tag:theconversation.com,2011:/fr/topics/sex-chromosomes-18932/articlesSex chromosomes – The Conversation2023-08-31T12:20:15Ztag:theconversation.com,2011:article/2047772023-08-31T12:20:15Z2023-08-31T12:20:15ZTrans students benefit from gender-inclusive classrooms, research shows – and so do the other students and science itself<figure><img src="https://images.theconversation.com/files/541976/original/file-20230809-15-2j6fem.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Teaching sex and gender more accurately can counter gender stereotypes and encourage all students to study STEM.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/girl-in-denim-t-shirt-with-rainbow-symbol-wear-royalty-free-image/1365444357">Iurii Krasilnikov/iStock via Getty Images Plus</a></span></figcaption></figure><p>Across the U.S., legislators are debating how and when sex and gender should be discussed in the classroom and beyond. Specifically, <a href="https://www.transformationsproject.org/state-anti-trans-legislation">these bills</a> are considering whether anything beyond male or female can be included in library books and lesson plans. These bills are part of a larger debate on how to define and regulate sex and gender, and there are no immediate answers that satisfy everyone.</p>
<p>Many of the bills draw on science to make claims about sex and gender. For example, <a href="https://www.flsenate.gov/Session/Bill/2023/1069">Florida House Bill 1069</a>, which legislates pronoun use in schools, assumes that all of a person’s sex markers – listed as sex chromosomes, “naturally occurring” sex hormones and internal and external genitalia at birth – will align as female or male “based on the organization of the body … for a specific reproductive role.” The bill claims that “a person’s sex is an immutable biological trait and that it is false to ascribe to a person a pronoun that does not correspond to such person’s sex.”</p>
<p>Invoking biology is a way to sound objective, but it’s not so simple. Science itself is still grappling with the nature of sex and gender.</p>
<p>My co-author Sam Long and I are <a href="https://doi.org/10.1525/abt.2021.83.7.427">high school</a> and <a href="https://scholar.google.com/citations?user=rZ-cbGUAAAAJ&hl=en">college science educators</a> who research how to <a href="https://www.genderinclusivebiology.com">increase student motivation, interest and retention in biology</a>. Our work and that of our colleagues show that teaching sex and gender more accurately in classrooms benefits not only gender-diverse students but all students and the field of science.</p>
<h2>Science of sex and gender</h2>
<p>Bills like Florida’s define sex as a binary set of biological traits. But scientists know that sex is far more complicated.</p>
<p>In nature, there is a <a href="https://doi.org/10.1371/journal.pbio.1001899">huge diversity</a> in how sexes are arranged within bodies. For example, the sex of some organisms is classified by the size of their gametes, or sperm and eggs. Some species produce both gametes in one body. Some change whether they produce sperm or eggs over their lifetime. Others technically don’t have a sex at all.</p>
<p>Sex in humans is actually an <a href="https://doi.org/10.4324/9780203127971">amalgamation of many traits</a>, which include the type of gametes a person produces as well as their reproductive tract anatomy, hormone levels and secondary sex characteristics like hair growth and chest shape. These traits are determined not just by a few genes on the X and Y chromosomes but also by a <a href="https://doi.org/10.1038/s41598-019-53500-y">myriad of genes</a> on other chromosomes as well as the <a href="https://doi.org/10.1038/s41598-019-53500-y">developmental environment</a>. When <a href="https://courses.lumenlearning.com/wm-biology1/chapter/reading-polygenic-inheritance-and-environmental-effects/">many genes</a> contribute to a trait, it appears as a continuum.</p>
<p>The continuum of human sex is illustrated by the experiences of intersex individuals. For nearly two out of every 100 people, a binary definition of sex <a href="https://www.hachettebookgroup.com/titles/anne-fausto-sterling/sexing-the-body/9781541672895/">would not work</a>. People <a href="https://theconversation.com/not-everyone-is-male-or-female-the-growing-controversy-over-sex-designation-172293">who are intersex</a> don’t have chromosomes, hormones or internal and external genitalia that completely match cultural expectations of what males and females should look like. Under these bills, what pronouns would they be allowed to use? There is <a href="https://doi.org/10.1038/518288a">no universal scientific rule</a> for pronoun assignment.</p>
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<figcaption><span class="caption">Sex is a spectrum.</span></figcaption>
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<p>If sex is not binary, then <a href="https://theconversation.com/sex-and-gender-both-shape-your-health-in-different-ways-98293">gender</a> – or personal perceptions of masculinity, femininity, a mix of both, or neither – cannot be either. A 2022 Pew Research Center survey found that roughly <a href="https://www.pewresearch.org/short-reads/2022/06/07/about-5-of-young-adults-in-the-u-s-say-their-gender-is-different-from-their-sex-assigned-at-birth/">1.6% of U.S. adults</a> describe their gender as not aligned with their sex assigned at birth, which can be captured by the terms transgender or nonbinary.</p>
<p>Overall, science <a href="https://doi.org/10.1086/692517">does not have a definitive answer</a> for how to define sex and gender in people that lawmakers can draw upon – science only indicates that these traits are nuanced and complex.</p>
<h2>Limiting teaching on sex and gender affects everyone</h2>
<p>Bills limiting how sex and gender are taught exacerbate the disproportionate obstacles that transgender students already face. The 2019 National School Climate Survey of over 16,700 students in the U.S., conducted by national education nonprofit Gay, Lesbian and Straight Education Network, or GLSEN, reported that trans teens in <a href="https://www.glsen.org/research/2019-national-school-climate-survey">schools without gender-inclusive curricula</a> experienced more bullying, a decreased sense of belonging, poor academic performance and low psychological well-being.</p>
<p>Restrictive bills also discourage LGBT students from studying science. The 2013 GLSEN Network National School Climate Survey found that LGBT teens were <a href="https://www.glsen.org/sites/default/files/2020-03/GLSEN-2013-National-School-Climate-Survey-Full-Report.pdf">less interested in majoring in STEM</a> and the social sciences when the high school classes they took in those fields were not taught with inclusive curricula. </p>
<p>I and my colleagues found similar downstream effects on <a href="https://doi.org/10.1187/cbe.21-12-0343">college students</a>: Trans and nonbinary students reported feeling isolated and uncomfortable in biology courses that teach sex and gender only as a binary. They felt they couldn’t form relationships with their teachers or peers, and this lack of a supportive personal network prevented them from requesting letters of recommendation or getting involved in research. Some dropped out of STEM, and many others contemplated it.</p>
<p>Limiting gender-inclusive curricula in schools can ultimately have negative effects on all students. Children begin <a href="https://doi.org/10.1146/annurev.psych.093008.100511">developing and testing</a> their understanding of sex and gender starting as young as 2 years old. Erasing gender diversity even in elementary schools reinforces <a href="https://doi.org/10.1037/amp0000307">inaccurate conceptions of sex and gender</a> that can last a lifetime. For example, a 2018 study of 132 college students found that those who read a paper emphasizing binary sex and typical gender roles exhibited <a href="https://doi.org/10.1007/s11199-017-0786-3">increased prejudice against transgender people</a>. A 2019 study of 460 eighth through 10th grade students found that those taught an oversimplified and inaccurate definition of sex – as defined by sex chromosomes – had increased beliefs about the genetic basis of sex and in <a href="https://doi.org/10.1002/sce.21502">stereotypes about men and women</a>, including unchangeable sex differences in intelligence and scientific ability. These studies suggest that teaching oversimplified narratives about sex and gender influences not only how students conceive sex and gender but also beliefs about their own and others’ abilities.</p>
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<a href="https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Protestors holding signs reading 'Protect trans kids' and other slogans" src="https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/541788/original/file-20230808-27-jcydy2.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">People rally in front of the Kentucky State Capitol on Mar. 29, 2023, to protest the passing of Senate Bill 150, a ‘Don’t Say Gay’ bill that bans gender-affirming care for trans youth, limits discussion of LGBTQ topics in K-12 schools and allows teachers to misgender students.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/people-many-of-whom-are-adolescents-gather-during-a-rally-news-photo/1249909096">Jon Cherry/Stringer via Getty Images</a></span>
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<p>The trans and nonbinary college biology students we interviewed suggest there is another long-term harm of oversimplifying sex and gender: <a href="https://doi.org/10.1187/cbe.21-12-0343">lack of preparation</a> for a future career in science or medicine. An oversimplified understanding of sex and gender does not train students to work with the diverse patients and clients they might encounter, and it can <a href="https://mashable.com/article/transgender-healthcare">worsen health disparities</a> for trans people.</p>
<p>Lack of exposure to a broader range of sex and gender roles also limits potential scientific discoveries. Being taught only binary sex and genders biases the research questions scientists consider and the way they interpret their findings.</p>
<p>The study of <a href="https://theconversation.com/women-have-disrupted-research-on-bird-song-and-their-findings-show-how-diversity-can-improve-all-fields-of-science-142874">birdsong</a> offers one example of how this bias can influence research. A common stereotype is that male birds are more competitive than female birds. Because competition occurs partially through song, researchers studied birdsong only in males for a long time. Some scientists recently challenged these beliefs about sex roles by finding that females sing in <a href="https://doi.org/10.1098/rsbl.2019.0059">about 64% of songbird species</a>, opening doors to greater understanding of the function of birdsong.</p>
<h2>What educators and scientists can do</h2>
<p>When science is being misrepresented to justify oversimplified ideas about sex and gender in schools, scientists and science educators have an important role to play. </p>
<p>Sharing perspectives about gender diversity with school boards and elected officials can make a difference. Bringing conversations about sex and gender into the classroom can help all students feel seen and reduce gender stereotypes. Through his work with educators, my co-author, Sam Long, knows it can be intimidating to get into these conversations, but they do not have to be fights about who is right or wrong. Encouraging curiosity about human variation and questioning the portrayal of any trait as pathological simply because it is different or uncommon can help students think critically about sex and gender in respectful ways. </p>
