tag:theconversation.com,2011:/ca-fr/topics/x-chromosome-18931/articlesX chromosome – La Conversation2023-08-24T04:51:52Ztag: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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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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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/1959032022-12-05T19:05:08Z2022-12-05T19:05:08ZMen are slowly losing their Y chromosome, but a new sex gene discovery in spiny rats brings hope for humanity<figure><img src="https://images.theconversation.com/files/498865/original/file-20221205-12013-wfzmkt.jpg?ixlib=rb-1.1.0&rect=516%2C0%2C4393%2C2813&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">X and Y chromosome.</span> <span class="attribution"><span class="source">Nathan Devery/Shutterstock</span></span></figcaption></figure><p>The sex of human and other mammal babies is decided by a male-determining gene on the Y chromosome. But the human <a href="https://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">Y chromosome is degenerating</a> and may disappear in a few million years, leading to our extinction unless we evolve a new sex gene.</p>
<p>The good news is two branches of rodents have already lost their Y chromosome and have lived to tell the tale.</p>
<p>A new paper in <a href="https://www.pnas.org/doi/10.1073/pnas.2211574119">Proceedings of the National Academy of Science</a> shows how the spiny rat has evolved a new male-determining gene.</p>
<h2>How the Y chromosome determines human sex</h2>
<p>In humans, as in other mammals, females have two X chromosomes and males have a single X and a puny little chromosome called Y. The names have nothing to do with their shape; the X stood for “unknown”. </p>
<p>The X contains about 900 genes that do all sorts of jobs unrelated to sex. But the Y contains <a href="https://www.genome.gov/about-genomics/fact-sheets/Y-Chromosome-facts">few genes (about 55)</a> and <a href="https://genomebiology.biomedcentral.com/articles/10.1186/gb-2003-4-9-226">a lot of non-coding DNA</a> – simple repetitive DNA that doesn’t seem to do anything.</p>
<p>But the Y chromosome packs a punch because it contains an all-important gene that kick-starts male development in the embryo. At about 12 weeks after conception, this master gene switches on others that regulate the development of a testis. The embryonic testis makes male hormones (testosterone and its derivatives), which ensures the baby develops as a boy. </p>
<p>This master sex gene was identified as SRY (sex region on the Y) <a href="https://www.newscientist.com/article/mg12717262-400-science-the-gene-that-makes-a-man-of-you/">in 1990</a>. It works by triggering a genetic pathway starting with a gene called SOX9 which is key for male determination in all vertebrates, although it does not lie on sex chromosomes.</p>
<h2>The disappearing Y</h2>
<p>Most mammals have an X and Y chromosome similar to ours; an X with lots of genes, and a Y with SRY plus a few others. This system comes with problems because of the unequal dosage of X genes in males and females.</p>
<p>How did such a weird system evolve? The surprising finding is that <a href="https://genome.cshlp.org/content/18/6/965.abstract">Australia’s platypus</a> has completely different sex chromosomes, more like those of birds.</p>
<p>In platypus, the XY pair is just an ordinary chromosome, with two equal members. This suggests the mammal X and Y were an ordinary pair of chromosomes not that long ago.</p>
<p>In turn, this must mean the Y chromosome has lost 900–55 active genes over the 166 million years that humans and platypus have been evolving separately. That’s a loss of about five genes per million years. At this rate, the last 55 genes will be gone in <a href="https://www.nature.com/articles/415963a">11 million years</a>.</p>
<p>Our claim of the imminent demise of the human Y <a href="https://core.ac.uk/download/pdf/10638174.pdf">created a furore</a>, and to this day there are claims and counterclaims about the expected lifetime of our Y chromosome – estimates <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139287/">between infinity</a> and <a href="https://www.amazon.com/Adams-Curse-Future-without-Men/dp/0393326802">a few thousand years</a></p>
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Read more:
<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>
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<h2>Rodents with no Y chromosome</h2>
<p>The good news is we know of two rodent lineages that have already lost their Y chromosome – and are still surviving.</p>
<p>The mole voles of eastern Europe and the spiny rats of Japan each boast some species in which the Y chromosome, and SRY, have completely disappeared. The X chromosome remains, in a single or double dose in both sexes.</p>
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<a href="https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A small brown rodent sitting on leaf litter among branches" src="https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=440&fit=crop&dpr=1 600w, https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=440&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=440&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=553&fit=crop&dpr=1 754w, https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=553&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/498837/original/file-20221205-25475-vogco0.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=553&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">The Amami spiny rat (Tokudaia osimensis) is endemic to the Japanese island of Amami Ōshima.</span>
<span class="attribution"><a class="source" href="https://www.global.hokudai.ac.jp/blog/novel-sex-determination-mechanism-revealed-in-mammals/">Asato Kuroiwa</a></span>
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<p>Although it’s not yet clear how the mole voles determine sex <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704219/">without the SRY gene</a>, a team led by Hokkaido University biologist Asato Kuroiwa has had more luck with the spiny rat – a group of three species on different Japanese islands, all endangered.</p>
<p>Kuroiwa’s team discovered most of the genes on the Y of spiny rats had been relocated to other chromosomes. But she found no sign of SRY, nor the gene that substitutes for it.</p>
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<a href="https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A young Japanese woman with tortoiseshell glasses smiling at the camera" src="https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=703&fit=crop&dpr=1 600w, https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=703&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=703&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=883&fit=crop&dpr=1 754w, https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=883&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/498856/original/file-20221205-24-hl2yi5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=883&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">Asato Kuroiwa leads the lab that discovered the ‘new’ sex determination gene in spiny rats.</span>
