Foundation. </span></em></p><p class="fine-print"><em><span>Hans-Jörg Rheinberger 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>They were discovered over 100 years ago – but we still don’t know exactly what genes are.Staffan Müller-Wille, Associate Professor, University of ExeterHans-Jörg Rheinberger, Emeritus Scientific Member, Max Planck Institute for the History of ScienceLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/901252018-01-17T14:09:21Z2018-01-17T14:09:21ZThe Y chromosome is disappearing – so what will happen to men?<p>The Y chromosome may be a symbol of masculinity, but it is becoming increasingly clear that it is anything but strong and enduring. Although it carries the <a href="https://ghr.nlm.nih.gov/gene/SRY">“master switch” gene, SRY,</a> that determines whether an embryo will develop as male (XY) or female (XX), it contains very few other genes and is the only chromosome not necessary for life. Women, after all, manage just fine without one.</p>
<p>What’s more, the Y chromosome has degenerated rapidly, leaving females with two perfectly normal X chromosomes, but males with an X and a shrivelled Y. If the same rate of degeneration continues, the Y chromosome has just <a href="https://link.springer.com/article/10.1007%2Fs10577-011-9252-1">4.6m years left</a> before it disappears completely. This may sound like a long time, but it isn’t when you consider that life has existed on Earth for 3.5 billion years.</p>
<p>The Y chromosome hasn’t always been like this. If we rewind the clock to 166m years ago, to the very first mammals, the story was completely different. The early “proto-Y” chromosome was originally the same size as the X chromosome and contained all the same genes. However, Y chromosomes have a fundamental flaw. Unlike all other chromosomes, which we have two copies of in each of our cells, Y chromosomes are only ever present as a single copy, passed from fathers to their sons.</p>
<p>This means that genes on the Y chromosome cannot undergo genetic recombination, the “shuffling” of genes that occurs in each generation which helps to eliminate damaging gene mutations. Deprived of the benefits of recombination, Y chromosomal genes degenerate over time and are eventually lost from the genome. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=470&fit=crop&dpr=1 600w, https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=470&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=470&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=591&fit=crop&dpr=1 754w, https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=591&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/201978/original/file-20180115-101502-1tinnv3.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=591&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Chromosome Y in red, next to the much larger X chromosome.</span>
<span class="attribution"><span class="source">National Human Genome Research Institute</span></span>
</figcaption>
</figure>
<p>Despite this, recent research has shown that the Y chromosome has developed some pretty convincing mechanisms to “put the brakes on”, slowing the rate of gene loss to a possible standstill. </p>
<p>For example, a recent Danish study, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591018/">published in PLoS Genetics</a>, sequenced portions of the Y chromosome from 62 different men and found that it is prone to large scale structural rearrangements allowing “gene amplification” – the acquisition of multiple copies of genes that promote healthy sperm function and mitigate gene loss.</p>
<p>The study also showed that the Y chromosome has developed unusual structures called “palindromes” (DNA sequences that read the same forwards as backwards – like the word “kayak”), which protect it from further degradation. They recorded a high rate of “gene conversion events” within the palindromic sequences on the Y chromosome – this is basically a “copy and paste” process that allows damaged genes to be repaired using an undamaged back-up copy as a template. </p>
<p>Looking to other species (Y chromosomes exist in mammals and some other species), a <a href="http://www.annualreviews.org/doi/abs/10.1146/annurev-genet-112414-055311">growing</a> body of evidence indicates that Y-chromosome gene amplification is a general principle across the board. These amplified genes play critical roles in sperm production and (at least in rodents) in regulating offspring sex ratio. Writing in <a href="https://academic.oup.com/mbe/article-abstract/34/12/3186/4211124">Molecular Biology and Evolution</a> recently, researchers give evidence that this increase in gene copy number in mice is a result of natural selection.</p>
<p>On the question of whether the Y chromosome will actually disappear, the scientific community, like the UK at the moment, <a href="https://link.springer.com/article/10.1007%2Fs10577-011-9252-1">is currently divided</a> into the “leavers” and the “remainers”. The latter group argues that its defence mechanisms do a great job and have rescued the Y chromosome. But the leavers say that all they are doing is allowing the Y chromosome to cling on by its fingernails, before eventually dropping off the cliff. The debate therefore continues. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=412&fit=crop&dpr=1 600w, https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=412&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=412&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=517&fit=crop&dpr=1 754w, https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=517&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/202283/original/file-20180117-53328-kim7f9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=517&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Mole voles have no Y chromosomes.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Northern_mole_vole#/media/File:Ellobius_talpinus.jpg">wikipedia</a></span>
</figcaption>
</figure>
<p>A leading proponent of the leave argument, <a href="http://www.latrobe.edu.au/she/staff/profile?uname=jgraves">Jenny Graves from La Trobe University</a> in Australia, claims that, if you take a long-term perspective, the Y chromosomes are inevitably doomed – even if they sometimes hold on a bit longer than expected. In a 2016 paper, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094562/">she points out</a> that <a href="https://en.wikipedia.org/wiki/Muennink%27s_spiny_rat">Japanese spiny rats</a> and mole voles have lost their Y chromosomes entirely – and argues that the processes of genes being lost or created on the Y chromosome inevitably lead to fertility problems. This in turn can ultimately drive the formation of entirely new species.</p>
<h2>The demise of men?</h2>
<p>As we argue in a chapter in a <a href="http://www.springer.com/us/book/9783319704968">new e-book</a>, even if the Y chromosome in humans does disappear, it does not necessarily mean that males themselves are on their way out. Even in the species that have actually lost their Y chromosomes completely, males and females are both still necessary for reproduction. </p>
<p>In these cases, the SRY “master switch” gene that determines genetic maleness has moved to a different chromosome, meaning that these species produce males without needing a Y chromosome. However, the new sex-determining chromosome – the one that SRY moves on to – should then start the process of degeneration all over again due to the same lack of recombination that doomed their previous Y chromosome. </p>
<p>However, the interesting thing about humans is that while the Y chromosome is needed for normal human reproduction, many of the genes it carries are not necessary if you use assisted reproduction techniques. This means that genetic engineering may soon be able to <a href="https://www.ncbi.nlm.nih.gov/pubmed/26823431">replace the gene function of the Y chromosome</a>, allowing same-sex female couples or infertile men to conceive. However, even if it became possible for everybody to conceive in this way, it seems highly unlikely that fertile humans would just stop reproducing naturally. </p>
<p>Although this is an interesting and hotly debated area of genetic research, there is little need to worry. We don’t even know whether the Y chromosome will disappear at all. And, as we’ve shown, even if it does, we will most likely continue to need men so that normal reproduction can continue. </p>
<p>Indeed, the prospect of a “farm animal” type system where a few “lucky” males are selected to father the majority of our children is certainly not on the horizon. In any event, there will be far more pressing concerns over the next 4.6m years.</p><img src="https://counter.theconversation.com/content/90125/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Darren Griffin has current collaborative grants with JSR Genetics and Topigs Norsvin. Including BBSRC and Innovate UK funding.