<p>Disability advocates offer an <a href="https://odpc.ucsf.edu/clinical/patient-centered-care/medical-and-social-models-of-disability">inclusive approach</a> that focuses on changing the environment to fit the person rather than changing the person to fit the environment. Physical and mental variations do not inherently reduce a person’s ability to thrive; instead, it is environmental and culture barriers that are limiting or disabling. Educators can pose questions that encourage students to explore this idea. For example, red hair is as rare as intersex traits. Of the two, why are only intersex traits often framed as a disorder? Likewise, human height varies across people. How are buildings, products and services designed to accommodate a spectrum of heights? Why haven’t other physical variations been accommodated in the same way?</p>
<p>Initiatives like <a href="https://www.genderinclusivebiology.com/">Gender-Inclusive Biology</a>, <a href="https://projectbiodiversify.org/sex/">Project Biodiversity</a>, and <a href="https://welcomingschools.org/resources">Welcoming Schools</a> offer additional resources to help adapt the curriculum to acknowledge and celebrate variation in the living world. My co-author Sam is a founding member of Gender-Inclusive Biology.</p>
<p>Encouraging students to think critically about the complexity of sex and gender will encourage everyone to pursue their passions regardless of gender stereotypes, promote creative thinking in science and medicine and support trans students. In this way, teaching about sex and gender complexity can benefit everyone.</p><img src="https://counter.theconversation.com/content/204777/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sarah Eddy receives funding from the National Science Foundation.</span></em></p>‘Don’t Say Gay’ bills claim to use science to justify a binary definition of sex based on certain traits. But the biology of sex and gender is not so simple.Sarah Eddy, Assistant Professor of Biological Sciences, Florida International UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2121122023-08-24T04:51:52Z2023-08-24T04:51:52ZThe ‘weird’ male Y chromosome has finally been fully sequenced. Can we now understand how it works, and how it evolved?<p>The Y chromosome is a never-ending source of fascination (particularly to men) because it bears genes that determine maleness and make sperm. It’s also small and seriously weird; it carries few genes and is full of junk DNA that makes it horrendous to sequence. </p>
<p>However, new “<a href="https://www.nature.com/articles/s41592-022-01730-w">long-read</a>” sequencing techniques have finally provided a reliable sequence from one end of the Y to the other. The paper describing this Herculean effort has been <a href="https://www.nature.com/articles/s41586-023-06457-y">published</a> in Nature.</p>
<p>The findings provide a solid base to explore how genes for sex and sperm work, how the Y chromosome evolved, and whether – as predicted – it will disappear in a few million years.</p>
<h2>Making baby boys</h2>
<p>We have known for <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443938/#">about 60 years</a> that specialised chromosomes <a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">determine birth sex</a> in humans and other mammals. Females have a pair of X chromosomes, whereas males have a single X and a much smaller Y chromosome.</p>
<p>The Y chromosome is male-determining because it bears a gene <a href="https://pubmed.ncbi.nlm.nih.gov/1695712/">called SRY</a>, which directs the development of a ridge of cells into a testis in the embryo. The embryonic testes make male hormones, and these hormones direct the development of male features in a baby boy.</p>
<p>Without a Y chromosome and a SRY gene, the same ridge of cells develops into an ovary in XX embryos. Female hormones then direct the development of female features in the baby girl.</p>
<h2>A DNA junkyard</h2>
<p>The Y chromosome is very different from X and the 22 other chromosomes of the human genome. It is smaller and bears few genes (only 27 compared to about 1,000 on the X).</p>
<p>These include SRY, a few genes required to make sperm, and several genes that seem to be critical for life – many of which have partners on the X.
Many Y genes (including the sperm genes RBMY and DAZ) are present in multiple copies. Some occur in weird loops in which the sequence is inverted and genetic accidents that duplicate or delete genes are common.</p>
<p>The Y also has a lot of DNA sequences that don’t seem to contribute to traits. This “junk DNA” is comprised of highly repetitive sequences that derive from bits and pieces of old viruses, dead genes and very simple runs of a few bases repeated over and over. </p>
<p>This last DNA class occupies big chunks of the Y that literally glow in the dark; you can see it down the microscope because it preferentially binds fluorescent dyes.</p>
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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/2030552023-04-19T20:07:51Z2023-04-19T20:07:51ZSex and the single gene: new research shows a genetic ‘master switch’ determines sex in most animals<figure><img src="https://images.theconversation.com/files/521535/original/file-20230418-784-rphstd.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C2366%2C1767&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>In humans and other animals, sex is usually determined by a single gene. However, there are <a href="https://www.cell.com/current-biology/fulltext/S0960-9822(13)00412-0">claims</a> that in some species, such as platyfish, it takes a whole “parliament” of genes acting together to determine whether offspring develop as a male or female. </p>
<p>In <a href="https://doi.org/10.1016/j.tig.2022.12.002">a new analysis</a>, we took a close look at these claims. We found they describe abnormal situations, such as hybrids between two species with different sex-determining systems, or when one sex system is in the process of replacing another. </p>
<p>We conclude that sex is normally determined by a single gene. Evolutionary theory suggests this is the most stable state of affairs, as it ensures a 1:1 ratio of male and female animals. </p>
<h2>The human ‘master switch’ for sex</h2>
<p>In mammals, females have two X chromosomes, whereas males have an X and a Y. The Y chromosome bears a gene called SRY, which acts as a “<a href="http://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">master switch</a>”: an XY embryo, carrying SRY, develops into a biological male, and an XX embryo, lacking SRY, develops into a biological female.</p>
<p>This makes the inheritance of sex simple. Females make eggs, which carry a single X chromosome, while males make sperm, half carrying an X and half carrying a Y. </p>
<p>Random fusion of eggs and sperm delivers half XX females and half XY males, for a 1:1 sex ratio.</p>
<h2>Sex in other vertebrates</h2>
<p>Among animals with backbones (vertebrates), there is a huge variety of systems that determine sex. However, they usually come down to the action of a single gene.</p>
<p>Many fish, frogs and some turtles have <a href="https://www.mdpi.com/2073-4425/12/4/483">systems like ours</a>, in which a male-dominant gene on the Y chromosome directs testis development. Some vertebrates have the opposite – a female-dominant gene on the X chromosome. </p>
<p>Other vertebrates use <a href="https://www.nature.com/articles/nature08298">a dosage difference of a single gene</a>. In birds, males have two copies of a Z chromosome with the sex-determining gene DMRT1. Females have a single Z and a W chromosome that lacks DMRT1. Sex depends on DMRT1 dosage: two copies in ZZ males, versus one in ZW females.</p>
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Read more:
<a href="https://theconversation.com/how-birds-become-male-or-female-and-occasionally-both-112061">How birds become male or female, and occasionally both</a>
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<p>Surprisingly, <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001899">many different genes</a> act as the master switch in different species. But they all act by triggering the same male or female differentiation pathway. </p>
<p>These single-gene systems deliver equal numbers of males and females, which theory says is the optimal balance for a stable system. If the ratio favours one sex, individuals that produce more of the other sex will leave more descendants and their genes will spread until a 1:1 ratio is achieved.</p>
<h2>Some exceptional species</h2>
<p><a href="https://link.springer.com/article/10.1007/BF02135395">Some aquarium fish</a> have <a href="https://www.biodiversitylibrary.org/page/51116062">more complex systems</a>. Genetic crosses in platyfish appear to show two or more genes that determine male or female development; the sea bass seems to have at least three sex genes. </p>
<p>Some <a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/mec.14831">frogs</a> and lizards seem to determine sex using two or more sex genes. </p>
<figure class="align-center ">
<img alt="A photo of a platypus swimming with a worm dangling from its beak." src="https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=430&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=430&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=430&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=541&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=541&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521748/original/file-20230419-16-bwu4lr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=541&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">The platypus genome carries five X chromosomes and five Y chromosomes.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
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<p>Then there are species with two or more pairs of sex chromosomes. The platypus has <a href="https://www.nature.com/articles/nature03021">five X and five Y chromosomes</a>. Is there a sex gene on each Y? How will a poor baby platypus know how to develop if it gets three Ys and two Xs from its dad? </p>
<p>And what about species, like the <a href="https://www.nature.com/articles/nature19840">African clawed toad</a>, which have two copies of their whole genome, so should have two pairs of sex chromosomes and sex genes?</p>
<p>So there are lots of exceptional species that seem to have multiple sex chromosomes and sex genes in defiance of the expectation that only a single sex gene can produce a stable system.</p>
<h2>Polygenic sex – is there any such thing?</h2>
<p>In species where we cannot find a single master switch gene, it is common to talk about “<a href="https://www.mdpi.com/2073-4409/11/11/1764">polygenic sex</a>”. But how robust are these examples?</p>
<p>In our <a href="https://doi.org/10.1016/j.tig.2022.12.002">recent paper</a> we examine classic examples and recent claims for polygenic sex determination. We conclude the few systems that qualify represent abnormal and transient situations.</p>
<p>Multiple sex chromosomes need not mean multiple sex genes. <a href="https://www.nature.com/articles/nature13151">In the platypus</a>, all five Y chromosomes move together into sperm, and a single gene on the smallest Y directs male development. The African clawed toad <a href="https://www.pnas.org/doi/10.1073/pnas.0712244105">solved</a> the problem of its doubled genome by evolving a novel female-determining gene on a newly minted W chromosome.</p>
<p>In several systems, two sex genes are detected, but they control different steps of the same pathway that are regulated by a single master gene. </p>