<span class="attribution"><a class="source" href="https://www.global.hokudai.ac.jp/blog/novel-sex-determination-mechanism-revealed-in-mammals/">Asato Kuroiwa</a></span>
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<p>Now at last they have <a href="https://www.pnas.org/doi/10.1073/pnas.2211574119">published a successful identification in PNAS</a>. The team found sequences that were in the genomes of males but not females, then refined these and tested for the sequence on every individual rat.</p>
<p>What they discovered was a tiny difference near the key sex gene SOX9, on chromosome 3 of the spiny rat. A small duplication (only 17,000 base pairs out of more than 3 billion) was present in all males and no females.</p>
<p>They suggest this small bit of duplicated DNA contains the switch that normally turns on SOX9 in response to SRY. When they introduced this duplication into mice, they found that it boosts SOX9 activity, so the change could allow SOX9 to work without SRY.</p>
<h2>What this means for the future of men</h2>
<p>The imminent – evolutionarily speaking – disappearance of the human Y chromosome has elicited speculation about our future.</p>
<p>Some lizards and snakes are female-only species and can make eggs out of their own genes via what’s known as <a href="http://theconversation.com/is-virgin-birth-possible-yes-unless-you-are-a-mammal-52379">parthenogenesis</a>. But this can’t happen in humans or other mammals because we have at least 30 crucial “imprinted” genes that work only if they come from the father via sperm. </p>
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Read more:
<a href="https://theconversation.com/what-we-learn-from-a-fish-that-can-change-sex-in-just-10-days-129063">What we learn from a fish that can change sex in just 10 days</a>
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<p>To reproduce, we need sperm and we need men, meaning that the end of the Y chromosome could herald the extinction of the human race.</p>
<p>The new finding supports an alternative possibility – that humans can evolve a new sex determining gene. Phew!</p>
<p>However, evolution of a new sex determining gene comes with risks. What if more than one new system evolves in different parts of the world?</p>
<p>A “war” of the sex genes could lead to the separation of new species, which is exactly what has happened with mole voles and spiny rats.</p>
<p>So, if someone visited Earth in 11 million years, they might find no humans – or several different human species, kept apart by their different sex determination systems.</p>
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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>
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<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council. </span></em></p>The human Y chromosome could disappear over time, putting our species in jeopardy. But some rodents have managed just fine without it – and we now know how.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/1711772022-03-04T13:21:29Z2022-03-04T13:21:29ZThe sex of your cells matters when it comes to heart disease<figure><img src="https://images.theconversation.com/files/449560/original/file-20220302-21-1y7qlnj.png?ixlib=rb-1.1.0&rect=1090%2C0%2C2862%2C1822&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">How many X chromosomes you have can affect your health.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/purple-and-red-line-drawing-of-heart-royalty-free-illustration/694018603">John M Lund Photography Inc/Digital Vision via Getty Images</a></span></figcaption></figure><p>Most mammals, including humans, have two <a href="https://doi.org/10.3389/frym.2019.00134">sex chromosomes</a>, X and Y. One sex chromosome is usually inherited from each parent, and they pair up as either XX or XY in every cell of the body. People with XX chromosomes typically identify as female, and people with XY chromosomes typically identify as male. The genes on these chromosomes play a key role in development and function – including <a href="https://doi.org/10.1161/CIRCULATIONAHA.121.054108">how heart disease develops</a>.</p>
<p>Before I became a <a href="https://scholar.google.com/citations?user=rC48z5UAAAAJ&hl=en">biomedical engineer</a> studying how sex chromosomes affect the heart, I learned about one curious function of X chromosomes in my high school science class, with the <a href="https://letstalkscience.ca/educational-resources/stem-in-context/science-behind-calico-cats-colours">calico cat</a> example. </p>
<p>Female calico cats almost always have orange and black splotches of fur, because the gene that defines coat color is found on the X chromosome. When an orange cat mates with a black cat, female offspring, which typically inherit one X chromosome from each parent, will have a mixture of orange and black fur – one X chromosome encodes for orange fur while the other encodes for black fur. For this reason, male cats, which typically have one X and one Y chromosome, have solid orange or black coats.</p>
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<figcaption><span class="caption">Calico and tortoiseshell cats have multicolored patches of fur because only one of their two X chromosomes is activated in each cell.</span></figcaption>
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<p>How does this sex difference in fur color happen biologically? As it turns out, cells with XX chromosomes experience <a href="https://doi.org/10.1186/jbiol95">X-inactivation</a>: The X chromosome from one parent is turned off in some cells, while the X chromosome inherited from the other parent is turned off in others. In the cells of female calico cats, X-inactivation can lead to splotches of orange and black fur if one X chromosome comes from a parent with orange fur and the other X chromosome comes from a parent with black fur.</p>
<p>X-inactivation happens because organisms like cats and people need only one X chromosome to function properly. To ensure the correct “<a href="https://doi.org/10.1016/j.cub.2019.09.065">dosage</a>,” one of the X chromosomes is turned off in every cell. But some of the genes on the inactivated X chromosome <a href="https://doi.org/10.1186/s12864-019-5507-6">escape inactivation</a> and stay turned on. In fact, <a href="https://doi.org/10.1038/nature24265">up to one-third</a> of the genes on the X chromosome in people can escape inactivation, and they are thought to play a role in <a href="https://www.the-scientist.com/features/genes-that-escape-silencing-on-the-second-x-chromosome-may-drive-disease-67124">regulating health and disease</a>. </p>
<p>Because X-inactivation happens only in those people with more than one X chromosome, researchers like me have been looking at how the genes that escape inactivation on the second X affect the health of people with XX chromosomes. We’ve found that for certain conditions, <a href="https://doi.org/10.1016/j.yjmcc.2021.04.010">cell sex</a> may be at the heart of the matter.</p>
<h2>A change of heart</h2>
