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Unit 11: Biology of Sex and Gender
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David Page, MD

David Page, MD
Page is an investigator at Massachusetts Institute of Technology and is also the associate director of Science at the Whitehead Institute for Biomedical Research, and professor of biology at the Massachusetts Institute of Technology. In 1992 his laboratory mapped and cloned the entire Y chromosome. Today, he uses the map and other tools to trace the genetic causes of male infertility, the history of the Y chromosome and human populations, and the origins of common genetic diseases.

Why is the field of sex and gender so well studied?

I think people are obsessed with sexuality, obsessed with what it means to be male or female in part because it's one of the first things that little kids become focused on as they look at the world. I can say from my own experience. I have three daughters. I have nieces, relatives.

I see little kids decide pretty early on that it's an important thing to sort out what your gender is as part of who you are. Perhaps it feels as important to a child as their name or how old they are. That's the fundamental basis of why there is so much interest in this question of are you a male or you a female; how does all of this fit into our understanding of ourselves and our individual identities.

Besides the medical implications, what are the other things useful in studying the Y chromosome in this field?

Studying the Y is interesting in part because it's actually been studied for a long time and with much misunderstanding, so the Y is a chromosome that people have been trying to read things into for the better part of a century.

People care about the Y chromosome because at some fundamental level it has to do with the difference between being a male and being a female. We know that females have two X chromosomes, that males have an X and a Y and that otherwise the genes, the genomes, the chromosomes of male and females are absolutely identical.

There have been cartoons made of the gene content of the Y chromosome. It's probably the only human chromosome about which cartoons are made. Y chromosome cartoons are full of genes that have to do with the ability to identify aircraft at considerable distance, the inability to stop and ask directions, and belching, burping, and spitting.

The Y is seen as a kind of Rorschach test for people's notions of what it is to be male or female and that's why the Y has such a broad appeal in the popular imagination.

Where did the Olympic Committee go wrong regarding the Maria Patino story?

The challenge for that Olympic Committee-and actually for anybody who thinks about the development of sexuality today-is one of definitions and our need to define things. [The] Olympic Committee had a desperate need to have a simple definition of what it is to be male or to be female. We know from our own personal experience that there is no such thing as a simple definition and even within a scientific context, sex or gender has been defined at many different levels.

The class formulation now in humans or in mammals starts with a sex chromosome definition. Are you XX or are you XY? The classic formulation then moves on to a definition which looks at the gonads. Do you have testes or ovaries? And then moves on to the internal accessory structures. Do you have a uterus and fallopian tubes or do you have an epididymis and a vas deferens. It then moves on to the external genitalia. Do you have a clitoris and labia or do you have a penis. [It finally] moves on to a sort of behavioral or brain-based, more gender-oriented definition. And we could go on and on [with] legal definitions of what it means to be male or female.

The world-kids, adults, and scientists-is obsessed with this question of how to define sex and often we fall over ourselves because of the limitations of the definitions we try to impose. That's precisely the situation that that Olympic Committee found itself in.

Can the definition be simplified?

The reality is that being male or being female-maleness/femaleness-must be captured in all these dimensions. When approaching questions of genetics and of biology, it's appropriate to focus on one aspect of the definition. But as the scientific work on the biological basis of sex and gender filters out into society, it tends to collide with these many different levels of definition and that provides great opportunity for misinterpretation and misapplication and that's exactly where the Olympic Committee found itself.

Can you discuss the history of the discovery of the SRY gene?

How did we come to an understanding that a single gene on the Y chromosome, SRY, plays a pivotal role in determining whether the embryonic gonad develops as a testes or ovary and hence drives the development of a male or female?

Prior to 1959, it was actually thought that sex in humans was determined by the number of X chromosomes. That was simply because that had been shown to be the case in fruit flies, Drosophila melanogaster, back in 1916. Since we, like flies, have XY sex chromosomes, it was assumed that we [also] determined our sex according to the number of X's.