<p>In some of the classic fish systems, like platyfish, the different variants <a href="https://www.biodiversitylibrary.org/page/51116062">all spring from the same chromosome</a>, suggesting sex is controlled by different variants of the same gene. A Japanese frog has <a href="https://link.springer.com/article/10.1007/s10577-008-1217-7">different sex chromosomes on different islands</a>, but they are all variants of the same chromosome. </p>
<figure class="align-center ">
<img alt="A photo of zebrafish swimming" src="https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521745/original/file-20230419-94-bzlmvh.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Laboratory zebrafish have lost a chromosome and evolved new systems for determining sex.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
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<p>Other examples suggest systems in transition. <a href="https://www.nature.com/articles/s41437-018-0157-z">Sea bass</a> shows different frequencies of variants over its range. There are signs of a new system gradually replacing an old one in <a href="https://www.nature.com/articles/hdy201622">a European frog</a>.</p>
<p>The zebrafish is <a href="https://academic.oup.com/genetics/article/198/3/1291/6065698">particularly interesting</a>. Strains bred independently in laboratories for 30 or 40 years have aberrant sex ratios and multiple sex genes.</p>
<p>But it turns out wild zebrafish have a regular ZW sex chromosome system. Lab stocks independently lost their W chromosome during lab breeding. All the lab fish are ZZ, and sex of the hatchlings is determined by weaker sex-differentiating genes that were lurking in the background. </p>
<h2>Winning the war of the sex genes</h2>
<p>Many “polygenic” systems turn out to be hybrids between two species. Species hybrids often have problems with reproduction, such as sterility or skewed sex ratios.</p>
<p>Their problem is incompatibility of different sex chromosomes and sex genes. If an XY male mates with a ZW female, offspring have all sorts of combinations of sex genes. </p>
<p>Incompatibilities can play out differently. For instance, <a href="https://academic.oup.com/evolut/article-abstract/64/2/486/6854216?redirectedFrom=fulltext">two species of cichlid fish</a> living side by side in Lake Malawi in Africa have unrelated XY and ZW systems. In their XYZW offspring, the W partially overrides the male determining effect of the Y, so XYZW fish have intersex traits. But, in another species combination, the W gene triumphs and XYZW fish are fertile females.</p>
<figure class="align-center ">
<img alt="A photo of cichlid fish" src="https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/521750/original/file-20230419-16-hg9dc3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Some species of cichlid fish with different sex-determining systems can interbreed, with complicated results.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
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</figure>
<p>Species hybrids may reveal many genes with major and minor effects on sex determination. For instance, <a href="https://www.frontiersin.org/articles/10.3389/fgene.2022.789573/full">crossing two catfish species</a>s revealed seven male-associated and 17 female-associated genes on different chromosomes.</p>
<p>So there are certainly species where two or more genes act together or in opposition. However, in the long term there is strong selection for one or the other to gain the upper hand. This will turn an inefficient polygenic system into a single-gene system, delivering fertile males and females in a 1:1 ratio.</p>
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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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<img src="https://counter.theconversation.com/content/203055/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from the Australian Research Council. </span></em></p>Some animals appear to use a ‘parliament’ of genes to determine sex. But a closer look reveals these are the exception rather than the rule.Jenny Graves, Distinguished Professor of Genetics and Vice Chancellor's Fellow, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/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>
<figure class="align-center zoomable">
<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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<em>
<strong>
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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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/did-sex-drive-mammal-evolution-how-one-species-can-become-two-62535">Did sex drive mammal evolution? How one species can become two</a>
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<img src="https://counter.theconversation.com/content/195903/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>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/1867972022-07-14T18:35:13Z2022-07-14T18:35:13ZY chromosome loss through aging can lead to an increased risk of heart failure and death from cardiovascular disease, new research finds<figure><img src="https://images.theconversation.com/files/474141/original/file-20220714-32290-2fajn7.jpg?ixlib=rb-1.1.0&rect=3%2C9%2C2106%2C1404&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chromosomes change over time, whether through the process of aging or exposure to harmful substances in the environment.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/and-y-chromosomes-royalty-free-image/88179880">Steven Puetzer/The Image Bank</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>The Y chromosome can be lost through the process of aging, and this can lead to an increased risk of heart failure and cardiovascular disease, according to a 2022 study my colleagues <a href="https://scholar.google.com/citations?user=hM9Ve60AAAAJ&hl=en">and I</a> published in the journal <a href="https://science.org/doi/10.1126/science.abn3100">Science</a>.</p>
<p>While most women have two X chromosomes, most men have one X and one Y. And many people with Y chromosomes start to lose them in a fraction of the cells in their body as they age.</p>
<p>While loss of the Y chromosome was <a href="https://doi.org/10.1038/1971080a0">first observed in 1963</a>, it was not <a href="https://doi.org/10.1038/ng.2966">until 2014</a> that researchers found an association between loss of the Y chromosome and shorter life span. Y chromosome loss has since been linked to a number of <a href="https://doi.org/10.1038/ng.2966">age-related diseases</a>, such as cancer and Alzheimer’s disease. However, it has been unknown whether this loss is just another benign indicator of aging, like gray hair or skin wrinkles, or whether it has a direct role in promoting disease.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/of7vrIIcTa0?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Over time, the degrading Y chromosome may play an increasingly smaller role in development.</span></figcaption>
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<p>My colleagues and I wanted to figure out if Y chromosome loss directly causes disease and, if so, how. Historically, the Y chromosome has been difficult to study because much of its genetic material is repetitive – it’s easy to get “lost” trying to decipher the sequence.</p>
<p>However, we were able to take advantage of these repeat sequences by targeting them with the DNA-editing tool <a href="https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/">CRISPR</a>. We used CRISPR to introduce breaks into the Y chromosome DNA of white blood cells in mice, destroying and eliminating the Y chromosome. We chose white blood cells in particular because they tend to have a <a href="https://doi.org/10.1038/s41598-020-59963-8">high prevalence</a> of Y chromosome loss.</p>
<p>We found that while loss of the Y chromosome did not have immediate effects on the young mice, they ended up aging poorly, dying at an earlier age than mice that still had Y chromosomes. They also had more buildup of scar tissue in the heart, a condition called <a href="https://doi.org/10.1038%2Fnri1412">fibrosis</a>, as well as a stronger decline in heart function after induced heart failure. Treating the mice with a drug that blocks heart scarring, however, was able to restore lost heart function. </p>
<p>We then evaluated the effects of Y chromosome loss in people. We analyzed data from the <a href="https://www.ukbiobank.ac.uk">U.K. Biobank</a>, a large database of medical and genetic data from 500,000 participants in the U.K. We found that men who had lost their Y chromosomes in over 40% of their white blood cells had a 31% increased risk of dying from cardiovascular disease compared with men who hadn’t lost their Y chromosomes, including a two- to threefold increased risk of dying from congestive heart failure or heart disease. In other words, those with the greatest Y chromosome loss had the greatest risk of death from cardiovascular disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Human karyotype missing a Y chromosome" src="https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=491&fit=crop&dpr=1 600w, https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=491&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=491&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=617&fit=crop&dpr=1 754w, https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=617&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/474167/original/file-20220714-32349-yfkrfr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=617&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Screening for Y chromosome loss could help lead to earlier treatments for age-related conditions.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/digitally-generated-image-of-karyotype-over-white-royalty-free-image/649121991">Olympia Valla/EyeEm via Getty Images</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>Men are reported to have shorter life spans than women in many countries. In industrialized countries like the U.S., this is typically a <a href="https://www.census.gov/library/publications/2020/demo/p25-1145.html">difference of five years</a>. While <a href="https://time.com/5538099/why-do-women-live-longer-than-men/">social, behavioral and other genetic factors</a> may also be at play, they don’t entirely account for the differences in life span.</p>
<p>Our work shows that loss of the Y chromosome can directly contribute to age-related diseases like heart disease through tissue scarring. We believe that a better understanding of how the Y chromosome may contribute to age-related diseases, and potentially the process of aging itself, could lead to ways to screen and prevent excessive tissue scarring that can lead to cardiovascular disease.</p>
<h2>What still isn’t known</h2>
<p>While our study primarily focused on the heart, we also found that mice with Y chromosome loss also had scarring in their kidneys and lungs as well as accelerated cognitive impairment as they aged. Further research can help clarify the role of Y chromosome loss in diseases affecting other parts of the body.</p>
<h2>What’s next</h2>