<p>One disease that X chromosome escape genes partially regulate is <a href="https://medlineplus.gov/ency/article/000178.htm">aortic valve stenosis</a>, a condition in which the part of the heart that controls blood flow to the rest of the body stiffens and narrows. This makes the heart work harder to pump blood and can ultimately lead to heart failure. Much like a person trying to push open a door with rusty hinges, the heart gets tired. There are currently no effective drugs available to slow or halt AVS disease symptoms.</p>
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<img alt="Diagram comparing a heart with a healthy aortic valve and a heart with aortic valve stenosis. The healthy valve opens fully while the diseased valve has a ragged and narrow opening." src="https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=278&fit=crop&dpr=1 600w, https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=278&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=278&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=350&fit=crop&dpr=1 754w, https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=350&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/449290/original/file-20220301-21-1na400c.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=350&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">Hearts with aortic valve stenosis must pump harder to push blood through a narrowed aortic valve to the rest of the body.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:En_rask_og_en_syg_aortaklap.png">SuneErichsen/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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<p><a href="https://aguado.eng.ucsd.edu">My lab</a> studies how sex chromosomes can affect cardiovascular conditions like AVS. <a href="https://doi.org/10.1161/CIRCRESAHA.116.309306">Previous studies</a> have shown that the valves of people with XX versus XY chromosomes can stiffen in different ways. Generally, people with XX chromosomes have increased scarring, called fibrosis, whereas people with XY chromosomes have increased calcium deposits. Given these differences, I suspected that giving the same drug to everyone might not be the best way to treat AVS. But what could be causing these differences?</p>
<p>By and large, researchers think <a href="https://doi.org/10.1152/physiol.00025.2016">sex hormones</a> drive sex differences in valve tissue stiffening. Indeed, <a href="https://doi.org/10.1186/s13293-017-0152-8">decreasing estrogen levels</a> during menopause can exacerbate heart fibrosis. However, studies on cardiovascular disease in XX and XY mice have found that sex differences still persist even after <a href="https://doi.org/10.1093/cvr/cvu064">surgically excising</a> the reproductive organs that produce sex hormones.</p>
<p>My team and I <a href="https://doi.org/10.1161/CIRCULATIONAHA.121.054108">hypothesized</a> that the genes that escape X-inactivation, being unique to people with XX chromosomes, may be driving these differences in valve stiffening. To test this idea, we developed bioengineered models of valve tissue using <a href="https://doi.org/10.1038/nmeth.3839">hydrogels</a>. Hydrogels mimic the stiffness of valve tissue <a href="https://doi.org/10.1073/pnas.1306369110">better than the traditional petri dish medium</a>, allowing us to study heart cells in an environment that more closely resembles the body.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy images comparing the presence of scar-promoting cells XY and XX heart cells, colored green with blue nuclei." src="https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=451&fit=crop&dpr=1 600w, https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=451&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=451&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=567&fit=crop&dpr=1 754w, https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=567&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/448432/original/file-20220224-33008-kdlor2.PNG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=567&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Heart tissue with XX chromosomes has a higher concentration of cells (colored green, with blue nuclei) that promote scarring than do cells with XY chromosomes.</span>
<span class="attribution"><span class="source">Brian Aguado</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
</figcaption>
</figure>
<p>We found that the cells we grew on our hydrogel models were able to replicate the sex differences seen in valve tissue – namely, valve cells with XX chromosomes had more scarring than cells with XY chromosomes. Moreover, when we decreased the activity of genes that escaped X-inactivation, we were able to decrease scarring in XX chromosome cells.</p>
<p>Our next step was to use our models to determine which treatments work best for AVS based on cell sex. We found that XX valve cells were less sensitive than XY cells to these drugs that targeted genes that promote scarring. Drugs that specifically target genes that escape X-inactivation, however, have a stronger effect on XX cells.</p>
<h2>Equitable care for all</h2>
<p>Sex and gender disparities in cardiovascular disease are rampant. For example, <a href="https://doi.org/10.1161/JAHA.119.014742">women are less likely</a> than men to be prescribed cardiovascular medications despite guideline recommendations, and <a href="https://doi.org/10.1161/CIRCOUTCOMES.119.005597">transgender individuals</a> have higher rates of heart attacks than do cisgender folks. </p>
<p>Our work takes one more step toward achieving equity in developing medical therapeutics for cardiovascular disease. By taking sex chromosomes into consideration, my team and I believe that treatment strategies can be optimized for everyone, irrespective of cell “seXX.”</p>
<p>[<em>Like what you’ve read? Want more?</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-likethis">Sign up for The Conversation’s daily newsletter</a>.]</p><img src="https://counter.theconversation.com/content/171177/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Brian Aguado receives funding from the National Institutes of Health and the Burroughs Wellcome Fund. </span></em></p>A one-size-fits-all approach may not be best for treating cardiovascular disease. Taking sex chromosomes into account could make for more effective and equitable care.Brian Aguado, Assistant Professor, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1227642019-09-03T13:40:36Z2019-09-03T13:40:36ZStop calling it a choice: Biological factors drive homosexuality<figure><img src="https://images.theconversation.com/files/290563/original/file-20190902-175705-15kuqu2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Biological factors shape sexual preference.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/lgbt-lesbian-couple-moments-happiness-concept-575079754?src=-1-53">Rawpixel.com/SHutterstock.com</a></span></figcaption></figure><p><a href="https://doi.org/10.1126/science.aat7693">Across cultures, 2% to 10% of people report having same-sex relations</a>. In the U.S., <a href="https://www.statista.com/topics/1249/homosexuality/">1% to 2.2% of women and men</a>, respectively, identify as gay. Despite these numbers, <a href="https://www.pewresearch.org/global/2013/06/04/the-global-divide-on-homosexuality/">many people still consider homosexual behavior to be an anomalous choice</a>. However, biologists have <a href="https://us.macmillan.com/books/9780312253776">documented homosexual behavior in more than 450 species</a>, arguing that same-sex behavior is not an unnatural choice, and may in fact play a vital role within populations.</p>