Enhancing oocyte quality to improve assisted reproduction in peri-pubertal pigs and cattle (BBSRC) - About to start. £335,000
Technology Strategy Board (BBSRC - Inovate UK). Pig IVF and genetics: A route to global sustainability. </span></em></p><p class="fine-print"><em><span>Peter Ellis receives funding from the BBSRC.</span></em></p>Research shows that the Y chromosome may be able to protect itself from extinction in the short term. But what about in a future where we all reproduce artificially?Darren Griffin, Professor of Genetics, University of KentPeter Ellis, Lecturer in Molecular Biology and Reproduction, University of KentLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/900672018-01-15T16:06:50Z2018-01-15T16:06:50ZRevealed: adult leukaemia can be caused by gene implicated in breast cancer and obesity<figure><img src="https://images.theconversation.com/files/201962/original/file-20180115-101505-1tj72tw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">AML under the microscope. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/blood-smear-under-microscopy-showing-on-550330186?src=1RRsQj8cvHJjbcMN_p5BAw-1-37">Medtech THAI STUDIO LAB 249</a></span></figcaption></figure><p>When people think of leukaemia, they usually think of blood cancers that affect children. These mostly come under the category of acute lymphoblastic leukaemia – or ALL – and are different to the group of blood cancers which predominantly affect adults over the age of 60, known as acute myeloid leukaemia (AML). </p>
<p>AML accounts for about 90% of all leukaemias in adults, though it affects some children too. With <a href="http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/leukaemia-aml/incidence#heading-One">some 3,000</a> new cases each year in the UK alone, it is tougher to treat than ALL. </p>
<p>Where advances in ALL treatment have raised survival rates to <a href="https://www.stjude.org/disease/acute-lymphoblastic-leukemia-all.html">around 90%</a> over the past several decades, the rates for surviving the less well researched AML are <a href="https://www.healthline.com/health/acute-myeloid-leukemia-survival-rates-outlook">more like</a> 65%. Older adults respond least well to treatment, with only 5% of over-65s surviving more than five years. </p>
<p>I am therefore pleased to report a promising discovery. Work in which I have been involved has shown that a particular gene can play a critical role in the development of the disease. This could be the precursor to a breakthrough that could be life-saving for patients. </p>
<h2>Cells and treatments</h2>
<p>Your bone marrow contains stem cells which divide and differentiate into red blood cells and the main groups of white blood cells – myeloid cells, neutrophils and lymphocytes. Normally this happens in a very controlled manner, ensuring you have all the red blood cells needed to carry oxygen around your body, and all the white blood cells needed to fight off infections. </p>
<p>In AML too many immature myeloid cells are produced too quickly by the bone marrow. They are mutant cells which don’t mature, meaning they fail to defend against infection. </p>
<p>For this reason, early signs of AML include flu-like symptoms, aches and pains in the joints, and rapid weight loss. As the abnormal cells build up inside the bone marrow or the blood they grow and divide aggressively. Left untreated, AML patients can have only weeks to live. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=913&fit=crop&dpr=1 600w, https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=913&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=913&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1148&fit=crop&dpr=1 754w, https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1148&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/201963/original/file-20180115-101505-e9kfw7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1148&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Bone marrow transplant.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/bone-marrow-transplant-operation-786989008?src=V3Gd5UZImFRTdR5V6xaclg-1-7">El-Roi</a></span>
</figcaption>
</figure>
<p>Patients are normally treated by two stages of chemotherapy over a few months: an induction phase which reduces the number of cancer cells to undetectable levels, then a consolidation phase to kill any cancerous cells hiding in the body. Patients often also receive a bone marrow transplant, effectively giving them a new immune system. </p>
<p>Treating AML is complicated by patients generally being older, since they tolerate the intensive chemotherapy less well. In many cases, they receive some treatment and end up only living a few months. Better understanding the mutations to develop more targeted and less harsh treatments looks like the key to improving survival. </p>
<h2>Step forward, PTPN1</h2>
<p>A number of mutations are associated with AML, and often occur in combinations. It’s these mixtures of mutations that are thought to cause the <a href="https://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/how-classified.html">complex subtypes</a> of cancers within the AML group. One common mutation is called <a href="http://www.cytocell.com/probes/23-del20q-deletion">Del20q</a>. It involves the deletion of part of <a href="https://ghr.nlm.nih.gov/chromosome/20">chromosome 20</a>, one of the 23 pairs of chromosomes most humans have in all their cells. </p>
<p>It has <a href="http://www.bloodjournal.org/content/bloodjournal/82/11/3424.full.pdf?sso-checked=true">long been suspected</a> that genes on this part of the chromosome may function, either individually or together, to suppress cancer. Until recently, however, researchers have found it hard to say which genes are responsible. </p>
<p>One candidate is known as PTPN1, or protein tyrosine phosphatase, non-receptor type 1. First discovered in the late 1980s and linked to metabolic function, it is more famously known for its roles in <a href="https://www.ncbi.nlm.nih.gov/pubmed/27465552">breast cancer</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/25120222">type 2 diabetes</a>. Its location on chromosome 20 has long made specialists suspect it could also be involved in AML. </p>
<p>It was <a href="https://www.nature.com/articles/leu201731">shown recently</a> that when you switch off the equivalent gene in mice, it leads to what are known as <a href="https://www.cancersupportcommunity.org/myeloproliferative-neoplasms">myeloproliferative neoplasm</a>, which is the wider family of blood cancers of which AML is a member. In <a href="http://cancerres.aacrjournals.org/content/early/2017/11/09/0008-5472.CAN-17-0946">our new study</a>, we have taken this a step forward: we have shown that if you delete this gene in older mice, it specifically gives rise to AML – and in a similar way to how the disease develops in older humans. </p>
<p>The previous study showed that PTPN1 is deleted from chromosome 20 in the cells of patients in around 17% of AML cases, which raises questions about the remaining majority of cases. We were able to show that deleting the mouse equivalent of PTPN1 activates a molecule called STAT3, which is important to regulating cell growth and division. </p>
<p>If a patient has too much STAT3, it leads to the generation of too many immature myeloid cells – that hallmark of AML I mentioned earlier. This is potentially a very useful finding for further studies into the genetics behind the disease: in the two other most common mutations linked to AML, which relate to a protein called JAK2 and a receptor called FLT-3, STAT3 is also over-activated. In all, STAT3 is relevant to maybe three quarters of all AML cases. Uncovering exactly how they relate looks critical to developing an eventual cure. </p>
<h2>The future</h2>
<p>In short, we’re closing in on understanding the links between PTPN1, STAT3 and AML. A few years from now, as the cost of genome sequencing falls, it will become a question of identifying which combination of mutations has affected a patient and prescribing a treatment accordingly. </p>