<p>We are currently searching for specific genes that are lost with the Y chromosome that may be responsible for the disease-causing effects of Y chromosome loss. This information can help us better analyze exactly how loss of the Y chromosome can lead to disease and aid in the development of treatments for it.</p><img src="https://counter.theconversation.com/content/186797/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kenneth Walsh receives funding from the National Institutes of Health and the National Aeronautics and Space Administration. </span></em></p>The negative health effects of Y chromosome loss could be one potential reason women tend to live longer than men.Kenneth Walsh, Professor of Internal Medicine, University of VirginiaLicensed 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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<iframe width="440" height="260" src="https://www.youtube.com/embed/vKfVmR51nQA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<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>
<figure class="align-center ">
<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">
<figcaption>
<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>
</figcaption>
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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>
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<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>
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<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/1290632020-01-24T02:37:55Z2020-01-24T02:37:55ZWhat we learn from a fish that can change sex in just 10 days<figure><img src="https://images.theconversation.com/files/310086/original/file-20200114-151862-1ffyikc.jpg?ixlib=rb-1.1.0&rect=64%2C93%2C3818%2C2491&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The male bluehead wrasse defends his group of yellow females, one of whom has to step-up and take charge if he leaves.</span> <span class="attribution"><span class="source">Kevin Bryant</span>, <span class="license">Author provided</span></span></figcaption></figure><p>The bluehead wrasse is a fish that lives in small social groups in coral reefs in the Caribbean. Only the male has a blue head – signalling his social dominance over a harem of yellow-striped females. </p>
<p>If this male is removed from the group, something extraordinary happens: the largest female in the group changes sex to become male. Her behaviour changes within minutes. Within ten days, her ovaries transform into sperm-producing testes. Within 21 days she appears completely male. </p>
<p>But how does the wrasse change sex, and why did evolution select this system? </p>
<p>Also, given that fish share sex-determining genes with mammals, would an understanding of this provide new insight into how sex works in humans and other animals?</p>
<h2>How does the transformation happen?</h2>
<p>The trigger for sex change in the bluehead wrasse and some other species <a href="https://www.ncbi.nlm.nih.gov/pubmed/29304633">is social</a>. When the male fish is removed, the largest female immediately senses his absence and adopts full male breeding behaviours the same day.</p>
<p>How this social cue translates into molecular action remains a bit of a mystery, but it probably involves stress. High levels of the stress hormone cortisol <a href="https://www.ncbi.nlm.nih.gov/pubmed/28890443">are associated with</a> temperature-based sex determination in other fish and reptiles. Cortisol probably alters reproductive function by impacting sex hormone levels. </p>
<p>Stress could be the unifying mechanism that channels environmental information into a change in sex.</p>
<p>Our <a href="https://advances.sciencemag.org/content/5/7/eaaw7006">research</a> traced changes in the activity of all 20,000-odd bluehead wrasse genes during the female to male transformation. </p>
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Read more:
<a href="https://theconversation.com/sex-lives-of-reptiles-could-leave-them-vulnerable-to-climate-change-69567">Sex lives of reptiles could leave them vulnerable to climate change</a>
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<p>Unsurprisingly, we found the gene that produces the female hormone (estrogen) rapidly shuts off, and genes responsible for making male hormones (androgens) are turned on.</p>
<p>Hundreds of other genes required for being female (including genes that make egg components) also progressively shut down, while genes required for maleness (including genes that make sperm components) turn on. </p>
<h2>Epigenetics</h2>
<p>We also noticed changes in the activity of developmentally important genes whose roles in sex determination remain unknown. This included genes known to “epigenetically” regulate the activity of other genes.</p>
<p>Epigenetics refers to regulation “above the gene”. For example, there are many fish and reptile species in which the sex of developing embryos is determined <a href="https://www.ncbi.nlm.nih.gov/pubmed/28804140">by environmental cues</a>, such as the temperature at which eggs are incubated. The sex is not determined by different genes, but by the environment impacting the activity of these genes. </p>
<p>Similar mechanisms regulate adult sex change in fish, so this may be important in translating the social cue into molecular action.</p>
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<p><a href="https://giphy.com/gifs/W0KHx55m6l7LbiYOa0"></a></p>
<p>Surprisingly, we saw the turn-on of some powerful genes that are active in embryos and stem cells. These genes keep cells in a neutral embryo-like state, from which they can mature (differentiate) into any tissue type. They can also revert differentiated cells to an embryo-like state. </p>
<p>This suggests that transitioning from ovaries to testes in wrasse involves reversing the cell differentiation process – something scientists have argued about for decades. </p>
<h2>What are the advantages?</h2>
<p><a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1467-2979.2007.00266.x">Researchers have identified</a> more than 500 fish species that regularly change sex as adults.</p>
<p>Clown fish begin life as males, then change into females, and kobudai do the opposite. Some species, including gobies, can change sex back and forth. The transformation may be triggered by age, size, or social status. </p>
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Read more:
<a href="https://theconversation.com/climate-change-can-tip-the-gender-balance-but-fish-can-tip-it-back-39053">Climate change can tip the gender balance, but fish can tip it back</a>
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<p>Sex change is an <a href="https://ourblueplanet.bbcearth.com/blog/?article=incredible-sex-changing-fish-from-blue-planet">advantage</a> when an individual’s reproductive value is greater as one sex when it is small, and greater as the other sex when it grows bigger.</p>
<p>If females benefit more than males from being larger (because they can lay more eggs), male-to-female sex change is most advantageous. But if (as for wrasse) males gain more from being large, because they can better defend their breeding territories and mate with many females, female-to-male sex change is optimal.</p>
<p>Sex change might also <a href="https://www.eurekalert.org/pub_releases/2020-01/esoa-tao011320.php">advantage</a> a population recovering from overfishing, which often targets larger fish and leaves the population deficient in one sex. Thus, a mechanism for replacing the missing sex would be an advantage.</p>
<h2>Why can’t humans change sex naturally?</h2>
<p>Male and female wrasse differ in size, colour, behaviour, but especially in their reproductive organs – the ovary and testes. </p>
<p>Sex change in the wrasse involves complete remodelling of the gonad from an ovary producing eggs to a testis producing sperm. </p>
<p>This differs from other fish that routinely change sex when they get big enough. Their gonads contain both male and female tissues, and sex change occurs when one outgrows the other. So, fish employ all sorts of strategies to get the most out of sex.</p>
<p>In contrast, humans and other mammals determine sex via a gene on the male-only Y chromosome. This gene triggers the formation of testes in the embryo, which unleash male hormones and direct male development of the baby.</p>
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Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
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<p>The human sex system is nowhere near as flexible as that of fish or reptiles. There is no evidence any environmental factors influence the sex determination of mammalian embryos, let alone cause sex change in adults. </p>
<p>That said, humans share with all vertebrates (including fish) about 30 genes that control ovary or testis differentiation. Mutation in any of these genes can tilt development toward male or female, resulting in atypical sexual development, but never sex change.</p>
<p>Perhaps an understanding of epigenetic changes in fish sex can offer us valuable insight, as we wrestle with new ideas about human sex and gender.</p><img src="https://counter.theconversation.com/content/129063/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><p class="fine-print"><em><span>Erica Todd has received funding from the Royal Society of New Zealand Rutherford Foundation and the University of Otago for work on sex-changing fish. </span></em></p><p class="fine-print"><em><span>Neil Gemmell has received funding from the Royal Society of New Zealand Marsden Fund and the University of Otago for work on sex-changing fish.</span></em></p>When a male bluehead wrasse is removed from the group he dominates, the largest female changes sex, rapidly transforming ovaries into sperm-producing testes. Molecular research shows how.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityErica Todd, Lecturer, Deakin UniversityNeil Gemmell, Sesquicentennial Distinguished Professor, University of OtagoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1164482019-05-09T20:07:52Z2019-05-09T20:07:52ZTen ethical flaws in the Caster Semenya decision on intersex in sport<figure><img src="https://images.theconversation.com/files/273417/original/file-20190508-183103-1eva5jd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Caster Semenya is legally female, was from birth raised as female and identifies as a female.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/ciamabue/7968832970/in/photolist-d9bmpU-6WYxJP-gbWqNq-faB1Ei-d2L35o-QYHomP-aciLfF-X6bjAG-27BHwNd-doMJTN-cT2bCb-RNztaz-cTaov7-74mBHV-cUT2rq-dXYK7q-cRCJDY-cQ9hZQ-RoFRBk-24xxRw2-8RuT7h-cUSVzh-dyUu74-dyUuRP-o4j6Zs-d6XYyN-74qwom-cUT6A5-d6XYpL-dyZXuN-6Rdv6M-d6XYw5-a9coyA-6YGtw4-dyZZsS-dyUuyt-d6XYdN-dyUuKK-25Xb6zb-dyZXsq-dyUuWM-25Xb5Zd-dyZXKL-dyZY9s-dyZXvw-dyZYfL-dyZXES-dyUtKa-dyZXq7-dyZXLW">Jon Connell on flickr </a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p><em>This essay is part of our occasional series <a href="https://theconversation.com/au/topics/zoom-out-51632">Zoom Out</a>, where authors explore key ideas in science and technology in the broader context of society and humanity.</em></p>
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<p>Middle-distance runner Caster Semenya will need to take hormone-lowering agents, or have surgery, if she wishes to continue her career in her chosen athletic events.</p>
<p>The Court of Arbitration in Sport (<a href="https://www.tas-cas.org/en/index.html">CAS</a>) <a href="https://www.tas-cas.org/en/general-information/news-detail/article/semenya-asa-and-iaaf-executive-summary.html">decided last week</a> to uphold a rule requiring athletes with certain forms of what they call “disorders of sex development” (DSD) – more commonly called “intersex” conditions – to lower their testosterone levels in order to still be eligible to compete as women in certain elite races. </p>