<p>In <a href="https://doi.org/10.1126/science.aat7693">a 2019 issue of Science magazine</a>, geneticist Andrea Ganna at the Broad Institute of MIT and Harvard, and colleagues, described the largest survey to date for genes associated with same-sex behavior. By analyzing the DNA of nearly half a million people from the U.S. and the U.K., they concluded that genes account for between 8% and 25% of same-sex behavior. </p>
<p><a href="https://www.nature.com/news/sex-redefined-1.16943">Numerous studies have established that sex is not just male or female</a>. Rather, it is a continuum that emerges from a person’s genetic makeup. Nonetheless, misconceptions persist that same-sex attraction is a choice that warrants condemnation or <a href="https://www.apa.org/pi/lgbt/resources/just-the-facts">conversion</a>, and leads to discrimination and persecution.</p>
<p><a href="https://wjsulliv.wixsite.com/sullivanlab">I am a molecular biologist</a> and am interested in this new study as it further illuminates the genetic contribution to human behavior. As the author of the book, <a href="https://www.penguinrandomhouse.com/books/608709/pleased-to-meet-me-by-bill-sullivan/9781426220555/">“Pleased to Meet Me: Genes, Germs, and the Curious Forces That Make Us Who We Are,”</a> I have done extensive research into the biological forces that conspire to shape human personality and behavior, including the factors influencing sexual attraction.</p>
<h2>The hunt for ‘gay genes’</h2>
<p>The new finding is consistent with multiple earlier studies of twins that indicated same-sex attraction is a heritable trait.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1200&fit=crop&dpr=1 600w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1200&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1200&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1508&fit=crop&dpr=1 754w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1508&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/290580/original/file-20190902-175663-baya3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1508&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A new study suggests that genes are responsible for between 8% and 25% of same-sex preference.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/dna-multi-color-isolated-on-white-717211195?src=-1-47">Guru 3D</a></span>
</figcaption>
</figure>
<p>The 2019 study is the latest in a hunt for “gay genes” that began in 1993, when Dean Hamer <a href="https://doi.org/10.1126/science.8332896">linked male homosexuality to a section of the X chromosome</a>. As the ease and affordability of genome sequencing increased, additional gene candidates have emerged with potential links to homosexual behavior. So-called <a href="https://doi.org/10.1038/s41598-017-15736-4">genome-wide association studies identified a gene called <em>SLITRK6</em></a>, which is active in a brain region called the diencephalon that differs in size between people who are homosexual or heterosexual.</p>
<p>Genetic studies in mice have uncovered additional gene candidates that could influence sexual preference. A 2010 study <a href="https://doi.org/10.1186/1471-2156-11-62">linked sexual preference to a gene called fucose mutarotase</a>. When the gene was deleted in female mice, they were attracted to female odors and preferred to mount females rather than males. </p>
<p>Other studies have shown that <a href="https://doi.org/10.1038/nature06089">disruption of a gene called <em>TRPC2</em></a> can cause female mice to act like males. <a href="https://doi.org/10.1126/science.1069259">Male mice lacking <em>TRPC2</em></a> no longer display male-male aggression, and they initiate sexual behaviors toward both males and females. Expressed in the brain, <em>TRPC2</em> functions in the recognition of pheromones, chemicals that are released by one member of a species to elicit a response in another.</p>
<p>With multiple gene candidates being linked to homosexuality, it seemed highly unlikely that a single “gay” gene exists. This idea is further supported by <a href="https://doi.org/10.1126/science.aat7693">the new study</a>, which identified five new genetic loci (fixed positions on chromosomes) correlating with same-sex activity: two that appeared in men and women, two only in men, and one only in women.</p>
<h2>How might these genes influence same-sex behavior?</h2>
<p>I find it intriguing that some of the genes from men identified in Ganna’s study are associated with olfactory systems, a finding that has parallels to the work in mice. Ganna’s group found other gene variants that may be linked with sex hormone regulation, which other scientists have previously suggested plays a large role in shaping the brain in ways that influence sexual behavior. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=846&fit=crop&dpr=1 600w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=846&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=846&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1063&fit=crop&dpr=1 754w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1063&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/290575/original/file-20190902-175691-1l5i9pk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1063&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Conditions in the uterus during pregnancy are thought to influence the sexual preferences of the child.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/beautiful-pregnant-woman-shopping-bags-outdoors-503149633?src=-1-18">Anna Om/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Males with a genetic condition called <a href="https://ghr.nlm.nih.gov/condition/androgen-insensitivity-syndrome">androgen insensitivity syndrome</a> can develop female genitalia and are usually brought up as girls, despite being genetically male – with an X and Y chromosome – and they are attracted to men. This suggests that testosterone is needed to “masculinize” a prenatal brain; if that doesn’t happen, the child will grow up to desire men. </p>
<p>Similarly, girls who have a genetic condition called <a href="https://www.nichd.nih.gov/health/topics/cah">congenital adrenal hyperplasia</a> are exposed to unusually high levels of male hormones like testosterone while in the womb, which may masculinize their brain and increase the odds of lesbianism. </p>
<p>It’s also possible that hormonal shifts during pregnancy could affect how a fetus’ brain is configured. In rats, <a href="https://doi.org/10.1210/en.2011-0277">manipulation of hormones during pregnancy</a> produces offspring that exhibit homosexual behavior.</p>
<h2>Why does homosexual behavior exist?</h2>