<p>This treatment will probably be more bespoke chemotherapy for patients that can tolerate it, and perhaps gene editing using tools such as <a href="https://www.broadinstitute.org/what-broad/areas-focus/project-spotlight/questions-and-answers-about-crispr">CRISPR</a> for those that cannot. Doctors would edit the correct versions of genes like PTPN1 back into the patient’s bone marrow, potentially restoring normal function and negating the often difficult search for a compatible bone marrow donor. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/201964/original/file-20180115-101498-q5v593.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">New edition.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/bone-marrow-transplant-operation-786989008?src=V3Gd5UZImFRTdR5V6xaclg-1-7">vchal</a></span>
</figcaption>
</figure>
<p>There is much research still to be done. We need to understand what PTPN1 is doing in healthy myeloid cells to grasp which processes are disturbed when it becomes deleted. The other big question is whether instead of getting deleted, PTPN1 sometimes more subtly mutates and how this relates to AML. Besides this, there are many other genes on the Del20q deletion that we need to better understand, too. </p>
<p>In the meantime, showing that removing PTPN1 leads to AML is an important piece of the puzzle. It brings the day closer when survival rates for AML make the same climb that we have seen in other kinds of leukaemia, and hopefully even beyond.</p><img src="https://counter.theconversation.com/content/90067/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Samantha Le Sommer 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>Improvements in survival rates for acute myeloid leukaemia have failed to keep pace with other leukaemias. That may be about to change.Samantha Le Sommer, Postdoctoral Researcher, University of AberdeenLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/895782018-01-04T10:14:45Z2018-01-04T10:14:45ZHow alcohol damages stem cells and increases cancer risk – new research<figure><img src="https://images.theconversation.com/files/200661/original/file-20180103-26154-rw424a.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/download/confirm/430479463?src=PNXioFM5jl99EmSj8EOoEg-1-33&size=huge_jpg">enzozo/Shutterstock.com</a></span></figcaption></figure><p>After cigarettes, alcohol is perhaps the most common carcinogen that humans voluntarily expose themselves to. How this simple substance promotes cancer, though, has not been clear. But our <a href="https://www.nature.com/articles/nature25154">latest study</a>, using genetically modified mice, sheds some light on the possible mechanism.</p>
<p>Our previous research revealed the principle mechanism that protects us from alcohol-induced DNA damage. The first level of this protection consists of an enzyme that converts acetaldehyde – a toxic byproduct created in the body when alcohol is metabolised – into a harmless substance. </p>
<p>The second level of protection consists of a repair system that fixes the damage that acetaldehyde causes to DNA. Now we have extended this work to show how alcohol, and subsequently its toxic byproduct, damages the DNA of the cells that supply blood – the blood stem cell. </p>
<p>Inherited gene defects that impair this protection mechanism are common in humans. About 500m people in Southeast Asia don’t have the biological system for dealing with acetaldehyde (the first level of protection). People from this region often get a flushed complexion after drinking alcohol, and they often feel unwell. They are also at increased risk of oesophageal cancer.</p>
<h2>Fourfold increase in damage</h2>
<p>We show that mice that have been genetically modified to emulate this loss of protection accumulate four times more DNA damage in their blood cells after exposure to a single dose of alcohol, so they are highly reliant on the DNA repair system to ensure that these cells don’t accumulate irreversible DNA damage. </p>
<p>Although it is quite rare, some people lack the DNA repair system (level two protection) that undoes the damage. They suffer from a devastating illness called <a href="https://en.wikipedia.org/wiki/Fanconi_anemia">Fanconi’s anaemia</a> that leads to premature death due to loss of blood production, blood cancer and other types of cancer. </p>
<p>Using mice that lack both protection mechanisms, we show conclusively that alcohol exposure causes damage to the chromosomes in the blood cells resulting in rearrangements of their chromosomes – the structures in the nucleus of the cells where DNA is packaged. Using state-of-the-art DNA sequencing technology, we deciphered the genomes of the rare stem cells that supply the blood in these mice and show how they are altered by this damage. </p>
<p>Damage to the genome of stem cells may cause them to dysfunction. However, because these vital cells give rise to a large number of specialised blood cells, the altered genome of single stem cells can be transmitted to many daughter cells. Altered genomes ultimately lead to altered genes, which, in some instances, cause cells to become cancerous. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/200744/original/file-20180103-26145-1cb5zg2.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">Our body’s protection mechanism against alcohol can be overwhelmed.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/282849857?src=ydDbKK7mgE_FiDhQYOGXLQ-1-32&size=huge_jpg">William Perugini/Shutterstock</a></span>
</figcaption>
</figure>
<h2>No certainty, but valuable new insights</h2>
<p>We have primarily studied the blood cells in our mice, but we can’t say for certain that alcohol causes blood cancers. However, it is well-known that alcohol does affect the production of blood. Our results explain, to some extent, why this happens. </p>
<p>The main advantage of studying blood is that it is easy experimentally to examine. This is particularly the case for the blood stem cells, which can be quantified and functionally assessed by a technique known as bone marrow transplantation. This involves transplanting stem cells that one may wish to assess into a mouse that no longer has such cells. Over time the transplanted stem cells start producing new blood and the efficacy of doing so relates to the fitness of the transplanted stem cell. So the analysis of blood stem cells provides a window into how alcohol may damage other stem cells in the body, such as those that make the gut and the liver.</p>
<p>Our new research explains how alcohol damages DNA in our vital stem cells. Although we show that this damage is limited by a robust protection mechanism, inherited dysfunction of this mechanism is common in humans. Nevertheless, it is also important to stress that, like all protective mechanisms they are not perfect and can be overwhelmed. Most life on Earth, from bacteria to mammals, also possess this protective mechanism, but, unlike humans, they have not yet developed the capacity to manufacture alcohol on an industrial scale for consumption.</p><img src="https://counter.theconversation.com/content/89578/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>KJ Patel receives funding from the MRC , CRUK, Wellcome Trust.</span></em></p>New mouse model study sheds light on why alcohol is so harmful.Ketan Patel, Professor, University of CambridgeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/866132017-11-01T03:40:18Z2017-11-01T03:40:18ZNot just about sex: throughout our bodies, thousands of genes act differently in men and women<figure><img src="https://images.theconversation.com/files/192548/original/file-20171031-18683-1s8p972.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">In skin, muscle, fat and more tissues, genes behave differently in men and women. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/multiracial-serious-people-lineup-mugshot-standing-399773986?src=_EELAU_D3VIkAFLKUOTd9g-1-1">from www.shutterstock.com </a></span></figcaption></figure><p>Most of us are familiar with the genetic differences between men and women. </p>
<p>Men have X and Y sex chromosomes, and women have two X chromosomes. We know that genes on these chromosomes may act differently in men and women. </p>
<p>But a <a href="https://doi.org/10.1186/s12915-017-0352-z">recent paper</a> claims that beyond just genes on X and Y, a full third of our genome is behaving very differently in men and women. </p>
<p>These new data pose challenges for science, medicine and maybe even gender equity.</p>
