National Geographic

The Tenuous Beginnings of Men

Daughters inherit many things from their fathers, but a select few get something unusual—a Y chromosome. Women typically have two X chromosomes while men have an X and a Y, but some XY people are born with female genitals and a uterus. They’re almost always raised as girls from birth, and their hidden Y chromosome only becomes obvious during puberty. That’s because they don’t develop working ovaries, and without these organs providing a flood of hormones, they don’t menstruate, grow body hair, or develop larger breasts on their own. They’re also sterile.

This condition, known as Swyer syndrome, is often caused by changes to SRY, a gene on the Y chromosome that acts as a master switch for maleness. Human embryos develop into females by default, but SRY diverts them from this course. It switches on many genes that transform an embryonic ridge into testes instead of ovaries. But SRY can pick up mutations that interfere with this role, and prevents it from launching its male-making programme. As a result, embryos develop into baby girls despite their Y chromosome.

But sometimes, fathers and daughters carry identical copies of SRY. He develops into a typical fertile male. She grows up as a sterile female. How can this be?

Michael Weiss from Case Western Reserve University has the answer. His team, led by graduate student Yen-Shan Chen, studied several pairs of fathers and daughters with identical Y chromosomes, and showed that SRY just isn’t a very strong switch. It doesn’t cleanly flip between on (male) and off (female). Instead, it does just enough to divert an embryo down the male path, and it’s easily affected by the environment or by other genes. Their results show that becoming a boy is a surprisingly precarious event.

Melissa Wilson-Sayres from the University of Berkeley, who studies sex chromosomes and was not involved in the study, compares SRY to a dimmer switch. At its ‘bright’ setting, it sets embryos down a male path; at lower ones, it fails to activate other genes, leading to female traits. “In humans, the dimmer switch isn’t normally set very ‘brightly’, so that slight variations are sufficient to affect the formation of gonads,” she explains.

This idea isn’t new, says Robin Lovell-Badge from the National Institute for Medical Research, who first discovered SRY. Since the 1990s, studies in mice have shown that SRY is active at just above the right threshold for producing testes. Peter Koopman summed up the idea in 2007: “What is clear is that instead of the robust gene one might expect as the pillar of male sexual development, SRY function hangs by a thin thread.”

“But while there have been clues that the same is true in humans, it has not been possible to prove this because of the difficulty of looking at human early gonads,” says Lovell-Badge. Weiss has now done so, and he says it was a necessary experiment. SRY works very differently in rodents and humans, so “there was no reason to believe that this result was true for humans. We now believe it is.”

SRY creates a protein of the same name, and it’s this protein that activates other male-making genes. Weiss’ team showed that their XY father-daughter pairs carried two SRY mutations that don’t much alter the protein’s abilities. Instead, they change its location.

Like all other proteins, SRY is made in the cytoplasm—the soupy liquid that forms the bulk of a cell. But to activate other genes, it needs to get into the nucleus—the central compartment where DNA resides. To do this, it sticks to other proteins that smuggle it in and out of the nucleus. Mutations in SRY can change the balance of these trips so that, for example, it can’t be efficiently imported into the nucleus. When this happens, it can’t do its job effectively, and the activity of its dependent genes falls by a factor of two.

Under some conditions, this difference doesn’t matter and the dependent genes are still active enough to launch the male-making programme. Under other conditions, they aren’t.

This is why fathers can develop as males and daughters can develop as females, even though they share the same copy of SRY. The whole set-up sits balanced on a knife-edge. Random factors like other genes or environmental conditions could send it in either direction, producing either a fertile male or a sterile female.

That’s very strange. There are many master genes that play pivotal roles in our development, controlling the growth of eyes, limbs and more. If these genes don’t work properly, the results could be catastrophic. So, they ought to be exceptionally stable—enforcing the status quo in the face of all but the most severe mutations or environmental conditions. It should take much more than a 2-fold difference in activity to change what they do. “We’d expect to see factors of 50-fold or more,” says Weiss. “These master switches are meant to be rigorously locked in. They’re not meant to be this tenuous.”

So, why does SRY operate from such a wobbly position? Why have a set-up that could so easily lead to infertility? For the variety, says Weiss. He thinks that the vagaries of SRY leads to a wide variety within developing testes, and a wide variation in the amount of testosterone they produce. This hormone influences our behaviour, including many aspects of our social lives. So, at the risk of the occasional infertile XY female, a precariously-set master switch leads to a broad spectrum of male brains, which may make for a better-functioning society. “You can’t have all alpha-males in a group,” suggests Weiss.

It’s a fairly speculative idea, and Wilson-Sayres isn’t convinced. She says that the far simpler explanation is that the Y-chromsome is especially prone to picking up mutations with weak harmful effects. Other chromosomes come in pairs and can swap parts of their DNA—a process that unites bad mutations in the same place, and allows them to be more easily weeded out by natural selection. The Y chromosome doesn’t get this benefit because it’s alone, and has nothing to swap with. It builds up harmful mutations more quickly, making it a treacherous place for a master switch to exist.