<p>Several hypotheses have been advanced to explain how homosexuality can be beneficial in perpetuating familial genes. One idea involves the concept of kin selection, whereby people work to ensure the passage of their family’s genes into subsequent generations. Gay uncles and aunts, for example, are “<a href="https://doi.org/10.1177/0956797609359623">helpers in the nest</a>” that help raise other family members’ children to nurture the family tree.</p>
<p>Another idea suggests that homosexuality is a “trade-off trait.” For example, certain genes in women help increase their fertility, but <a href="https://doi.org/10.1111/j.1743-6109.2008.00944.x">if these genes are expressed in a male</a>, they predispose him toward homosexuality.</p>
<p>Sexual behavior is widely diverse and governed by sophisticated mechanisms throughout the animal kingdom. As with other complex behaviors, it is not possible to predict sexuality by gazing into a DNA sequence as if it were a crystal ball. Such behaviors emerge from constellations of hundreds, perhaps thousands, of genes, and how they are regulated by the environment.</p>
<p>While there is no single “gay gene,” there is overwhelming evidence of a biological basis for sexual orientation that is programmed into the brain before birth based on a mix of genetics and prenatal conditions, none of which the fetus chooses.</p>
<p>[ <em>You’re smart and curious about the world. So are The Conversation’s authors and editors.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=youresmart">You can read us daily by subscribing to our newsletter</a>. ]</p><img src="https://counter.theconversation.com/content/122764/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Bill Sullivan does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A new study of nearly 500,000 individuals finds that many genes affect same-sex behavior, including newly identified candidates that may regulate smell and sex hormones.Bill Sullivan, Professor of Pharmacology & Toxicology, Indiana University School of MedicineLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/921842018-03-11T09:02:16Z2018-03-11T09:02:16ZSex: birds do it, bees do it - and fungi do it too. Here’s how, and why it matters<figure><img src="https://images.theconversation.com/files/209695/original/file-20180309-30958-1w7hmly.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The sweet-smelling, fluffy white fungus, _Huntiella moniliformis_, engaging in sexual reproduction in the lab.</span> <span class="attribution"><span class="source">Author supplied</span></span></figcaption></figure><p>Sex is an essential part of life. You, me and almost every other living organism on this planet are only here because two individuals got together at some point in the past to have their genes represented in the next generation. </p>
<p>For many species on earth – especially humans – that’s a pretty inflexible process. There are strict requirements: for instance, having two partners of the opposite sex tends to be indispensable for the production of offspring. </p>
<p>But there are a number of exceptions to this rigidity. Some of the most beautiful and interesting are exemplified by certain species of fungi.</p>
<p>Fungi play a variety of roles in our lives. Some are food sources, like button mushrooms; some are used in the production of cheese, wine, beer and bread. Others have provided humans with antibiotics for almost a century. And still others can cause great harm, wiping out trees by the hectare – or even killing humans.</p>
<p>And of course, like most species, fungi have sex lives. I study the sexual behaviour of <em>Huntiella moniliformis</em>, a sweet-smelling and fluffy white fungus that’s found in plantations all over the world. It’s fairly unique in that it’s unisexual – able to reproduce completely alone. </p>
<p>This makes it potentially very dangerous: even if it’s the only fungus in, say, an entire forest, it can keep mating and reproducing. It gets all the evolutionary benefits of sex, without having to go through all the trouble of finding a mating partner. </p>
<p>If we understand its sex life, we can come up with ways to control, manage or even stop it. That’s important in the case of species like <em>Huntiella moniliformis</em>, because they can infect damaged trees and cause disease. </p>
<h2>Fungal mating strategies</h2>
<p>In humans and most other mammals there is only one way to produce sexual offspring: sexual intercourse between a male and a female. Reptiles and birds often also reproduce heterosexually. </p>
<p>Fungi, meanwhile, can utilise one or more of six different sexual strategies. These range from the fungal equivalent of heterosexuality to changing their mating type as necessary.</p>
<p><strong><a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1469-185X.1949.tb00582.x/pdf">Heterothallism</a></strong>: is like heterosexuality in humans and requires two partners. In humans, having two X chromosomes makes you female; having an X and a Y chromosome makes you male. Some fungi use a similar system but instead of a whole chromosome they use single genes. A fungus with the <em>MAT1</em> gene is of the MAT1 mating type; having the <em>MAT2</em> gene means its mating type is MAT2. </p>
<p>For sex to take place, MAT1 and MAT2 partners need to get together. This means that out of everyone you meet, only half are sexually compatible with you. This severely limits the number of successful partners a fungus can meet in its search for a mate.</p>
<p>So how do they find each other? Smell. Or, at least, something similar: pheromones. These are small molecules that let a MAT1 individual know that a MAT2 individual is close, and vice versa. This ensures that no one wastes time and energy slowly growing towards an incompatible partner. </p>
<p><strong>Primary homothallism:</strong> is when a single fungus has sex completely alone. Instead of having either the <em>MAT1</em> or the <em>MAT2</em> gene, they have both. In this way a single individual can make both pheromones and recognise itself as a partner. There are other forms of self-sex too. Two of these include the ability to change mating type. These systems mimic those of some fish that can switch between male and female, depending on what partners are available. The third relies on having two genomes and is functionally very similar to heterothallism. </p>
<p>The fourth lonely sexual strategy completely changed the way we think about sex in fungi. <strong>Unisexuality</strong> occurs in individuals we would classically have thought to be either MAT1 or MAT2. We would have expected them to need a partner, but they don’t.</p>
<p>My PhD research at the <a href="https://www.fabinet.up.ac.za/">Forestry and Agricultural Biotechnology Institute</a> in South Africa has revealed that unisexual reproduction is possible in <em>H. moniliformis</em>. My supervisors and I have recently <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192517">shown</a> that MAT2 individuals are able to secrete both pheromones, despite the absence of the <em>MAT1</em> gene. </p>
<p>This means that a single mating type can recognise itself as a compatible partner and respond appropriately. We are currently working on understanding how this system evolved and whether related species could be manipulated to employ the same strategy.</p>
<h2>Why does this matter?</h2>