<hr>
<p><em><strong>Read more:</strong> <a href="https://theconversation.com/x-y-and-the-genetics-of-sex-professor-jenny-graves-awarded-the-prime-ministers-prize-for-science-2017-85740">X, Y and the genetics of sex: Professor Jenny Graves awarded the Prime Minister’s Prize for Science 2017</a></em> </p>
<hr>
<h2>The human genome</h2>
<p>Men and women have practically the same set of about <a href="https://theconversation.com/how-many-genes-does-it-take-to-make-a-person-64284">20,000 genes</a>. The only physical difference in their genetic make up is in the sex chromosomes. Only males have a Y chromosome. Although the X chromosome is present in both sexes, there are two copies in females and only one in males.</p>
<p>The human Y contains only 27 genes. One of these is the sex-determining region Y gene (<a href="https://ghr.nlm.nih.gov/gene/SRY">SRY</a>), which kick-starts the pathway that causes a ridge of cells in a 12 week-old embryo to develop into a testis. </p>
<p>Until recently, many believed that only the presence or absence of SRY distinguishes men and women.</p>
<p>Writing previously, I pointed out that there are 26 other genes on the Y chromosome, and perhaps another hundred or so genes on the X chromosome that are active in two doses in women and a single dose in men. <a href="https://theconversation.com/differences-between-men-and-women-are-more-than-the-sum-of-their-genes-39490">I speculated</a> that there may be a few hundred more genes directly affected by these X or Y genes, or by the hormones that they unleash. </p>
<p>This new paper suggests I underestimated by a huge margin.</p>
<h2>Genes, proteins and tissues</h2>
<p>Genes are parts of a long string of DNA, and composed of molecules that contain four different bases. The sequences of these bases encode the proteins of the body.</p>
<p>Our 20,000 genes make proteins that do a variety of jobs. Some make the fibres in skin or hair, some make muscles contract, and others carry the oxygen in blood. Many are enzymes that drive basic reactions of turning food into flesh and energy.</p>
<p>Genes work by making copies of themselves; the base sequence of DNA is copied into RNA molecules that engage with cell machinery to churn out protein. The more RNA a gene makes, the more protein will be produced.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=377&fit=crop&dpr=1 600w, https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=377&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=377&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=474&fit=crop&dpr=1 754w, https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=474&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/192551/original/file-20171031-18730-od0s8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=474&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Around one third of our genes act differently in men and women.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/linvoyage/14922004086/in/photolist-bo4wyM-5dopRY-EWZVj7-NqjsaQ-qC9U1v-CMeR5Z-iZgWXx-pFk19q-c9rcku-j22Zvq-j3e1by-j4NScA-j6yecr-oJBaWw-bpckz9-j6eKMU-aXM1fX-j7Xakj-aUnuZX-j4RbXf-nPo8je-oFYmha-j1DRTL-j59HvW-cVuNTG-cULXxu-diAD2U-wuN8vM-99Uqxt-LeB7TE-KJaSuX-cVv2Nd-8CDB7R-cVuJPS-9b3oW2-iXc6g-nNdw5w-9b9M6W-cVuRPb-cVuVi1-5eRCqt-9b3p3P-omcuj-9b6CY8-2jX9wX-E3TTnh-E6dMep-FhfFiX-Lspxem-aXM8Rx">linvoyage/flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>We can now <a href="http://www.cell.com/cell-reports/fulltext/S2211-1247(15)01491-6">measure the number of RNA copies each gene makes</a>. A really active gene may make thousands of copies, an inactive gene may make only a few, or none at all.</p>
<p>This epigenetic (“over the gene”) regulation of gene activity allows specialisation of different body tissues. Your liver and your brain share the same genes, but express them differently; one subset of genes is active in the liver, and a different subset of genes is active in the brain.</p>
<h2>Activity of genes in men and women</h2>
<p>In their new paper, the authors <a href="https://doi.org/10.1186/s12915-017-0352-z">Gershoni and Pietrokovsk</a> looked at how active the same genes are in men and women. They measured the RNA produced by 18,670 genes in 53 different tissues (45 common to both sexes) in 544 adult post mortem donors (357 men and 187 women).</p>
<p>They found that about one third of these genes (more than 6,500) had very different activities in men and women. Some genes were active in men only or women only. Many genes were far more active in one sex or the other.</p>
<p>A few of these genes showed sex biased activity in every tissue of the body. More commonly, the difference was seen in one or a few tissues.</p>
<p>Most of these genes were not on sex chromosomes: only a few lay on the Y or the X.</p>
<p>How could a third of our genes be differently controlled in men and women? </p>
<p>We now understand that proteins work in extensive networks. Change the amount of one protein produced by one gene, and you change the amounts of all the proteins produced by many genes in a long chain of command.</p>
<p>We also know that hormones have powerful influences on gene activity. For instance, testosterone and estrogen dial up or down many genes in reproductive and body tissues.</p>
<h2>Impact on physical features</h2>
<p>The functions of sex biased genes makes some sense. Most affect the reproductive system, which we know to be very different in men and women. For instance, the new study shows that mammary glands have highest frequency of female-biased gene expression, and testis has the highest frequency of male-biased genes.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/192552/original/file-20171031-18686-xtdkba.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">Your muscle development and hairiness are affected by genes.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/asian-woman-instructor-trainer-showing-how-734666779?src=6eJMPgAT1-5-4R5KRihbmQ-2-47">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Other sex biased genes were involved with skin (particular hairiness), muscle, fat tissue and heart, which could relate to sex differences in body morphology and metabolism. </p>
<p>Confirming an <a href="https://www.nature.com/articles/ncomms3771">earlier report</a>, some sex biased genes were involved in brain function, reopening the debate about differences in male and female behaviour.</p>
<h2>Impact on disease susceptibility</h2>
<p>These new findings could explain why men and women are often differently susceptible to diseases, and suggests treatments need to be based on studies of both sexes.</p>
<hr>
<p><em><strong>Read more:</strong> <a href="https://theconversation.com/medicines-gender-revolution-how-women-stopped-being-treated-as-small-men-77171">Medicine’s gender revolution: how women stopped being treated as ‘small men’</a></em> </p>
<hr>
<p>We have <a href="https://www.ncbi.nlm.nih.gov/books/NBK53393/">long known</a> that many diseases are far more common in men (e.g. Parkinsons) or in women (e.g. Multiple Sclerosis).</p>
<p>This study showed that some sex-biased genes were associated with diseases. For instance, a female-biased gene is implicated in cardiovascular homeostasis and osteoporosis, and a male-biased gene in high blood pressure.</p>
<p>The new study also showed a big difference in expression of a gene previously found to be important for <a href="https://www.ncbi.nlm.nih.gov/pubmed/27267697">drug metabolism</a>, which could explain why men and women may respond quite differently. </p>
<p>The <a href="http://www.ossdweb.org/">Organization for the Study of Sex Differences</a> has campaigned to <a href="https://www.theguardian.com/lifeandstyle/2015/apr/30/fda-clinical-trials-gender-gap-epa-nih-institute-of-medicine-cardiovascular-disease">include women in clinical trials</a>. These results should strengthen their hand.</p>
<p>Like it or not, evidence now shows that men and women differ genetically far more profoundly that we have previously recognised. </p>