<p>The case was brought to CAS by Semenya, as <a href="https://theconversation.com/caster-semenyas-impossible-situation-testosterone-gets-special-scrutiny-but-doesnt-necessarily-make-her-faster-116407">she argued discrimination</a> linked to a 2018 decision preventing some women, including herself, from competing in some female events. </p>
<p>This ruling is flawed. On the basis of <a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">science and ethical reasoning</a>, there are ten reasons CAS’s decision does not stand up. </p>
<p>But first let’s take a quick look at the biology involved.</p>
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Read more:
<a href="https://theconversation.com/caster-semenya-how-much-testosterone-is-too-much-for-a-female-athlete-116391">Caster Semenya: how much testosterone is too much for a female athlete?</a>
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<p><a href="https://www.bbc.co.uk/sport/athletics/48128682">Semenya underwent medical testing in 2009</a>: at the time she was told it was a doping test. The results are confidential, but it has been widely reported that she does have an intersex condition. It seems reasonable to assume she has XY chromosomes, as she is covered by the CAS ruling. Her testosterone levels have not been disclosed, but since the ruling applies to her, they must almost certainly be in what they classify as the “male range”.</p>
<p>According to CAS, the DSD regulations require athletes who want to compete in some female events, who have XY chromosomes and in whom testosterone has a biological effect to reduce their natural testosterone levels to an agreed concentration (below 5 nmol/L). </p>
<p>In women referred to as “46 XY DSD” – the most common intersex condition among female athletes – the presence of a Y chromosome causes the development of testes. These do not descend from the abdomen but do produce testosterone. However the receptors for testosterone are abnormal, with the result that the individual develops as female with a vagina, but no ovaries or uterus. Circulating testosterone may have no biological effect in the case of complete androgen insensitivity syndrome (AIS), or some effect in partial AIS.</p>
<p>Now let’s consider what’s wrong with the ruling. </p>
<h2>1. It confuses sex with gender</h2>
<p>Sex refers to biology, and gender refers to social role or self-identification. In sport, the definition of male and female used to be based solely on sex. <a href="https://bjsm.bmj.com/content/39/10/695.info">This was assessed anatomically in the 1960s</a>, then by biological tests such as the presence of a structure called a “Barr body” in cells (found only in genetic females), or the gene for testicular development. </p>
<p>Sex determination was abandoned in the 1990s in favour of gender. From the 2000 Sydney Olympics forwards, <a href="https://bjsm.bmj.com/content/39/10/695.info">there were no tests of gender other than self-identification</a>. </p>
<p>Caster Semenya’s gender is uncontroversially female. She is legally female, was from birth raised as female and identifies as a female. So, on the current definition, Semenya is a female. Indeed, there has been no question of her gender.</p>
<p>Sex determination itself is not simple, with chromosomal, gonadal (presence of ovaries or testes), or secondary sex characteristics (physical) all possible definitions that would include or exclude different groups. </p>
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Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
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<p>The CAS decision relates to “XY females with disorders of sexual development.” XY denotes the male sex chromosomes. This reverts back to the old biological categories. Behind this ruling is the view that Semenya is really a man competing in the women’s category. This view is embodied beautifully in an article entitled “<a href="https://quillette.com/2019/05/03/a-victory-for-female-athletes-everywhere/">A victory for female athletes everywhere</a>.” </p>
<p>But Semenya is a female by the rules used by the International Association of Athletics Federations (<a href="https://www.iaaf.org/home">IAAF</a>) – so she should be allowed to compete to the best of her potential in her category.</p>
<p>An alternative is to retreat to the old sex-based definition based on the presence of a Y chromosome. But that carries its own questions on definitions, and also comes at great political and individual cost. It would imply that Semenya is a male with a disorder of sexual development. </p>
<h2>2. It discriminates against some forms of hyperandrogenism</h2>
<p>Hyperandrogenism is a term used to describe high levels of testosterone. </p>
<p>But the CAS decision does not cover all forms of hyperandrogenism. It only refers to women who have XY chromosomes, such as <a href="https://www.nhs.uk/conditions/androgen-insensitivity-syndrome/">partial androgen insensitivity syndrome (AIS)</a>. </p>
<p>It does not cover a condition called <a href="https://rarediseases.info.nih.gov/diseases/1467/congenital-adrenal-hyperplasia">congenital adrenal hyperplasia</a>, which can cause elevated levels of testosterone in women with XX chromosomes. </p>
<p>The implication is that XX females are real women, while those with XY chromosomes are not. </p>
<h2>3. It’s based on inadequate science</h2>
<p>The significant problem in partial AIS is that although testosterone is elevated in the blood, the receptors for testosterone do not respond to the hormone in the usual way. That is why these individuals have typical external female physical characteristics. </p>
<p>While the testosterone may have some impact on how the body works, it is impossible to quantify how much effect it is having. For example, the difference testosterone makes between males and females in all events is estimated to be <a href="https://sportsscientists.com/2019/05/on-dsds-the-theory-of-testosterone-performance-the-cas-ruling-on-caster-semenya/">up to 12% (all other items being equal)</a>. But Semenya’s best time is only <a href="https://shows.pippa.io/the-science-of-sport-podcast/episodes/the-caster-semenya-decision-explained">2% faster than her competitors</a>. It is not possible to determine how much of this 2% is due to testosterone, and how much due to other factors about her as an athlete, or her psychology.</p>
<p>The study on which the current decision is based contains only correlations and is flawed in several ways, with a call for its <a href="https://doi.org/10.1007/s40318-019-00143-w">retraction on scientific grounds</a>. It is a single study, conducted by the IAAF and the full data have not been released for independent replication. The sole ground for the claim that Semenya derives “material androgenizing effect” (that is, biological impact) appears to be the “statistical over-representation of female athletes with 46 XY DSD” in the relevant events, as documented in this single, poorly conducted study.</p>
<p>Even if Semenya’s times were to drop after the reduction of testosterone, this could be a side-effect of the drugs used to reduce testosterone, or a function of reductions in mental or physical functions which are themselves legitimate entitlements of the athlete. </p>
<p>Her body has grown up in the presence of a certain level of testosterone of uncertain function. Our bodies are complex, and still poorly understood. A change of this kind may lead to unexpected results. Some of these reductions in functions may be unjust. </p>
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Read more:
<a href="https://theconversation.com/testosterone-why-defining-a-normal-level-is-hard-to-do-113587">Testosterone: why defining a 'normal' level is hard to do</a>
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<p>No one has given a complete description of the role of testosterone in someone like Semenya, nor how much it ought to be reduced to achieve a supposedly fair outcome. The comparisons are only with XX chromosome women, who have a very different physiology and normal functioning testosterone receptors. </p>
<p>Put simply, a level of 5 nMol/L testosterone is meaningless in Semenya’s case because the receptors are not responding in the usual way. It does not achieve a “<a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">level hormonal playing field</a>”. </p>
<p>This is an example of “decimal point science smokescreen.” There is the impression of much greater confidence and sensitivity than the science warrants by appealing to figures with multiple decimal points. The science around testosterone in intersex conditions is poorly understood, let alone as it applies to individuals. This is a level chosen for convenience, not a level that will negate any perceived advantage, but go no further.</p>
<h2>4. It’s inconsistent with values of sport and human rights</h2>
<p>The self-professed values of sport include the <a href="https://www.wada-ama.org/sites/default/files/resources/files/wada_ethicspanel_setofnorms_oct2017_en.pdf">development of one’s own talent</a> . </p>
<p>Yet Semenya is asked to cobble her natural potential as a female competitor. She must take risky biological interventions to reduce her performance. </p>
<p>The United Nations Human Rights Council has stated that the regulations <a href="https://theconversation.com/its-not-clear-where-human-rights-fit-in-the-legal-ruling-on-athlete-caster-semenya-116417">contravene human rights</a> “including the right to equality and non-discrimination […] and full respect for the dignity, bodily integrity and bodily autonomy of the person”. </p>
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Read more:
<a href="https://theconversation.com/its-not-clear-where-human-rights-fit-in-the-legal-ruling-on-athlete-caster-semenya-116417">It's not clear where human rights fit in the legal ruling on athlete Caster Semenya</a>
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<h2>5. It’s inconsistent with treatment of other athletes</h2>
<p>Other women with disorders resulting in higher than expected levels of testosterone, such as congenital adrenal hyperplasia, are not required to reduce their biological advantage.</p>
<p>Competitors with genetic mutations causing increases in red blood cell mass, and who experience enhanced oxygen-carrying capacity as a result, are not required to reduce their biological levels. </p>
<p>The Finnish skier Eero Mäntyranta had a genetic mutation that boosted his red blood cell count by 25-50% (he produced more blood hormone erythropoetin, or EPO). He and won several Olympic medals with this <a href="https://bjsm.bmj.com/content/bjsports/37/3/192.full.pdf">natural form of doping</a>. </p>
<h2>6. It’s unjust</h2>
<p>The decision is unjust in several ways. </p>
<p>Firstly, it was the IAAF which moved from sex to gender definition of female in 1990s. Semenya has entered competition, trained and competed fairly under the rules. To change them now will be undermine her capacity to compete, work and live, after a lifetime of investment. </p>
<p>If the rules are to be changed, they should not affect athletes who agreed to the current rules, but future athletes. There should be a “grandmother clause” for current athletes, like Semenya or else they are unfairly burdened by the bungles of the IAAF. Even if these rules could be considered justified, they should apply to future athletes as soon as possible after puberty.</p>
<p>Secondly, justice is about giving priority to the worst off in our society – but this ruling adds disadvantage to the worst off. Those with intersex conditions are already stigmatised, discriminated against, in many cases cannot bear children even if they want to. They are the socially disadvantaged. This ruling adds further discrimination and disadvantage.</p>