<p>There are obvious evolutionary benefits to species having sex. The most obvious is because it ensures a species’ longevity. But there are downsides – not for <em>H. moniliformis</em>, in this case, but for forestry plantations. </p>
<p>Sex combines genes from different individuals and produces genetically unique offspring. In disease causing fungi this has been shown to enable host jumping – the movement from a susceptible host species such as a Pine tree in a plantation, to a previously resistant species, like an indigenous tree in a natural forest. </p>
<p>This means that hosts previously thought to be immune to infection could get infected in the future, and can cause serious disease outbreaks that are difficult to control. </p>
<p>The other downside to sex in fungi like <em>H. moniliformis</em> is that it produces easily dispersible spores. These are often the agent that enhances fungal spread and infection. </p>
<p>Understanding these processes, and the sex lives of fungi like <em>H. moniliformis</em>, can help us find answers to how to control the spread of diseases. This will ultimately mean keeping plantations – and humans – safer.</p><img src="https://counter.theconversation.com/content/92184/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andi Wilson receives funding from the National Research Foundation (NRF). </span></em></p>Understanding the sex lives of fungi can help in finding answers about disease control.Andi Wilson, PhD: Genetics Candidate, University of PretoriaLicensed 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>
</figcaption>
</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/519422016-01-11T16:49:20Z2016-01-11T16:49:20ZWhy is the X chromosome so odd? Traffic analogy helped us crack the mystery<figure><img src="https://images.theconversation.com/files/105055/original/image-20151209-15558-1302hfh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The X-chromosome at some point evolved to be different from all other chromosomes.</span> </figcaption></figure><p>You may not be aware of it, but one of your chromosomes – <a href="http://ghr.nlm.nih.gov/chromosome/X">the X chromosome</a> – is considerably different from the rest and has posed a puzzle for scientists for over a decade. Early in mammalian evolutionary history, what is now the X chromosome was just like any of our other chromosomes. But at some point it evolved to be different. </p>
<p>Unlike all other chromosomes, one of the two X chromosomes in women is inactivated in nearly all cells. It also has an extremely low mutation rate and – most perplexingly – the genes that are found on it are active in relatively few of our tissues. Now <a href="http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002315">a study we recently published</a> in PLOS Biology, has begun to shed light on what’s going on – by using a traffic analogy.</p>
<h2>Battle of the sexes</h2>
<p>In humans, each cell normally contains <a href="https://www.genome.gov/26524120">23 pairs of chromosomes</a>. Only one of these pairs – the sex chromosomes – differs in men and women. If you are biologically a woman, you inherited one X chromosome from your father and one from your mother. If you are biologically a man, you inherited one from your mother and a Y chromosome from your father. </p>
<p>Like all other chromosomes, the X chromosome carries genes that are used to create proteins that go on to produce observable traits. This happens through the process of transcription, in which a single strand copy of the DNA is made, which is then decoded into a protein. When a gene is processed like this it is said to be “expressed”. Essentially, gene expression interprets the genetic information stored in DNA, converting it into traits.</p>
<p>In the 1980s <a href="http://www.jstor.org/stable/2408385?seq=1#page_scan_tab_contents">a study predicted</a> that the genes on X chromosomes should be prone to evolve to be switched on in only one of the two sexes, making them different. This could explain certain biological differences between women and men (the study looked specifically at the difference in the size and shape of horns in bighorn sheep). And when new mutations happen on X chromosomes their effects in women are subject to selection twice as often as their effects in men. So a mutation that is beneficial in women but harmful in men could nonetheless persist. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=470&fit=crop&dpr=1 600w, https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=470&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=470&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=591&fit=crop&dpr=1 754w, https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=591&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/104883/original/image-20151208-32371-1g2s2hr.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">The 46 chromosomes of a man. Women differ by having an X chromosome where the Y chromosome is.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Y_chromosome#/media/File:Human_male_karyotpe_high_resolution_-_Y_chromosome.png">National Human Genome Research Institute</a></span>
</figcaption>
</figure>
<p>But this doesn’t really explain why the genes on our X chromosome are not expressed in as many tissues as other genes. Looking at the <a href="http://fantom.gsc.riken.jp/5/">human gene atlas that is FANTOM5</a>, we found this trend to be true even after genes expressed in sex-specific tissues (like the womb, testes, ovaries) are taken out of the equation. </p>
<p>Our study tested an alternative possibility – the idea that it is hard to increase the amount a gene is expressed on the X chromosome. To express a gene we need other proteins, known as transcription factors. These proteins stick to the DNA in the vicinity of genes and function like “on switches”. To increase expression requires increasing the amount of these proteins that stimulate the expression by binding to that gene. But on the chromosome in men, these proteins can only bind to one site rather than two. And in women one of them is deactivated.</p>
<p>For similar genes on our other chromosomes there are two sites that can be activated in parallel if expression at a fast rate is needed. For example, in the cells where we need <a href="https://www.ebi.ac.uk/interpro/potm/2005_10/Page1.htm">haemoglobin</a> to carry more oxygen from the respiratory organs to other organs, the genes that produce it can be expressed at a higher rate than any other gene in any other tissue or cell. The X chromosome, however, is like a one-lane road that carries less traffic on it at peak periods than a two-lane road – leading to gene expression traffic jams.</p>
<h2>Traffic jams</h2>
<p>We expected that, when peak traffic rates are high, genes on the X chromosome will have a problem. And our statistical analysis revealed that, as expected, peak traffic flow rates on your X chromosome are under half that of your other genes.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/105056/original/image-20151209-15564-1gyl24r.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">It’s hard to speed up a traffic jam.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Trafficjam.jpg">US Census Bureau/wikimedia</a></span>