<p>What do these new insights mean for our progress toward gender equity? A bad outcome could be appeals to return to outdated sexual stereotypes. A good outcome will be recognition of sex differences in medicine and treatment.</p><img src="https://counter.theconversation.com/content/86613/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council. </span></em></p>Like it or not, evidence now shows that men and women differ genetically far more profoundly that we previously recognised. An analysis from the 2017 winner of the Prime Minister’s Prize for Science.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/826042017-08-17T18:00:39Z2017-08-17T18:00:39ZScientists may have found a way to overcome common genetic causes of male infertility<figure><img src="https://images.theconversation.com/files/182246/original/file-20170816-32624-1e1eucl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Many people with chromosomal abnormalities can't conceive,</span> <span class="attribution"><span class="source">Halfpoint/Shutterstock</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>One in seven couples sadly <a href="http://www.nhs.uk/conditions/Infertility/Pages/Introduction.aspx">struggles with infertility</a> – defined as failing to conceive after trying for more than 12 months. Approximately one third of these cases are due to problems with the man, another third are down to the woman and the last third are due to a combination of both partners. Although we don’t understand the cause of male infertility in the majority of cases, we do know there is a small genetic component. </p>
<p>Since 1959, we have known that an extra X chromosome in men (XXY instead of XY, also known as <a href="http://www.nhs.uk/Conditions/klinefelters-syndrome/Pages/Introduction.aspx">Klinefelter’s syndrome</a>) is associated with low sperm production and infertility. This is now recognised as the most common genetic cause of infertility. For a long time, scientists have pondered whether we can’t just delete the extra sex chromosome in these individuals to enable normal sperm production. But this has been considered a purely theoretical and fanciful idea – until now. </p>
<p>A new paper, <a href="http://science.sciencemag.org/lookup/doi/10.1126/science.aam9046">published in Science</a>, shows it is indeed possible to delete the extra sex chromosome and produce normal, healthy fertile sperm in mice. The research is really quite remarkable. It raises hopes for restoring fertility in those living with other chromosomal abnormalities, too. </p>
<p>Klinefelter’s syndrome is relatively uncommon, affecting between one in 1,000 to one in 1,500 men. The extra X chromosome appears to have a relatively minimal impact on body tissue, but it can cause weaker muscles, smaller genitals, lower libido and breast growth in male individuals. For reasons that we don’t yet fully understand, it has a profound negative effect on the development of germ cells – the sperm and eggs – and subsequent sperm production and fertility. Men with Klinefelter’s syndrome have reduced testicular function and generally produce no or few sperm. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/182237/original/file-20170816-32640-1o9xjvz.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">A sperm being injected into an egg.</span>
<span class="attribution"><span class="source">RWJMS IVF Laboratory/wikipedia</span></span>
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</figure>
<p>Prior to the advent of ICSI (Intracytoplasmic sperm injection) – a procedure in which a single sperm is injected directly into an egg – these men were sterile. However, with the ability to recover a few sperm from the ejaculate or the testicles and inject these into eggs, scientists managed to successfully create an embryo using sperm recovered from an XXY patient <a href="https://www.ncbi.nlm.nih.gov/pubmed/7805909">in 1995</a>. Subsequently, <a href="https://www.ncbi.nlm.nih.gov/pubmed/28379559">there have been over 120 such births</a>.</p>
<h2>Deleting chromosomes</h2>
<p>When turning tissue from the ear of XXY (and XYY) mice into connective tissue knows as fibroblasts and subsequently into stem cells (cells that can produce indefinitely more cells), the scientists behind the new research noticed that some of the cells lost the extra sex chromosome. They also showed that this kind of chromosome loss happens when reprogramming human cells that have three instances of a particular chromosome, instead of the normal two.</p>
<p>Subsequently, they developed an experimental cocktail to produce germ cells from these stem cells in a lab dish. However, to produce fully functional sperm it was necessary to place these germ cells into the testicles of a male mouse. Remarkably, these sperm were fertile. When injected into eggs, they created healthy, fertile offspring free of the chromosomal abnormality. </p>
<p>The research boosts hopes that men with Klinefelter’s syndrome, for example, would be able to produce sperm and healthy offspring in cases where they don’t actually produce any sperm. The researchers showed similar chromosome loss in mice with the equivalent of Down’s syndrome. This is exciting, as men and women with Down’s syndrome tend to have lower fertility and have a <a href="http://www.nhs.uk/Conditions/Downs-syndrome/Pages/Treatment.aspx">high risk of their children having Down’s syndrome, too</a>. In fact people with a number of genetic conditions that are associated with infertility may one day be helped by the technique.</p>
<p>There are a number of substantial challenges to overcome for this to be realised in humans. The toughest one will be to produce functional germ cells outside the human body. We are still very much at the early stages of understanding these processes.</p>
<figure><img class="graf-image" src="https://cdn-images-1.medium.com/max/1600/1*eWCV2ztDHZZZfG3nwh8Wsg.gif"><figcaption>A swimming sperm.<a class="source" href="http://elifesciences.org/content/3/e02403"> From video by Kantsler et al.</a> (<a href="http://creativecommons.org/licenses/by/3.0/">CC BY 3.0</a>)</figcaption></figure>
<p>It will also be challenging to determine when to start human experiments. In the UK, we have a strict but permissive legislative framework for generating human embryos for research. As such, under research procedures, we would have to determine the viability, genetic and epigenetic profile of a blastocyst (a structure of cells formed in the early development of the fetus) created from germ cells in the lab. As long as these are normal then the next steps are to proceed to implantation of the embryos into the woman. </p>
<p>We are undoubtedly a long way from achieving this, but truly breath-taking progress is being made in the area of stem cell and germ cell biology. Coupled with a highly efficient reproductive medicine scene and permissive regulations, we are well placed to address the challenges of translating this exciting research into humans.</p><img src="https://counter.theconversation.com/content/82604/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Chris Barratt receives funding from MRC</span></em></p>A study in mice shows it is possible to delete extra chromosomes in a range of conditions that are associated with infertility, including Down’s syndrome.Chris Barratt, Professor of Reproductive Medicine, University of DundeeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/816812017-08-08T23:01:45Z2017-08-08T23:01:45Z‘Gene drives’ could wipe out whole populations of pests in one fell swoop<figure><img src="https://images.theconversation.com/files/181325/original/file-20170808-20141-gvybeg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Gene drives aim to deliberately spread bad genes when invasive species such as mice reproduce.</span> <span class="attribution"><span class="source">Colin Robert Varndell/shutterstock.com</span></span></figcaption></figure><p>What if there was a humane, targeted way to wipe out alien pest species such as mice, rats and rabbits, by turning their own genes on themselves so they can no longer reproduce and their population collapses?</p>
<p><a href="https://theconversation.com/au/topics/gene-drive-22966">Gene drives</a> – a technique that involves deliberately spreading a faulty gene throughout a population – promises to do exactly that. </p>