<p>Thirdly, it sets back integration of intersex people, by stigmatising and marginalising them. We have told them: be yourself, society will accept you. But this sends the message: you are really male, we don’t accept you, you should be castrated.</p>
<h2>7. It is an inappropriate reaction to fear of a ‘slippery slope’</h2>
<p>At the heart of this decision is the fear of displacement of cisgender women on the podia by increasing debate over transgender athletes. <a href="https://quillette.com/2019/05/03/a-victory-for-female-athletes-everywhere/">The concern is</a> that if “XY females” are allowed to compete in the female category, formerly male transgender females will follow and rob cisgender women of their medals. </p>
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Read more:
<a href="https://theconversation.com/explainer-what-does-it-mean-to-be-cisgender-103159">Explainer: what does it mean to be 'cisgender'?</a>
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<p>This is a separate issue. Transgender athletes have normal testosterone receptors and would have grown up in the presence of male levels of testosterone acting on normal receptors. Intersex athletes have not grown up in this way and are typically raised as female.</p>
<p>The perceived problem of transgender domination of female sports can be dealt with by separate rules that do not disadvantage existing intersex athletes, though they will raise contentious issues of their own. </p>
<h2>8. It is disproportionate and unreasonable</h2>
<p>All methods of reducing testosterone involve some risk. For example, the administration of <a href="https://www.ncbi.nlm.nih.gov/pubmed/2960241">high-dose birth control medication</a> involves risk of clots, including fatal lung clots. </p>
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Read more:
<a href="https://theconversation.com/how-to-choose-the-right-contraceptive-pill-for-you-87614">How to choose the right contraceptive pill for you</a>
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<p>These interventions interfere with a normally functioning organism for highly uncertain benefits to other people. This is disproportionate and unreasonable.</p>
<h2>9. It can’t be implemented</h2>
<p>The World Medical Association has advised doctors <a href="https://www.wma.net/news-post/wma-reiterates-advice-to-physicians-not-to-implement-iaaf-rules-on-classifying-women-athletes/">not to administer</a> testosterone-lowering interventions, describing the regulation as “<a href="https://www.wma.net/news-post/wma-urges-physicians-not-to-implement-iaaf-rules-on-classifying-women-athletes/">contrary to international medical ethics and human rights standards</a>”. </p>
<p>Their use would be “off label” and is for purposes other than the athlete’s health. The rules involve “strict liability” which means the athlete is responsible for any failure to comply, even if unintentional and outside of the athlete’s control.</p>
<h2>10. There are fairer, safer alternatives</h2>
<p>I have argued athletes <a href="https://www.bmj.com/content/347/bmj.f6150">should be able take performance-enhancing substances</a> within the normal physiological range. This would mean cisgender female athletes could take testosterone up to 5 nMol/L. This would reduce any advantage Semenya may have.</p>
<p>It would also deal with the problem that <a href="https://link.springer.com/article/10.1007/s40279-014-0247-x">up to 40%</a> of elite athletes are currently doping anyway. Semenya received the <a href="https://www.olympic.org/london-2012/athletics/800m-women">London 2012 800m gold medal</a> after the <a href="https://www.reuters.com/article/us-doping-russia-savinova/savinova-stripped-of-london-games-800m-gold-for-doping-idUSKBN15P1EO">original winner was disqualified for doping</a>. It is highly likely that some of her current competitors are also doping.</p>
<p>No doubt part of the resistance to allowing Semenya to “naturally dope” is that it will encourage other athletes to engage in doping. But they already are, and a better approach to “de-enhancing” Semenya is to <a href="https://www.bmj.com/content/347/bmj.f6150">regulate and monitor the enhancement of other athletes</a>. </p>
<h2>Spectacular fail</h2>
<p>Rarely does a public policy fail so spectacularly on so many ethical grounds. </p>
<p><a href="https://www.tas-cas.org/fileadmin/user_upload/Media_Release_Semenya_ASA_IAAF_decision.pdf">CAS acknowledged</a> that its decision constituted discrimination: </p>
<p>“The panel found that the DSD Regulations are discriminatory but the majority of the panel found that, on the basis of the evidence submitted by the parties, such discrimination is a necessary, reasonable and proportionate means of achieving the IAAF’s aim of preserving the integrity of female athletics in the restricted events.”</p>
<p>The UNHRC <a href="https://documents-dds-ny.un.org/doc/UNDOC/LTD/G19/072/46/PDF/G1907246.pdf?OpenElement">has refuted this claim of proportionality</a>: “there is no clear relationship of proportionality between the aim of the regulations and the proposed measures and their impact”.</p>
<p>This ruling is neither necessary, reasonable nor proportionate. It is simply unjust discrimination.</p>
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Read more:
<a href="https://theconversation.com/caster-semenyas-impossible-situation-testosterone-gets-special-scrutiny-but-doesnt-necessarily-make-her-faster-116407">Caster Semenya's impossible situation: Testosterone gets special scrutiny but doesn't necessarily make her faster</a>
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<p><em>Thanks to Michelle Telfer and Ken Pang for comments</em></p>
<p><em>This article builds on arguments presented in the paper <a href="https://www.ncbi.nlm.nih.gov/pubmed/20702382">Time to re-evaluate gender segregation in athletics?</a>.</em></p><img src="https://counter.theconversation.com/content/116448/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Julian Savulescu receives funding from Uehiro Foundation on Ethics and Education and the Wellcome Trust. </span></em></p>Athlete Caster Semenya will need to take hormone-lowering agents, or have surgery, if she wishes to continue her career in her chosen events. But the decision to ban her is flawed on many grounds.Julian Savulescu, Visiting Professor in Biomedical Ethics, Murdoch Children's Research Institute; Distinguished Visiting Professor in Law, University of Melbourne; Uehiro Chair in Practical Ethics, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1120612019-03-10T19:21:34Z2019-03-10T19:21:34ZHow birds become male or female, and occasionally both<p>The highly unusual “semi-identical” Australian twins reported last week are the result of a rare event. It’s thought the brother and sister (who have identical genes from their mother but not their father) developed from an egg fertilised by two different sperm <a href="https://theconversation.com/same-same-but-different-when-identical-twins-are-non-identical-112684">at the same moment</a>. </p>
<p>In humans, it’s the sperm that determines whether an embryo is pushed along a male or female development pathway. But in birds, it’s the other way around. Eggs are the deciding factor in bird sex.</p>
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Read more:
<a href="https://theconversation.com/same-same-but-different-when-identical-twins-are-non-identical-112684">Same same but different: when identical twins are non-identical</a>
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<p>There are other fascinating aspects of bird sex that are not shared with humans. Female birds seem to have some capacity to control the sex of their chicks. And occasionally a bird that is female on one side and male on the other is produced – as in recent reports of this <a href="https://www.nationalgeographic.com/animals/2019/01/half-male-half-female-cardinal-pennsylvania/">cardinal in the United States</a>. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/_hYOk8lPCZA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">A half-male, half-female cardinal was recently spotted in Pennsylvania.</span></figcaption>
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<h2>X and Y, Z and W chromosomes</h2>
<p>So what is it about bird chromosomes that makes bird sex so different from human sex? </p>
<p>In humans, cells in females have two copies of a large, gene-rich chromosome called X. Male cells have one X, and a tiny Y chromosome. </p>
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Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
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<p>Birds also have sex chromosomes, but they act in completely the opposite way. Male birds have two copies of a large, gene-rich chromosome called Z, and females have a single Z and a W chromosome. The tiny W chromosome is all that is left of an original Z, which degenerated over time, much <a href="https://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">like the human Y</a>.</p>
<p>When cells in the bird ovary undergo the special kind of division (called “meiosis”) that produces eggs with just one set of chromosomes, each egg cell receives either a Z or a W. </p>
<p>Fertilisation with a sperm (all of which bear a Z) produces ZZ male or ZW female chicks.</p>
<h2>Birds can control the sex of their chicks</h2>
<p>We would expect that, during meiosis, random separation of Z and W should result in half the chicks being male and half female, but birds are tricky. Somehow the female is able to manipulate whether the Z or W chromosome gets into an egg. </p>
<p>Most bird species produce more males than females on average. Some birds, such as kestrels, produce different sex ratios at <a href="http://www.ornis.hu/articles/OrnisHungarica_vol20(1)_p26-36.pdf">different times of the year and others respond to environmental conditions or the female’s body condition</a>. For example, when times are tough for zebra finches, more females are produced. Some birds, such as the kookaburra, contrive usually to <a href="https://academic.oup.com/beheco/article/12/5/524/311658">hatch a male chick first, then a female one</a>.</p>
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Read more:
<a href="https://theconversation.com/ive-always-wondered-can-two-chickens-hatch-out-of-a-double-yolk-egg-94165">I've always wondered: can two chickens hatch out of a double-yolk egg?</a>
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<p>Why would a bird manipulate the sex of her chicks? We think she is optimising the likelihood of her offspring mating and rearing young (so ensuring the continuation of her genes into future generations). </p>
<p>It makes sense for females in poor condition to hatch more female chicks, because weak male chicks are unlikely to surmount the rigours of courtship and reproduction.</p>
<p>How does the female do it? There is some evidence she can bias the sex ratio by controlling hormones, <a href="http://news.cornell.edu/stories/2005/05/how-hatch-more-females-males-some-mother-birds-find-way-produce-more-progesterone">particularly progesterone</a>. </p>
<h2>How male and female birds develop</h2>
<p>In humans, we know it’s a <a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">gene on the Y chromosome called SRY</a> that kickstarts the development of a testis in the embryo. The embryonic testis makes testosterone, and testosterone pushes the development of male characteristics like genitals, hair and voice. </p>
<p>But in birds a completely different gene (called <a href="https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2011.08032.x">DMRT1</a>) on the Z but not the W seems to determine sex of an embryo. </p>