</figcaption>
</figure>
<p>Moreover, genes that have moved from the X to the other chromosomes over evolutionary time and those that have gone the other way are different: the ones moving onto the X chromosome have much lower peak rates of expression that those making the reverse trip. And the more highly expressed genes on the X chromosome are less prone to increasing their expression level over evolutionary time than are other genes. It is hard to speed up when you’re in a single lane traffic jam.</p>
<p>The same traffic jam idea also explains the old mystery of why genes on your X chromosome are expressed in few tissues. Genes expressed in many tissues tend to be genes with very high peak rates of expression. According to the traffic jam model, really highly expressed genes cannot function on the X chromosome and indeed, as the X chromosome evolved, there seems to have been an exodus of such genes away from the X. Similarly, tissue-specific genes with very high peak expression are not found on the X chromosome. Tissues associated with very high peak traffic flow rates – for example tissues with very active secretion such as our pancreas – are also those in which X-linked genes tend not to be expressed.</p>
<p>These results suggest that to understand how our genes and chromosomes evolve we might need to think more about simple limitations of the physical systems they live in at a starting point, rather than only investigating the genetic basis for biological sex differences.</p>
<p>There are also some practical applications from this research. When it comes to <a href="https://theconversation.com/explainer-what-is-gene-therapy-19883">gene therapy</a>, for example, in which we artificially introduce a new version of a gene to compensate for a mutated version, we should probably avoid inserting it on the X chromosome if possible, as it may be hindered from being expressed properly.</p><img src="https://counter.theconversation.com/content/51942/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Laurence D. Hurst receives funding from the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the European Research Council. </span></em></p><p class="fine-print"><em><span>Lukasz Huminiecki receives funding from the Swedish Research Council.</span></em></p>Unlike other chromosomes, the X chromosome is inactivated in nearly all cells in women – and genes on it are active in very few tissues.Laurence D. Hurst, Professor of Evolutionary Genetics at The Milner Centre for Evolution, University of BathLukasz Huminiecki, Bioinformatician, Uppsala UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/394902015-07-30T20:15:42Z2015-07-30T20:15:42ZDifferences between men and women are more than the sum of their genes<figure><img src="https://images.theconversation.com/files/89607/original/image-20150724-3647-jx0xfk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">It's naive to pretend there are no profound genetic and epigenetic differences between the sexes.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/srslymark/3139392279/">Elephant Gun Studios/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>Gender differences and sexual preferences are frequently a point of conversation. What produces the differences between men and women? Are they trivial or profound? Are they genetic or environmental, or both? </p>
<p>Some people claim that, genetically, men are <a href="http://www.theregister.co.uk/2010/01/14/chimp_genome_y_chromosome_gumble">more closely related to male chimpanzees</a> than to women. Others discount sex differences because they’re determined by a single gene, called SRY, on the Y chromosome. </p>
<p>But the key to difference between men and women – and chimps – lies not just in the number of their differing genes but in what these genes do.</p>
<h2>A little background</h2>
<p>Let me first explain a bit about genes and chromosomes. Mammals (all vertebrates, in fact) share pretty much the same collection of about 20,000 genes. Each of these is a short stretch of DNA whose base sequence is copied into RNA, and then translated into a protein. </p>
<p>Our 20,000 genes are arrayed on about a metre of DNA (the genome), which is cut up into smaller pieces, which we can see down a microscope as chromosomes when they coil up to divide. The base sequence of genes can differ slightly from person to person, and differ a lot from species to species.</p>
<p>We all have two copies of the genome, one from mother and one from father, so there are two copies of each chromosome – except for the sex chromosomes. Women have two X chromosomes. Men have a single X (from their mother) and the male-specific Y (from their father). The genetic differences between men and women lie in these sex chromosomes. </p>
<p>The X bears more than 1,000 genes. But the Y has only 45, which are <a href="http://www.ncbi.nlm.nih.gov/pubmed/16530039">all that are left</a> of a once ordinary pair of chromosomes that differentiated to be the X and the Y. One of these 45 Y-borne genes (SRY) determines that a baby with XY chromosomes will develop as a boy.</p>
<p>But the Y chromosome is not all male-specific; 24 genes in its top little bit are shared with the X. These are unlikely to cause differences because they’re present in both sexes. </p>
<h2>Difference and the Y chromosome</h2>
<p>The rest of <a href="http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">the Y lost most of its genes</a> over 150 million years of evolution. A few still cling on, but they’re fatally damaged by mutation, so we can’t count these inactive “pseudogenes”. Indeed, there are only 27 active protein-coding genes on the male-specific part of the Y, although several are present in multiple copies (most of which are inactive). </p>
<p>Nor can we count all 27 because at least 17 have copies on the X chromosome too. Most of these 17 <a href="http://www.nature.com/nature/journal/v508/n7497/full/nature13206.html">remain dedicated</a> to their original purpose, backed up by their X copy. Only three have diverged to <a href="http://www.nature.com/nature/journal/v346/n6281/abs/346240a0.html">acquire male-specific properties</a>, such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/10391206">making sperm</a>.</p>
<p>The remaining ten genes on the human Y have no copy on the X. They are specific to males, so could contribute to differences between men and women. Some of them started off as copies of genes on the X but diverged far from their original function and acquired male-specific roles. Three originated as copies of genes on other chromosomes that were important for male functions.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/89146/original/image-20150721-24286-16xjfkz.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Many obvious differences between humans and chimps, like hairiness, may result from tiny alterations in one or a few genes.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/slightlyblurred/558000935/in/photolist-RiUeM-6P3si-4uhjG6-52yGZ8-qYjxE-7kWvYp-gLQhtK-9AXm4j-mNxeKR-ekynNF-8VyDXi-qYfNZ-8Go7dD-akAJLD-ekEhjW-9KDnq1-8Eoo8-4J9knx-8VAkLk-akkcax-a7thv8-48H5hV-33oZrf-5KWrJu-eAStQu-7gUS5e-4Q9c8y-zZ1P-5E4jTK-8hcfvW-qCmt4K-e9UKZp-qYfNX-arJixA-9KnNvq-5KSdGp-dKUnC-anFCTb-ed6MrT-rhFPRX-ajHCXZ-8g2VLa-8j31Xb-5KSd3V-rwRaVE-52zhxr-5KWsXC-dKUnP-9Z9bpD-989DZL">Willard Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>So the total number of genes possessed by men and completely absent from women may be as low as 13 (and no greater than 27) out of a total of 20,000 human genes. This proportion is clearly <a href="http://genome.cshlp.org/content/15/12/1746.full">not the equivalent to the supposed 4% genomic difference</a> between men and male chimps.</p>