<p>Conservationists are <a href="http://www.cell.com/trends/ecology-evolution/abstract/S0169-5347(16)30197-5">understandably excited</a> about the possibility of using gene drives to <a href="https://www.technologyreview.com/s/603533/first-gene-drive-in-mammals-could-aid-vast-new-zealand-eradication-plan/">clear islands of invasive species</a> and allow native species to flourish.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/gene-drives-may-cause-a-revolution-but-safeguards-and-public-engagement-are-needed-77012">Gene drives may cause a revolution, but safeguards and public engagement are needed</a>
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</em>
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<hr>
<p>Hype surrounding the technique continues to build, despite serious <a href="https://www.science.org.au/news-and-events/news-and-media-releases/evolution-bending-gene-editing-technology-discussion-paper">biosecurity, regulatory and ethical questions</a> surrounding this emerging technology. </p>
<p>Our study, published today in the journal Proceedings of the Royal Society B, suggests that under certain circumstances, genome editing could work.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/180412/original/file-20170731-22169-1mrrb2p.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">The penguins on Antipodes Island currently live alongside a 200,000-strong invasive mouse population.</span>
<span class="attribution"><span class="source">Wikimedia Commons</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
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<h2>Good and bad genes</h2>
<p>The simplest way to construct a gene drive aimed at suppressing a pest population is to identify a gene that is essential for the pest species’ reproduction or embryonic development. A new DNA sequence – the gene-drive “cassette” – is then inserted into that gene to disrupt its function, creating a faulty version (or “allele”) of that gene. </p>
<p>Typically, faulty alleles would not spread through populations, because the evolutionary fitness of individuals carrying them is reduced, meaning they will be less likely than non-faulty alleles to be passed on to the next generation. But the newly developed <a href="https://theconversation.com/au/topics/crispr-15704">CRISPR gene-editing technology</a> can <a href="http://www.nature.com/nrg/journal/v17/n3/abs/nrg.2015.34.html">cheat natural selection</a> by creating gene-drive sequences that are much more likely to be passed on to the next generation.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/now-we-can-edit-life-itself-we-need-to-ask-how-we-should-use-such-technology-68821">Now we can edit life itself, we need to ask how we should use such technology</a>
</strong>
</em>
</p>
<hr>
<p>Here’s how the trick works. The gene-drive cassette contains the genetic information to make two new products: an enzyme that cuts DNA, and a molecule called a guide RNA. These products act together as a tiny pair of molecular scissors that cuts the second (normal) copy of the target gene.</p>
<p>To fix the cut, the cell uses the gene drive sequence as a repair template. This results in a copy of the gene drive (and therefore the faulty gene) on both chromosomes. </p>
<p>This process is called “homing” and, when switched on in the egg- or sperm-producing cells of an animal, it should guarantee that almost all of their offspring inherit the gene-drive sequence.</p>
<p>As the gene-drive sequence spreads, mating between carriers becomes more likely, producing offspring that possess two faulty alleles and are therefore sterile or fail to develop past the embryonic stage.</p>
<h2>Will it work?</h2>
<p>Initial attempts to develop suppression drives will likely focus on invasive species with rapid life cycles that allow gene drives to spread rapidly. House mice are an obvious candidate because they have lots of offspring, they have been studied in great detail by biologists, and have colonised vast areas of the world, including islands.</p>
<p>In our study we developed a mathematical model to predict whether gene drives can realistically be used to eradicate invasive mice from islands.</p>
<p>Our results show that this strategy can work. We predict that a single introduction of just 100 mice carrying a gene drive could eradicate a population of 50,000 mice within four to five years.</p>
<p>But it will only work if the process of genetic homing – which acts to overcome natural selection – functions as planned. </p>
<h2>Evolution fights back</h2>
<p>Just as European rabbits in Australia have <a href="https://theconversation.com/controlling-rabbits-lets-not-get-addicted-to-viral-solutions-5701">developed resistance to the viruses</a> introduced to control them, evolution could thwart attempts to use gene drives for biocontrol.</p>
<p>Experiments with non-vertebrate species show that homing can fail in some circumstances. For example, the DNA break can be repaired by an alternative mechanism that stitches the broken DNA sequence back together without copying the gene-drive template. This also destroys the DNA sequence targeted by the guide RNA, producing a “<a href="http://www.genetics.org/content/205/2/827">resistance allele</a>” that can never receive the gene drive. </p>
<p>A <a href="http://www.nature.com/nbt/journal/v34/n1/full/nbt.3439.html">recent study in mosquitos</a> estimated that resistance alleles were formed in at least 2% of homing attempts. Our simulation experiments for mice confirm this presents a serious problem. </p>
<p>After accounting for low failure rates during homing, the creation and spread of resistance alleles allowed the modelled populations to rebound after an initial decline in abundance. Imperfect homing therefore threatens the ability of gene drives to eradicate or even suppress pest populations.</p>
<p>One potential solution to this problem is to encode <a href="https://www.nature.com/nrg/journal/v17/n3/full/nrg.2015.34.html">multiple guide RNAs</a> within the gene-drive cassette, each targeting a different DNA sequence. This should reduce homing failure rates by allowing “multiple shots on goal”, and avoiding the creation of resistance alleles in more cases. </p>
<p>To wipe out a population of 200,000 mice living on an island, we calculate that the gene-drive sequences would need to contain at least three different guide RNA sequences, to avoid the mice ultimately getting the better of our attempts to eradicate them.</p>
<h2>From hype to reality</h2>
<p>Are gene drives a hyperdrive to pest control, or just hype? Part of the answer will come from experiments with gene drives on laboratory mice (with appropriate containment). That will help to provide crucial data to inform the debate about their possible deployment.</p>
<p>We also need more sophisticated computer modelling to predict the impacts on non-target populations if introduced gene drives were to spread beyond the populations targeted for management. Using simulation, it will be possible to test the performance and safety of different gene-drive strategies, including strategies that involve <a href="http://www.sculptingevolution.org/daisydrives">multiple drives operating on multiple genes</a>.</p>
<hr>
<p><em>Addendum, March 22, 2018: Since the research described in this article was accepted for publication, Paul Thomas and Phill Cassey have received funding from the US Defense Advanced Research Projects Agency’s <a href="https://www.darpa.mil/program/safe-genes">Safe Genes</a> program, to further assess the safe development of gene drive technology for vertebrate pest management. The research described in this article was funded by the University of Adelaide’s Environment Institute and did not receive funding from any other source.</em></p><img src="https://counter.theconversation.com/content/81681/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Thomas Prowse receives funding from the ARC and NHMRC </span></em></p><p class="fine-print"><em><span>Joshua Ross receives funding from the ARC, NHMRC and D2D CRC. </span></em></p><p class="fine-print"><em><span>Paul Thomas receives funding from the Australian National Health and Medical Research Council. </span></em></p><p class="fine-print"><em><span>Phill Cassey has received funding from the ARC and the Invasive Animals CRC.</span></em></p>Releasing just 100 mice carrying a faulty gene designed to stop them reproducing can remove an entire population of 50,000, a new study shows, paving the way for new eradication efforts.Thomas Prowse, Postdoctoral research fellow, School of Mathematical Sciences, University of AdelaideJoshua Ross, Associate Professor in Applied Mathematics, University of AdelaidePaul Thomas, University of AdelaidePhill Cassey, Assoc Prof in Invasion Biogeography and Biosecurity, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/761242017-05-16T15:16:31Z2017-05-16T15:16:31Z22q11.2 deletion: the most common syndrome you have never heard of<figure><img src="https://images.theconversation.com/files/169543/original/file-20170516-11956-hwrc0v.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/dna-molecules-design-illustration-586973936?src=tJTB-OooY4fENPDOT0vCvg-1-80">Natali_Mis/www.shutterstock.com</a></span></figcaption></figure><p>You wouldn’t be blamed for thinking that 22q11.2 was a postcode or password. My guess is you wouldn’t have thought it was the most prevalent syndrome of its kind.</p>