<p>In a ZZ embryo, the two copies of DMRT1 induce a ridge of cells (the gonad precursor) to develop into a testis, which produces testosterone; a male bird develops. In a ZW female embryo, the single copy of DMRT1 permits the gonad to develop into an ovary, which makes estrogen and other related hormones; a female bird results. </p>
<p>This kind of sex determination is known as “<a href="http://aerg.canberra.edu.au/library/sex_general/2001_Graves_chromosomes.pdf">gene dosage</a>”. </p>
<p>It’s the difference in the number of sex genes that determines sex. Surprisingly, this mechanism is more common in vertebrates than the familiar mammalian system (in which the presence or absence of a Y chromosome bearing the SRY gene determines sex).</p>
<p>Unlike mammals, we never see birds with differences in Z and W chromosome number; there seems to be no bird equivalent to XO women with just a single X chromosome, and men with XXY chromosomes. It may be that such changes are <a href="https://www.ncbi.nlm.nih.gov/pubmed/14684995">lethal in birds</a>.</p>
<h2>Birds that are half-male, half-female</h2>
<p>Very occasionally a bird is found with one side male, the other female. The recently sighted cardinal has <a href="https://www.nationalgeographic.com/animals/2019/01/half-male-half-female-cardinal-pennsylvania/">red male plumage on the right, and beige (female) feathers on the left</a>.</p>
<p>One <a href="https://www.nature.com/news/2010/100310/full/news.2010.114.html">famous chicken</a> is male on the right and female on the left, with spectacular differences in plumage, comb and fatness. </p>
<p>The most likely origin of such rare mixed animals (called “chimaeras”) is from fusion of separate ZZ and ZW embryos, or from double fertilisation of an abnormal ZW egg.</p>
<p>But why is there such clear 50:50 physical demarcation in half-and-half birds? The protein produced by the sex determining gene DMRT1, as well as sex hormones, travels around the body in the blood so should affect both sides. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/curious-kids-how-can-chickens-run-around-after-their-heads-have-been-chopped-off-103701">Curious Kids: how can chickens run around after their heads have been chopped off?</a>
</strong>
</em>
</p>
<hr>
<p>There must be another biological pathway, something else on sex chromosomes that fixes sex in the two sides of the body and interprets the same genetic and hormone signals differently. </p>
<h2>What genes specify sex differences birds?</h2>
<p>Birds may show spectacular sex differences in appearance (such as size, plumage, colour) and behaviour (such as singing). Think of the peacock’s splendid tail, much admired by drab peahens.</p>
<p>You might think the Z chromosome would be a good place for exorbitant male colour genes, and that the W would be a handy place for egg genes. But the W chromosome seems to have <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468903/">no specifically female genes</a>. </p>
<p>Studies of the whole peacock genome show that the genes responsible for the spectacular tail feathers are scattered <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156156/">all over the genome</a>. So they are probably regulated by male and female hormones, and only indirectly the result of sex chromosomes.</p><img src="https://counter.theconversation.com/content/112061/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from ARC. </span></em></p>Birds have some of the most amazing sex differences of any animal. They can control the sex of offspring, and even produce rare half-male, half-females. And their sex genes and chromosomes are quite different from ours.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed 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/760162017-08-09T19:39:54Z2017-08-09T19:39:54ZWhat happens in the womb affects our health as adults, but girls and boys respond differently<figure><img src="https://images.theconversation.com/files/174836/original/file-20170621-30198-1q16ivi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A baby's sex determines how they will respond to exposures during pregnancy.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p><em>Men and women respond differently to diseases and treatments for biological, social and psychological reasons. In this series on <a href="https://theconversation.com/au/topics/gender-medicine-39178">Gender Medicine</a>, experts explore these differences and the importance of approaching treatment and diagnosis through a gender lens.</em></p>
<hr>
<p>We all know girls and boys are different. These differences include behaviour, DNA, hormones and risk of disease, to name a few. Differences between boys and girls start very early in life, <a href="http://www.reproduction-online.org/content/141/5/563.full.pdf">well before</a> the sex-specific organs form.</p>
<p>Our DNA is responsible for a lot that happens in our bodies. A key difference between men and women are the <a href="https://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">sex chromosomes</a>. Women have two X chromosomes and men have an X and a Y chromosome. Whether you’re an XX or XY will <a href="https://theconversation.com/why-males-are-more-likely-to-die-from-conception-to-old-age-62288">determine how you grow</a> and respond to different exposures during pregnancy.</p>
<p>In a minority of the population, people with either XX (girl) or XY (boy) chromosomes may develop in a way atypical for the sex these combinations usually determine. But, for the purposes of this article, we will talk about the typical traits found in XX and XY chromosome babies.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/boy-girl-or-dilemmas-when-sex-development-goes-awry-49359">Boy, girl or …? Dilemmas when sex development goes awry</a>
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</em>
</p>
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<p>The fetus is influenced by its environment and what it is exposed to. These exposures, such as what the mum eats and whether she smokes or drinks, <a href="https://theconversation.com/where-we-come-from-determines-how-we-fare-the-fetal-origins-of-adult-disease-3581">alter the fetus’s immediate health</a>, but also increase their risk of diabetes or heart disease in adulthood. </p>
<p>For example, babies that have a low birth weight and grow slowly are <a href="https://www.ncbi.nlm.nih.gov/pubmed/17124527">more likely</a> to have heart disease or type 2 diabetes as adults. The impacts of what the baby experiences while in the womb on their health as adults is known as <a href="http://www.bmj.com/content/301/6761/1111">the Barker hypothesis</a>. </p>
<p>A well-known example of this is the Dutch famine of 1944-45. This resulted in five to six months of calorie restriction for the affected population. Studies show mothers who faced calorie restriction early in pregnancy (the first 13 weeks) had a <a href="https://pdfs.semanticscholar.org/5a11/c2a0c671cc4e3e8f7e2026e5583b2f9947c9.pdf">child who was more likely</a> to suffer from heart disease as an adult. The children of those who were in the later stages of pregnancy during the famine (the last 13 weeks of pregnancy) were more likely to develop type 2 diabetes in adulthood.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/181140/original/file-20170807-19201-18ihp9c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A child is affected by what they are exposed to as a fetus.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<h2>Exposures during pregnancy</h2>
<p>Smoking during pregnancy is more likely to result in the birth of a small baby. It is also <a href="https://theconversation.com/an-incontrovertible-truth-smoking-harms-foetuses-23843">associated with behavioural problems</a> in infancy and adolescence, as well as adverse health outcomes such as birth defects, asthma and allergies. But the impacts of these exposures during pregnancy, as well as their severity, depend on the sex of the baby. </p>
<p>A <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133752/">recent Finnish study</a> examined how maternal smoking affected children’s mental health at ages 25 to 27. It found adult men whose mothers smoked during pregnancy had worse problem-solving skills and vocabulary than men not exposed to maternal smoking. But no negative effects were seen in the female children of mothers who smoked.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/passing-on-taste-how-your-mums-diet-affects-what-you-eat-35550">Passing on taste: how your mum’s diet affects what you eat</a>
</strong>
</em>
</p>
<hr>
<p>Too much exposure to heavy metals – such as cadmium – during pregnancy is associated with adverse health effects in children including cancer, diabetes and heart disease. Pregnant women can be exposed to heavy metals through work and manufacturing processes, as well as smoking and diet. </p>
<p>One study of more than 3,800 women and children <a href="https://www.ncbi.nlm.nih.gov/labs/articles/27778365/">showed higher levels of cadmium</a> in the mum’s blood at 9-13 weeks of pregnancy were associated with smaller female babies – but there was no impact on males. </p>
<p>Many other studies show how different sexes may respond differently to adverse exposures during pregnancy. These studies are difficult to explore in humans due to the number and range of adverse exposures one accumulates after birth. So they only offer associations between the two events, rather than evidence one caused the other.</p>
<p>For instance, studies of <a href="https://theconversation.com/explainer-what-is-twin-research-26468?sa=google&sq=twins+disease&sr=2">genetically identical twins</a> show, as adults, one twin may develop type 2 diabetes or heart disease while the other twin remains healthy. Although the twins shared an identical environment in the womb, their different environments after birth meant they were exposed to different things as they aged.</p>
<h2>The role of the placenta</h2>
<p>Sex differences in response to adverse exposures during pregnancy may be <a href="https://digital.library.adelaide.edu.au/dspace/handle/2440/57601">mediated by the placenta</a>. The placenta connects the developing fetus to the mother’s uterus, ensuring the baby receives the nutrients it needs. It also takes care of waste, gases and hormone production. The placenta actually has the same DNA sequence as the baby, not the mother. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=370&fit=crop&dpr=1 600w, https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=370&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=370&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=464&fit=crop&dpr=1 754w, https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=464&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/174840/original/file-20170621-30161-1afb25a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=464&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The placenta ensures the developing fetus receives all the nutrients it needs.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>A baby’s growth depends on the mother’s diet. Boys grow faster than girls during gestation and are on average 100 grams <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158807">heavier than girls</a> at birth. This is because they are more <a href="https://www.ncbi.nlm.nih.gov/pubmed/19875166">likely to extract</a> maximum nutrients from their placentas. </p>
<p>But this also means boys leave <a href="https://www.ncbi.nlm.nih.gov/pubmed/20004469">little in reserve</a> and are are more likely to be undernourished or stillborn if <a href="https://www.ncbi.nlm.nih.gov/pubmed/20004469">something goes wrong</a> in pregnancy. However, girls slow their growth when exposed to adversity during pregnancy in order to survive.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/why-males-are-more-likely-to-die-from-conception-to-old-age-62288">Why males are more likely to die from conception to old age</a>