Only in 1959 was it shown that Klinefelter's males are XXY and Turner females are XO. What that showed was that no matter how many X's you had-one or two, or even three or four-if you had a Y you developed testes and as male. But if you didn't have a Y-didn't matter how many X's you had, one, two, three or four-you develop as a female. So in 1959 it became clear that it's the presence or absence of the Y chromosome that determines testes vs. ovary, male or female.

From 1959 we now move fast forward into the 1980s when through the study of human XX males and XY females it became clear that it's just a small piece of the Y chromosome which by its presence or absence determines whether the embryo develops testes or ovaries. It turns out the XX males-one in 20,000 males are XX-carry a small portion of the Y chromosome which would prove to contain a single gene, SRY. XX males carry a small portion of the Y chromosome attached to one of their X's. And some XY females conversely are missing a piece of the Y. They're missing the piece of the Y that contains the SRY gene.

So that led to a narrowing down of a region on the Y that looked to be pivotal, but the final proof that SRY was the sex determining gene came in the form of two types of experiments, both genetic. One was the demonstration that some human XY females have very subtle mutations, so-called "point mutations," within the SRY gene. In other words, an individual who had a single base pair substituted in SRY but otherwise had an [normal] Y would nonetheless develop as a female was one piece of proof.

The other was the demonstration in transgenic mice that adding the mouse SRY gene to an otherwise XX mouse embryo caused that XX embryo to develop testes and as a male. That was the final smoking gun that SRY was the pivotal sex determining gene on the Y.

Did the search keep getting smaller?

It was a process of narrowing. In 1959 basically we learned that it was something about the Y chromosome-one or more genes on the Y chromosome.

Now truth be known, prior to 1959, it was suspected that there might not be even a single gene on the Y chromosome. So this was a sort of gift to the understanding of the Y that there was a sex determining gene on it. Then it basically took the coming of the recombinant DNA era, the modern era in human molecular genetics to come to a cleaner definition of the sex determining region of the Y chromosome and ultimately to the discovery at a molecular level of a single gene-and actually a quite small gene-on the Y chromosome, SRY.

Why is the Y chromosome so unique compared to the other chromosomes?

The Y chromosome is striking in a number of respects. First it's one of the smallest of the human chromosomes. It's about the same size actually as Chromosomes 21 and 22. But perhaps to even to a more striking degree it's got a relatively low content of genes. Our present understanding is that the Y carries about 40 or so distinct genes or gene families.

A typical human chromosome we think carries about a thousand genes.

The genes on the Y come in perhaps three flavors. There is one gene-SRY-that plays a pivotal role in determining whether the embryonic gonad develops its testes or ovary. About half of the genes have very close counterparts on the X chromosome, so we can think of these as XY gene pairs. The remarkable thing is that these XY genes, both the X copies and the Y copies, are expressed widely throughout the body in most if not all tissues. And it appeared to be involved in cellular housekeeping functions.

For instance, a protein that is a component of the ribosome is encoded by a gene on the Y chromosome and a counterpart gene on the X chromosome. It's been a source of amusement to some that there should be housekeeping functions encoded by the Y chromosome.

Finally a third class of genes on the Y-at least half the genes on the Y chromosome-are expressed in exactly one and only one part of the body and that's the testes. These testes genes on the Y actually appear to be active only in the spermatic genetic cells themselves. So a great many of the genes on the Y chromosome look to be involved in sperm production. This really sets the Y apart from all other chromosomes.

We think of most chromosomes as being fairly motley haphazard collections of genes involved in lung and liver and brain and skin and hair and so on. But it looks like the Y chromosome has a real functional specialization. At least half of its genes are involved in exactly one of the perhaps thousand cell types in the body, that is about half the genes on the Y are involved in the spermatic genetic cells.

What have you been trying to understand about the Y?