<h2>‘Junk DNA’ on the Y</h2>
<p>A lot of the DNA of the Y chromosome doesn’t code for proteins and has been regarded as junk, sequences that were left over from old viruses and repeated many times. But hidden in this junk are sequences that are <a href="http://www.ncbi.nlm.nih.gov/pubmed/24296535">copied into long RNA molecules</a> but are not translated into protein. </p>
<p>We’re identifying more and more of these non-coding genes, some of which have remained the same in all vertebrates and presumably have some function. At least some non-coding Y genes may have important roles in regulating sex differentiation genes, though this has not yet been demonstrated.</p>
<p>Even more intriguing is new evidence that among the junk DNA on the Y chromosome of the bull are sequences that work to skew the ratio of sperm that bear the Y chromosome, favouring the birth of male calves. When these sequences are deleted, the skewing goes the opposite way, favouring female calves. </p>
<p>This suggests that the X chromosome, too, has some tricks to get preferentially into sperm. It seems there’s <a href="http://www.scientificamerican.com/article/a-battle-of-the-sexes-is-waged-in-the-genes-of-humans-bulls-and-more/?WT.mc_id=SA_BS_20150703">an arms race in the genome of every mammal</a> as these “sexually antagonistic” genes battle it out. There are many sexually antagonistic genes, <a href="http://theconversation.co.born-this-way-an-evolutionary-view%20of-gay-genes-s6051/">possibly including “gay genes”</a> that influence mate choice.</p>
<h2>X genes and sex differences</h2>
<p>A rarely recognised difference between the genomes of men and women is the different copy number of the more than 1,000 protein-coding genes on the X chromosome. There are two copies of these in women and one in men. </p>
<p>Differences in X gene dosage have been ignored because they were supposedly compensated for by a mechanism that silences all the genes on the whole of the X chromosome in females. Known as <a href="http://www.ncbi.nlm.nih.gov/pubmed/21643983">X chromosome inactivation</a>, this mechanism silences one or other X in the cells of the embryo, and this silencing is passed on into groups of cells in the adult. </p>
<p>This “epigenetic” silencing doesn’t change the base sequence of the DNA. But it changes the way the DNA binds to other molecules so it can’t be copied into RNA, and so produces no protein product.</p>
<p>But now we know that <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911101">more than 150 genes escape inactivation</a> on the human – but not the mouse – X. And independent of sex, the number of X chromosomes has <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669494">profound effects on some basic metabolic pathways</a>, such as fat and carbohydrate synthesis, which may underlie sex differences in susceptibility to many diseases. Mice that have two X chromosomes are fatter than mice with only one, for instance, even if they have been altered so that they’re male.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/89147/original/image-20150721-24270-1v3qthd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">There’s a supposed 4% genetic difference between chimps and men.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/animalrescueblog/17080088705/in/photolist-daVK98-daV5dJ-daVfVf-daVNEs-daV1HK-daVnwD-daVanz-daVhsW-daV7G5-daV9s7-daVHk2-daVAk1-daVcsF-daVaWL-daVwBB-daVqWT-daVhct-s2iVj2-fDPzfu-oCjMXd-5LFr83-8YJ451-fDPAUQ-fDPCyJ-h9YQx-feYyLJ-6RrB-6AS2xL-nLy7zj-nLJh8F-7emYiv-daVnzd-daVDKS-8e66aV-daVriN-djQ1zk-bpNmoY-hAHFGV-6jZjU-bDDgda-bqJkS3-bq32sq-c6yNs1-c6AjkW-fTxJ4a-s2bgjL-feHPbR-fDPUnf-feJgKV-feY7uS">International Fund for Animal Welfare Animal Rescue Blog/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>These 150 “escapee” X genes brings us to about 163 genes that are either male-specific, or are active in different doses in men and women. </p>
<h2>What the different genes do</h2>
<p>It’s naïve to think that these 163 genes will all have the same level of influence. Some will code for proteins that are critical for life, or for sex. Others might have only a minor effect, or no visible effect at all.</p>
<p>In fact, the effects of at least some of these 163 genes are profound. The male-determining SRY gene, for instance, kick-starts a <a href="http://www.ncbi.nlm.nih.gov/pubmed/17237341">cascade of dozens of genes</a> that are either turned on in male embryos or turned off in female embryos during testis or ovary development. </p>
<p>Most of these genes are not on sex chromosomes, so they are present in both sexes. But they are turned on to different extents – or at different times or in different tissues – in males and females. Counting these brings up the total to over a 1% genomic difference between the sexes.</p>
<p>What’s more, the downstream effects of SRY are much more profound than simply testis determination. Male hormones, such as testosterone, are synthesised by the embryonic testis and have far-flung effects all over the developing body. Androgens <a href="http://www.ncbi.nlm.nih.gov/pubmed/20399963">turn on hundreds (maybe thousands) of genes</a> that determine male genitalia, male growth, hair, voice and elements of behaviour.</p>
<p>If we count these, we are getting near 800 out of 20,000 human genes, which is closer to the 4% difference of men and male chimpanzees.</p>
<h2>Humans and chimps</h2>
<p>But this often-quoted difference is an average over the whole genome, only a minority of which consists of genes that code for proteins. It tells us little about which genetic differences are important. </p>
<p>Many obvious differences between humans and chimps, such as hairiness and perhaps even speech, may result from tiny alterations in one or a few genes. Differences in timing, or minor regulatory differences, may have massive effects on growth and development. </p>
<p>It’s naive to pretend there are no profound genetic and epigenetic differences between the sexes. But we’re not going to settle issues of how far-reaching the biological differences are just by counting gene differences. How these genes are regulated and their downstream effects are what make the difference between men and chimps, or men and women.</p><img src="https://counter.theconversation.com/content/39490/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves received funding from ARC and NHMRC for research into sex chromosome evolution.</span></em></p>What produces the differences between men and women? Are they trivial or profound? Are they genetic or environmental, or both? And are men really closer genetically to chimpanzees than to women?Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.