<p>So let’s talk about “22q”. </p>
<p>Everyone has 23 pairs of chromosomes – that’s 46 all together. Chromosomes are made of genes, which themselves are built of DNA. Think of a chromosome as a complete puzzle: the genes are the individual pieces and the DNA is the pattern or picture. When the different pieces are fixed together, they create a complete chromosome. In people with a genetic syndrome like 22q, a piece of the puzzle is missing, leaving the picture incomplete.</p>
<p>In 22q, the missing section is found on the “q arm” of the 22nd chromosome, at a position identified as 11.2 which combined becomes 22q11.2. The missing section can differ in size, meaning people can experience different symptoms. However, there is a core region commonly deleted in all.</p>
<p>The prevalence of 22q is considered to be around <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526275/">one in 2,000 live births</a> globally. This number is constantly under review however, with the syndrome potentially more common than initially thought. Many people go through life without a diagnosis.</p>
<h2>What problems occur in 22q?</h2>
<p>Because of the myriad problems in 22q, many different specialists are involved in diagnosing and treating it. It doesn’t help that different specialists refer to 22q by different names <a href="http://www.nhs.uk/conditions/digeorge-syndrome/Pages/Introduction.aspx">such as DiGeorge syndrome</a>, or velocardiofacial syndrome. These share a 22q deletion yet are considered different syndromes. In my world of research however, we talk about it as “22q”. </p>
<p>When a diagnosis is first made, the focus is commonly on the physical effects of the syndrome, such as cleft palate and heart defects. These effects are of course dependent on when and why a diagnosis was sought or given. Some diagnoses occur because of behavioural or developmental problems – autism-like symptoms or inattention and hyperactivity, for example – not just physical. These developmental and psychiatric problems come with age but can be traced back to earlier years.</p>
<p>22q has one of the <a href="http://www.jpeds.com/article/S0022-3476(11)00244-7/fulltext">highest prevalences of developmental delay</a> and congenital heart disease, second only to Down’s syndrome. Further similarities include both having a broad range of symptoms – including poor muscle tone and differences in digit length, both fingers and toes – and facial features. These tend to be more stereotyped in Down’s syndrome, but can be evident in 22q.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=609&fit=crop&dpr=1 600w, https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=609&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=609&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=766&fit=crop&dpr=1 754w, https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=766&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/169540/original/file-20170516-11956-1c03s2g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=766&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A child with 22q11.2 deletion syndrome.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/File:DiGeorge_syndrome1.jpg">Prof Victor Grech/Wikimedia</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>22q also puts individuals at increased risk of schizophrenia. In the general population, 1-2% of people have schizophrenia. In 22q, this <a href="http://www.schres-journal.com/article/S0920-9964(14)00043-7/fulltext">rate is higher</a>, at around 25-30% of people. 22q is one of the highest implicated genetic changes of its kind for <a href="http://bjp.rcpsych.org/content/204/2/108.long">development of schizophrenia</a>. Strikingly, this elevated risk is higher than having one parent with schizophrenia, <a href="http://schizophrenia.com/family/FAQoffspring.htm">which is 10%</a>. Having such a pronounced and stigmatised disorder at this risk level highlights the need for more understanding of 22q, as well as better interventions and treatments.</p>
<p>Other psychiatric disorders are <a href="http://bjp.rcpsych.org/content/204/1/46">more prevalent in 22q as well</a>, including anxiety disorders, attention-deficit hyperactivity disorder (ADHD) and autism. Epilepsy and impaired motor coordination are also common.</p>
<p>One of the most uncharted problems of 22q is that of sleep disturbances, which is <a href="http://www.cardiff.ac.uk/mrc-centre-neuropsychiatric-genetics-genomics/research/themes/developmental-disorders/echo-study-cnv-research">what I am currently researching</a>. Some people with 22q have physical sleep-related problems such as <a href="http://www.ijporlonline.com/article/S0165-5876(14)00316-4/fulltext">obstructive sleep apnoea</a>, however sleep-related behavioural and psychological problems have yet to be fully investigated. </p>
<p>How people with 22q sleep, both from a physiological view of brain activity to comfort and restlessness, can open the doors to understanding more about 22q as a multiplex syndrome. My work involves assessing children and adolescents’ brain activity during a night’s sleep. Coupling electroencephalography (EEG), which records electrical activity in the brain, with other objective sleep measures, can help us to create a better picture of what sleep is like in 22q.</p>
<h2>Why is 22q important?</h2>
<p>Families taking part in our research give a brief window into their lives, and we get snippets of the day-to-day realities of living with the syndrome. Although I would never claim to know what it’s like to have a child or be an adult with 22q, I greatly sympathise with the problems they experience.</p>
<p>Immediate life threatening heart defects at birth, and developmental delay and sensory processing problems can aggregate in childhood. The emergence of hallucinations and delusions in early adolescence can manifest into schizophrenia and anxiety, which can have a debilitating impact in adulthood.</p>
<p>Dealing with each of these problems separately takes a lot of strength and perseverance on the part of a person and their family. The cocktail of problems faced everyday makes for a hard pill to swallow and are difficult to ignore.</p>
<p>However, society’s lack of awareness is unhelpful: having to explain yourself day after day, being stigmatised, judged, or confronted with a face of confusion and lack of empathy must be beyond unbearable.</p>
<p>Researchers like myself are working hard to make sure 22q is investigated, taught, and discussed more widely, so that people and their families who are affected are given the understanding they deserve.</p><img src="https://counter.theconversation.com/content/76124/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hayley Moulding receives funding from the Medical Research Council and is a PhD student at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University. Hayley works for The ECHO Study who receive funding from National Institute of Health. </span></em></p>1 in 2,000 people are born with 22q, yet the rest of society hardly knows about it.Hayley Moulding, PhD student in Neuropsychiatric Genetics and Genomics, Cardiff UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/625352016-07-26T03:47:56Z2016-07-26T03:47:56ZDid sex drive mammal evolution? How one species can become two<figure><img src="https://images.theconversation.com/files/131732/original/image-20160725-31171-dcogrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">There's a difference in the sex chromosomes between various mammals, such as the platypus compared to humans.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/darrenputtock/15220743500/">Flickr/Darren Puttock</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>How new species are created is at the very core of the theory of evolution. The reigning theory is that physically separated populations of one species drift apart gradually.</p>