Reference: Chen, Racca, Phillips & Weiss. 2013. Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold. PNAS http://dx.doi.org/10.1073/pnas.1300828110

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There are 10 Comments. Add Yours.

  1. Shecky R
    September 2, 2013

    Do we know how many other genes (and playing what roles) operate in a “wobbly” versus a discrete on-off fashion? Seems like there might be several circumstances where ‘wobbly’-ness might be more advantageous than disadvantageous.

  2. James V. Kohl
    September 2, 2013

    From Fertilization to Adult Sexual Behavior (1996) Review article published in Hormones and Behavior. http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1996-from-fertilization.htmlGenetic Considerations

    “There is a tendency to discuss only a limited number of genes as participants in sexual differentiation; the most prominent being the presence or absence of SRY. This does not do justice to the complexity of sexual development and biological sex differences. For instance, there are molecular differences between specific homologous genes on the X and Y chromosomes (Fisher, Beer-Romero, Brown, Ridley, McNeil, Lawrence, Willard, Bieber, and Page, 1990; North, Sargent, O’Brien, Taylor, Wolfe, Affara, and Ferguson-Smith, 1991; Schneider-Gadicke, Beer-Romero, Brown, Mardon, Luoh, and Page, 1989; Weller, Critcher, Goodfellow, German, and Ellis, 1995; Zinn, Alagappan, Brown, Wool, and Page, 1994). Some genes exist on the Y and have no counterpart on the X, and certain nongene structural elements on the X and Y are sex-linked (Smith, Young, Talbot, and Schmeckpeper, 1987; Wolfe, Darling, Erickson, Craig, Buckle, Rigby, Willard, and Goodfellow, 1985). These numerous sets of genes and structural features of the X and Y chromosomes are sex differences which exist independently of the Gd–H–B pathway.”

    We also elaborated on molecular epigenetics in a section that helped us to link sex differences in unicelluar yeasts to human male sexual orientation via conserved molecular mechanisms in species from microbes to man (sans mutations).

  3. JMW
    September 3, 2013

    So, if this study is to be believed, whether a person develops as fertile male or sterile female is a wibbly-wobbly, gendery-wendery thing?

  4. Keith
    September 4, 2013

    Clearly this wobbly SRY isn’t something that’s important enough to have been evolved out. (Indeed it could possibly be the opposite.) Given that in a crisis most species (including humans) need more females than males, then a fragile mechanism which would confer fewer males but a small percentage of infertile females could be a genetic advantage, especially if said infertile females still become a part of a family group and help raise their (fertile) siblings’ offspring.

  5. LD
    September 5, 2013

    This statement – ” leads to a broad spectrum of male brains, which may make for a better-functioning society. “You can’t have all alpha-males in a group,” suggests Weiss” – is overly group selectionist for my taste.

    [Weiss is definitely advocating a group-selectionist argument in his paper. Obviously, some people don't like that but it's worth noting what his view is. - Ed]

  6. Stephanie
    September 5, 2013

    With hermaphrodites, multiple kinds of Intersex, and this I can’t help but wonder how people think transexuals are unnatural and evil. There is so much that can go wrong with chromosomes/DNA/Genitals, they don’t always match, so if their DNA or whatever is telling them their a certain gender and that doesn’t match with their genitals that is not their fault and they are not evil! Seriously just think about that.

  7. RobRN
    September 12, 2013

    I thought this syndrome had no uterus – Just a blind pouch vagina. Is that a different syndrome? Maybe testiclular feminization?

  8. Kathy S.
    October 17, 2013

    “But while there have been clues that the same is true in humans, it has not been possible to prove this because of the difficulty of looking at human early gonads,” says Lovell-Badge. Weiss has now done so, and he says it was a necessary experiment.

    So what was the ‘necessary experiment’?

  9. doesn’t matter
    January 10, 2014

    Well,I have Swayer syndrome and i can answer some of your questions.Girls with this syndrome do have uterus,but without hormones added,it will remain small and not suited for in vitro when the girl wants to have children in the future.there are ovaries also,but they are to be removed,because they can develop cancer.And I really want to say,we DO NOT feel like boys(very rare),but because of the Y chromozome we understand them much better! Hope i helped you understand

  10. Hal
    February 21, 2014

    “So, why does SRY operate from such a wobbly position? Why have a set-up that could so easily lead to infertility? For the variety, says Weiss. . . . So, at the risk of the occasional infertile XY female, a precariously-set master switch leads to a broad spectrum of male brains, which may make for a better-functioning society. “You can’t have all alpha-males in a group,” suggests Weiss.”

    This is expressed too teleologically. These mechanisms don’t operate “so that”; they operate “with the result that.”

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