Over the years I've been trying to understand how to think about the Y chromosome. The way that we've come to think about the Y chromosome is by gathering lots of info about what it's made of and what its structure is.

What really motivates me in studying the Y chromosome is to understand how to think about it in part because I've become convinced that the Y has been for the better part of a century a deeply misunderstood chromosome. Actually in the first half of the 20th Century, people were finding evidence of things like genes for hairy ears on the Y chromosome or scaly skin. So there were all sorts of bizarre reports of families where the men had particular characteristics that were attributed to genes on the Y. Well, that understanding of the Y's genes fell apart in the middle of the 20th Century and was replaced by an understanding of the Y chromosome as a genetic wasteland.

I see in some sense our work as the undoing of the genetic wasteland model and the construction of a new sort of model where in the Y actually has genes and we have some understanding of its roles in now sperm production, in determining whether the embryo develops as a male or a female, and then in these housekeeping functions that the Y shares with the X chromosome.

I think the other thing that has completely reshaped our understanding of the Y is the realization that the Y and the X evolved from what was once a perfectly ordinary pair of chromosomes from a perfectly ordinary pair of autosomes. To be honest my whole thinking about the Y chromosome is now been transformed by that understanding that the Y together with the X represent a grand experiment of nature to transform a perfectly matched ordinary pair of chromosomes into this extraordinarily differentiated X and Y chromosomes, something that we understand has unfolded across the last 300 million years of our evolution.

How do some species determine their sex differently?

There are lots of animals that come as male and female that don't have sex chromosomes. Turtles, for instance: one makes eggs, one makes sperm but [there are] no sex chromosomes, just ordinary autosomes. In turtles, the sex of an individual embryo is determined by the temperature at which it is an egg incubates. In some species little warmer temperature gives you females and other turtle species the warmer temperature gives you the males.

And something of this sort was probably true of us, or I should say our ancestors, about 300 million years ago. When we were reptiles we existed as male and female but we had no sex chromosomes, only ordinary chromosomes, as in turtles today. We think that what happened about 300 million years ago-and I should say this is shortly after our ancestors parted company with the ancestors of birds-at that time a mutation arose on one of a perfectly ordinary pair of chromosomes. That mutation would give rise to what we now know today as SRY, the sex determining gene, and it would arise on a pair of chromosomes, perfectly matched at that time, but that would today reappear as the highly differentiated Y and X chromosomes.

The X and the Y touch but they swap parts only in a very limited region. Across most of their length, they're not swapping parts and during the course of the last 300 million years been able to differentiate one from another.

What we've come to understand is that one key step in a sense in the evolution of the sex chromosomes, was the invention of SRY, the sex determining gene on the Y. But having invented SRY the key driver of the evolution of the sex chromosomes was the shutting down of recombination of crossing over between this pair. Now ironically it is that swapping of genes between paired chromosomes that is the defining feature of sexual recombination, of sexual reproduction. So ironically the sex chromosomes arose by the shutting down of the process that is actually the defining feature of sex reproduction.

If you've a male and you have a Y chromosome, you inherited that Y chromosome in unbroken unshuffled form from your father and he from his father and he from his father. So in the guise of your Y chromosome, you can look back through a male lineage in unbroken unrecombined form. That is not true of any of the other chromosomes in the nucleus of a male cells nor is it true of any of the chromosomes in the nucleus of female cells.

So ironically, then, the Y is called a sex chromosome. It actually reproduces in an asexual fashion. The Y has been reproduced for generation upon generation in the same way that Dolly, the sheep, was produced.

How did your studies figure this out?

It turns out that the key to understanding the evolution of the sex chromosomes in humans has come through simply studying the DNA sequences of the X and the Y and in particular looking at the genes that the X and the Y chromosome share. So the strongest evidence that the X and the Y evolved from a single common ancestral pair of autosomes is those genes that today remain present in similar but non-identical form on the X and the Y chromosomes.