<p>But changes in chromosomes, particularly sex chromosomes, can interpose drastic barriers to reproduction. Mammals may be a good example. Comparisons of the sex chromosomes of the three major mammal groups show that there were two upheavals of sex chromosomes during mammal evolution.</p>
<p>The first corresponded to the divergence of monotreme mammals (platypus and echidna) from the rest, and the second to the divergence of marsupials from placental mammals (including humans).</p>
<p>In a <a href="http://onlinelibrary.wiley.com/doi/10.1002/bies.201600019/abstract">paper published in BioEssays</a>, I propose that drastic sex chromosome changes could have played a direct role in separating our lineage (placental mammals), first from the egg-laying monotremes, then from marsupials.</p>
<p>In humans and other placental mammals, such as mice, dogs and elephants, sex is determined by a pair of chromosomes. Females have two copies of the X while males have a single copy of the X and a small Y that contains the male-determining gene <a href="https://ghr.nlm.nih.gov/gene/SRY"><em>SRY</em></a>.</p>
<p>Other vertebrate animals also have sex chromosomes, but they are different. Birds have an unrelated sex chromosome pair called ZW, and a different sex determining gene called <em>DMRT1</em>.</p>
<p>Snakes also have a ZW system, but again it is a different chromosome with different genes. Lizards and turtles, frogs and fish have all sorts of sex chromosomes that are different from the mammal system and from each other.</p>
<h2>The rise and fall of sex chromosomes</h2>
<p>Sex chromosomes are really weird because of the way they evolved. They start off as ordinary chromosomes, known as autosomes. A new sex gene arises on one member of the pair, defining either a male-determining Y as in humans or a female-determining W as in birds.</p>
<p>The acquisition of a sex factor on one member of the pair is the kiss of death for that chromosome, and it <a href="http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">degrades quickly</a>. This explains why only a few active genes remain on the human Y and the bird W.</p>
<p>When old sex chromosomes self-destruct, a new sex gene and sex chromosomes may take over. This is fraught with peril because the interaction of old and new systems of sex determination is likely to cause severe infertility in hybrids. </p>
<p>Rival sex genes may be at war with each other, causing intersexual development, or at least infertility. For instance, what will be the sex of a hybrid that has both a male-determining Y and a female-determining W?</p>
<p>Added to this are problems with gene dosage because the degenerate Y and the W have few genes. If an XY male mates with a ZW female, most of the progeny will be short of genes. There may also be problems with gene dosage because genes on the X and the Z are used to working harder to compensate for their single dosage. </p>
<p>Rearrangement of sex chromosomes with autosomes also causes severe infertility because half the reproductive cells of a hybrid will have too many, or too few, copies of the fused chromosome.</p>
<p>Such hybrid infertility poses a reproductive barrier between populations with the new and the old sex system. So could such barriers drive apart populations to form distinct species? </p>
<h2>Reproductive barriers and new species</h2>
<p>The idea that chromosome change could drive the formation of new species was popular 50 years ago.</p>
<p>But it was thoroughly dismissed by evolutionary geneticists in favour of the idea that speciation, the formation of new and distinct species, must occur in populations already separated by a physical barrier such as a river or mountains, or behaviour such as mating time, and occupied different environments. </p>
<p>Small mutations would accumulate slowly and the two populations would be selected for different traits. Eventually they would become so different that they could no longer mate with each other and would form two species. This <a href="http://www.evolution.berkeley.edu/evosite/evo101/VC1bAllopatric.shtml">allopatric speciation</a> relied on external factors.</p>
<p>The alternate view, that <a href="http://www.evolution.berkeley.edu/evosite/evo101/VC1eSympatric.shtml">sympatric speciation</a> can happen within a population because of intrinsic genome changes, fell out of favour. Partly this was because it is hard to demonstrate speciation of populations sharing the same environment, the argument always being that the environment could be subtly different. </p>
<p>The other problem was imagining how a major chromosome change that occurred in one animal could spread to a whole population. Sex chromosome change is especially drastic because it directly affects reproduction. But our comparisons show that sex chromosomes have undergone dramatic changes throughout vertebrate evolution.</p>
<p>It is important to examine closely examples of evolutionary divergence that were accompanied by drastic sex chromosome change. Strangely, mammals may offer us a window into this evolutionary past. Their sex chromosomes are extremely stable, yet they have undergone rare dramatic changes, each of which lines up near when one lineage became two.</p>
<h2>Sex chromosome change and mammal divergence</h2>
<p>Placental mammals all share essentially the same XY. Marsupials, too, have XY chromosomes, but they are smaller; genes on the top bit of human X are on autosomes in marsupials. </p>
<p>Comparisons outside mammals shows that this bit was fused to ancient marsupial-like X and Y chromosomes before the different lines of placental mammals separated 105-million years ago.</p>
<p>Monotreme mammals (platypus and echidna) have bizarre multiple X and Y chromosomes. Surprisingly, comparing the genes they bear showed that they are completely unrelated to the XY of humans and marsupials. In fact, platypus sex chromosomes are related to bird sex chromosomes. </p>
<p>The human XY pair is represented by an ordinary chromosome in platypus. So our XY and <em>SRY</em> are quite young because they must have evolved after monotremes diverged from our lineage 190-million years ago.</p>
<p>Sex chromosome change has occurred very rarely in mammals, so it seems significant that each change corresponds to a major divergence. That’s why I propose that sex chromosome turnover separated monotremes from the rest of the mammals, and sex chromosome fusion occurred later to separate our lineage from marsupials.</p>
<p>Strengthening the argument that sex chromosome turnover begets speciation is evidence of a new round of sex chromosome change and speciation. </p>
<p>In Japan and eastern Europe, species in two rodent lineages have completely eliminated the Y chromosome and replaced <em>SRY</em> with a different gene on a different chromosome. In each lineage the Y-less rodents have recently diverged into <a href="http://molecularevolutionforum.blogspot.com.au/2012/05/rodents-with-no-y-chromosome-and-no-sry.html">three species</a>.</p>
<p>What does this mean for our own lineage? The primate Y seems to be more stable than the rodent Y. But if it continues to degrade at the same rate, it will disappear in about 4.6 million years. </p>
<p>Will it be replaced by some different gene and chromosome? And if so, will this unleash a new round of hominid speciation? We may have to wait another 4.6 million years to find out.</p><img src="https://counter.theconversation.com/content/62535/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from NHMRC and ARC. </span></em></p>How new species are created is at the core of the theory of evolution. Mammals may be a good example of how sex chromosome change drove major groups apart.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.