</strong>
</em>
</p>
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<p>A possible reason for these sex differences may hark back to our evolutionary past when relatively few males survived to adulthood and reproduced. Those who did tended to be the biggest and strongest and most able to compete to pass on their genes to the next generation. Females, on the other hand, were more likely to survive to adulthood because that level of competition wasn’t there, and the vast majority would reproduce.</p>
<p>We are not entirely sure why boys and girls respond differently to adverse exposures during pregnancy. And while sex chromosomes play a large role, they may not be wholly responsible. We <a href="https://www.ncbi.nlm.nih.gov/pubmed/24867328">assessed gene differences</a> in 303 placentas from uncomplicated pregnancies and found 142 genes that were different between boys and girls. More than half of these genes were not on the sex chromosomes. </p>
<p>A lot more research is needed to try to understand why boys and girls grow differently during pregnancy and why they respond differently to adverse exposures during pregnancy.</p>
<hr>
<p><strong><em>Read other articles in the series:</em></strong></p>
<p><em><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>
<p><em><a href="https://theconversation.com/man-flu-is-real-but-women-get-more-autoimmune-diseases-and-allergies-77248">Man flu is real, but women get more autoimmune diseases and allergies</a></em></p>
<p><em><a href="https://theconversation.com/women-have-heart-attacks-too-but-their-symptoms-are-often-dismissed-as-something-else-76083">Women have heart attacks too, but their symptoms are often dismissed as something else</a></em></p>
<p><em><a href="https://theconversation.com/biology-is-partly-to-blame-for-high-rates-of-mental-illness-in-women-the-rest-is-social-75700">Biology is partly to blame for high rates of mental illness in women – the rest is social</a></em></p>
<p><em><a href="https://theconversation.com/both-men-and-women-need-strong-bones-but-their-skeletons-grow-differently-across-ages-75915">Both men and women need strong bones, but their skeletons grow differently across ages</a></em></p><img src="https://counter.theconversation.com/content/76016/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Claire Roberts receives funding from NHMRC, NIH NICHD and the University of Adelaide. </span></em></p><p class="fine-print"><em><span>Tina Bianco-Miotto does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>If something goes wrong in pregnancy, a boy baby is more likely to be born malnourished or stillborn than a girl. This may have an evolutionary basis.Tina Bianco-Miotto, Senior Lecturer, University of AdelaideClaire Roberts, Lloyd Cox Professorial Research Fellow, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/625352016-07-26T03:47:56Z2016-07-26T03:47:56ZDid sex drive mammal evolution? How one species can become two<figure><img src="https://images.theconversation.com/files/131732/original/image-20160725-31171-dcogrr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">There's a difference in the sex chromosomes between various mammals, such as the platypus compared to humans.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/darrenputtock/15220743500/">Flickr/Darren Puttock</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span></figcaption></figure><p>How new species are created is at the very core of the theory of evolution. The reigning theory is that physically separated populations of one species drift apart gradually.</p>
<p>But changes in chromosomes, particularly sex chromosomes, can interpose drastic barriers to reproduction. Mammals may be a good example. Comparisons of the sex chromosomes of the three major mammal groups show that there were two upheavals of sex chromosomes during mammal evolution.</p>
<p>The first corresponded to the divergence of monotreme mammals (platypus and echidna) from the rest, and the second to the divergence of marsupials from placental mammals (including humans).</p>
<p>In a <a href="http://onlinelibrary.wiley.com/doi/10.1002/bies.201600019/abstract">paper published in BioEssays</a>, I propose that drastic sex chromosome changes could have played a direct role in separating our lineage (placental mammals), first from the egg-laying monotremes, then from marsupials.</p>
<p>In humans and other placental mammals, such as mice, dogs and elephants, sex is determined by a pair of chromosomes. Females have two copies of the X while males have a single copy of the X and a small Y that contains the male-determining gene <a href="https://ghr.nlm.nih.gov/gene/SRY"><em>SRY</em></a>.</p>
<p>Other vertebrate animals also have sex chromosomes, but they are different. Birds have an unrelated sex chromosome pair called ZW, and a different sex determining gene called <em>DMRT1</em>.</p>
<p>Snakes also have a ZW system, but again it is a different chromosome with different genes. Lizards and turtles, frogs and fish have all sorts of sex chromosomes that are different from the mammal system and from each other.</p>
<h2>The rise and fall of sex chromosomes</h2>
<p>Sex chromosomes are really weird because of the way they evolved. They start off as ordinary chromosomes, known as autosomes. A new sex gene arises on one member of the pair, defining either a male-determining Y as in humans or a female-determining W as in birds.</p>
<p>The acquisition of a sex factor on one member of the pair is the kiss of death for that chromosome, and it <a href="http://theconversation.com/sex-genes-the-y-chromosome-and-the-future-of-men-32893">degrades quickly</a>. This explains why only a few active genes remain on the human Y and the bird W.</p>
<p>When old sex chromosomes self-destruct, a new sex gene and sex chromosomes may take over. This is fraught with peril because the interaction of old and new systems of sex determination is likely to cause severe infertility in hybrids. </p>
<p>Rival sex genes may be at war with each other, causing intersexual development, or at least infertility. For instance, what will be the sex of a hybrid that has both a male-determining Y and a female-determining W?</p>
<p>Added to this are problems with gene dosage because the degenerate Y and the W have few genes. If an XY male mates with a ZW female, most of the progeny will be short of genes. There may also be problems with gene dosage because genes on the X and the Z are used to working harder to compensate for their single dosage. </p>
<p>Rearrangement of sex chromosomes with autosomes also causes severe infertility because half the reproductive cells of a hybrid will have too many, or too few, copies of the fused chromosome.</p>
<p>Such hybrid infertility poses a reproductive barrier between populations with the new and the old sex system. So could such barriers drive apart populations to form distinct species? </p>
<h2>Reproductive barriers and new species</h2>
<p>The idea that chromosome change could drive the formation of new species was popular 50 years ago.</p>
<p>But it was thoroughly dismissed by evolutionary geneticists in favour of the idea that speciation, the formation of new and distinct species, must occur in populations already separated by a physical barrier such as a river or mountains, or behaviour such as mating time, and occupied different environments. </p>
<p>Small mutations would accumulate slowly and the two populations would be selected for different traits. Eventually they would become so different that they could no longer mate with each other and would form two species. This <a href="http://www.evolution.berkeley.edu/evosite/evo101/VC1bAllopatric.shtml">allopatric speciation</a> relied on external factors.</p>
<p>The alternate view, that <a href="http://www.evolution.berkeley.edu/evosite/evo101/VC1eSympatric.shtml">sympatric speciation</a> can happen within a population because of intrinsic genome changes, fell out of favour. Partly this was because it is hard to demonstrate speciation of populations sharing the same environment, the argument always being that the environment could be subtly different. </p>
<p>The other problem was imagining how a major chromosome change that occurred in one animal could spread to a whole population. Sex chromosome change is especially drastic because it directly affects reproduction. But our comparisons show that sex chromosomes have undergone dramatic changes throughout vertebrate evolution.</p>
<p>It is important to examine closely examples of evolutionary divergence that were accompanied by drastic sex chromosome change. Strangely, mammals may offer us a window into this evolutionary past. Their sex chromosomes are extremely stable, yet they have undergone rare dramatic changes, each of which lines up near when one lineage became two.</p>
<h2>Sex chromosome change and mammal divergence</h2>
<p>Placental mammals all share essentially the same XY. Marsupials, too, have XY chromosomes, but they are smaller; genes on the top bit of human X are on autosomes in marsupials. </p>
<p>Comparisons outside mammals shows that this bit was fused to ancient marsupial-like X and Y chromosomes before the different lines of placental mammals separated 105-million years ago.</p>
<p>Monotreme mammals (platypus and echidna) have bizarre multiple X and Y chromosomes. Surprisingly, comparing the genes they bear showed that they are completely unrelated to the XY of humans and marsupials. In fact, platypus sex chromosomes are related to bird sex chromosomes. </p>
<p>The human XY pair is represented by an ordinary chromosome in platypus. So our XY and <em>SRY</em> are quite young because they must have evolved after monotremes diverged from our lineage 190-million years ago.</p>
<p>Sex chromosome change has occurred very rarely in mammals, so it seems significant that each change corresponds to a major divergence. That’s why I propose that sex chromosome turnover separated monotremes from the rest of the mammals, and sex chromosome fusion occurred later to separate our lineage from marsupials.</p>
<p>Strengthening the argument that sex chromosome turnover begets speciation is evidence of a new round of sex chromosome change and speciation. </p>
<p>In Japan and eastern Europe, species in two rodent lineages have completely eliminated the Y chromosome and replaced <em>SRY</em> with a different gene on a different chromosome. In each lineage the Y-less rodents have recently diverged into <a href="http://molecularevolutionforum.blogspot.com.au/2012/05/rodents-with-no-y-chromosome-and-no-sry.html">three species</a>.</p>
<p>What does this mean for our own lineage? The primate Y seems to be more stable than the rodent Y. But if it continues to degrade at the same rate, it will disappear in about 4.6 million years. </p>
<p>Will it be replaced by some different gene and chromosome? And if so, will this unleash a new round of hominid speciation? We may have to wait another 4.6 million years to find out.</p><img src="https://counter.theconversation.com/content/62535/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jenny Graves receives funding from NHMRC and ARC. </span></em></p>How new species are created is at the core of the theory of evolution. Mammals may be a good example of how sex chromosome change drove major groups apart.Jenny Graves, Distinguished Professor of Genetics, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.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.