We now view these XY gene pairs as a kind of living fossil. They give us a glimpse back into the past when the X and the Y had an absolutely identical gene content. Today we can see a small remnant of that shared gene content. We think that today's X chromosome largely retains the gene content of the ancestral autosome, whereas the Y retains a small fraction of those genes that it once shared with the X chromosome.

Nonetheless through the surviving XY gene pairs, we've been able to reconstruct, for instance, that our X chromosomes are in fact 300 million years old and that they've actually evolved in a very piecemeal, step-by-step fashion. The evolution of the sex chromosomes has unfolded over a very long period of time and is in many senses still incomplete. We can still see evidence that the X and the Y are evolving in directions that have not yet come to a logical conclusion.

Why is the Y shrinking?

It looks like the Y in its evolution is very much intended to lose genes. The question has been raised by many of my colleagues in science as to whether the Y is on its way out. The loss of genes on the Y is so inevitable and so rapid that some have questioned this year in the pages of Nature is the Y about to disappear entirely in the next 5 to 10 million years.

It looks like the Y has actually explored some roots that will ensure its longevity. It's clear that the Y has lost a great many genes. The ancestral loss gave rise to the X and the Y probably had a thousand or 1,500 genes on it. Let's say that the ancestral chromosome that gave rise to the X and the Y probably had about a thousand genes on it. Most of those thousand genes live on today on the X chromosome, but all but 20 or 30 have been lost from the Y chromosome.

So is it all downhill for the Y from here? Is the Y doomed to extinction in 5 to 10 million years as some of my colleagues have? We think not for a couple of reasons.

One is that we found that the Y has not only been throwing overboard most of the genes that it once shared with the X, but at the same time it's been taking on a few new genes. These have come from autosomes by various means. They mostly come in as chunks of DNA by so-called "transposition" or in some cases "retro transposition" from autosomes. These events have brought to the Y chromosome new genes that appear to be critical for spermagenesis. So at the same time that the Y has been losing many of its ancestral genes, it has been essentially been rejuvenated by new immigrants that are serving spermagenesis.

The other thing that seems to be operating on the Y chromosome-and this is a truly dramatic surprise for us-is the genes on the Y were thought to be rotting because those genes don't have a counterpart on a homologous chromosome with which to swap and sort of repair. Well, a very recent finding that we've come upon suggests that many of the spermagenesis or testes genes on the Y chromosome actually exist in two copies or four copies on the Y chromosome. So the Y carries many of these genes in partners with which they can swap for spare parts. Those partners are actually carried within the Y chromosome itself and it looks very much as though there's a high level of gene swapping going on within the Y chromosome. It looks like the Y has invented a whole new mechanism of gene swapping. It's not between paired chromosomes. It's within the Y itself.

What makes this chromosome difficult to study?

The Y chromosome is a hard chromosome to study. Historically, the Y was misunderstood because it comes in just one copy and is not participating in the swapping of parts that autosomes normally undergo. Those reasons lead to difficulties in applying pedigree analysis, the study of family trees, to the Y. In fact, no gene on the Y chromosome has had its existence correctly inferred from the study of family trees. We know of lots of genes that run in families on autosomes and on the X-the X link recessive, autosomal dominant/autosomal recessive modes of inheritance.

Nobody has ever found a gene on the Y chromosome by first identifying a strictly Y link mode of inheritance. Instead we've had to look strictly at the DNA level, to come to understand the Y chromosome through DNA-level-up studies. And those DNA-level-up studies of the Y are actually unusually difficult for one reason and that is that there are many massive repeated sequences on the Y chromosome.

A few years ago when people asked me: Why is it difficult to make maps and sequences of the Y chromosome? My answer was that it was like a hall of mirrors. Mapping the Y's a little bit like going into a house of mirrors, spending some time there, walking out, being handed a piece of paper and a pencil with the request to draw a sketch of the house or hall that you've just explored.

I didn't know it at the time but that analogy was perfectly accurate. It turns out the Y at the at the level of its sequence is a house of reflections of almost perfectly reflected sequence images and the epitome of this is in the form of palindromes. Palindromes are of course sequences that read the same backwards and forwards. "Madame, I'm Adam" is a short palindrome or "2002" is a short palindrome. Well, it turns out that a total of eight palindromes make up the functional part of the Y chromosome.

Just to put this in perspective, the largest of these palindromes on the Y chromosome has a wingspan of 3 million base pairs of DNA. In other words, there's a sequence that reads one and a half million nucleotides of DNA in one direction and then you flip it around and see it a million and a half in the opposite direction, a total wingspan of 3 million base pairs with 99.97% arm-to-arm identity. So these are almost perfectly reflected mirror images.

You could imagine that if you were walking around among these base pairs over on this side and you went to sleep and somebody moved you over to this arm and you woke up you wouldn't realize you'd moved. It's extraordinarily difficult to map the Y because of these almost perfectly reflected images. But there's a biological consequence as well and that is that these palindromes carry many of the spermagenesis genes, many of the testes genes, and we think that these palindromes actually are pivotal to this method of gene swapping within the Y chromosome that it has invented. In other words, we think that the testes genes on one arm of the palindrome find their spare parts on the opposite arm of the palindrome where an essentially an identical gene is located.

Could you explain more about how the Y underwent inversions in its evolution?

An interesting question is how did the X and the Y come to stop swapping genes. What drove this suppression of XY recombination? We don't absolutely know for sure, but we suspect that [there was] a series of inversions of big chunks of DNA on the Y chromosome. We think [this] made it unable to pair up or align precisely and accurately with the X chromosome. It's that series of inversions on the Y chromosome that led to a piecemeal region-by-region suppression of swapping or XY recombination. And it was those inversions and the resultant shutting down of XY swapping that allowed the X and the Y sequences to diverge, to become different, so that we can end up today with an X that is several times the size of the Y and containing far more genes.

Can you talk about the mapping history?

For years we've been making maps of the Y chromosome. Originally, they were fairly crude things. I should say that all these maps were made possible by the coming of the recombinant DNA era. So the maps of the Y that we understand today are really entirely based on the Human Genome Project and its predecessors, the recombinant DNA era of the late 1970s and the 1980s.

The use of restriction enzymes and then ultimately PCR, all of these methods that underlie the recombinant DNA revolution were critical to being able to make maps of the Y. Initially, our first coherent maps of the Y came together in the 1980s. These were rather rudimentary things where we could chop the Y up into seven pieces and recognize that one of these seven pieces contained, for instance, the sex determining function of the Y chromosome.

Ultimately, by the by the early 1990s these rudimentary maps with seven intervals had morphed into a map of about 40 intervals and now a set of overlapping recombinant DNA clones that span the entirety of the chromosome. So in fact the Y was the first human chromosome to be cloned as a set of overlapping DNA molecules.

That's where we were in 1992. Then the goal over the subsequent decade was to transform this clone-based map into the knowledge of the complete DNA sequence of the chromosome and that's where we are today. We now know that the functional portion of the Y chromosome spans about 24 million base pairs of DNA. In addition, there's a large heterochromatic region of the Y which is actually a bit larger in size, although that size varies tremendously among men.

So the mapping of the Y has really gone through several phases, again, beginning with this rather crude rudimentary map and ending today with a map that is based on the detailed knowledge of the sequence. It's really only with the complete sequence of the of the chromosome in hand that we can bring to bear tools of electronic prediction that allow us to identify genes in the sequence even when we have no prior hint of their existence.

Is female the default sex?

Biologists have been saying for half a century that female development is a default outcome, that somehow all human or mammalian embryos are initially female and then can have masculinity imposed on them. I don't think that the available data supports this idea. Certainly making an ovary, making a female, doesn't happen spontaneously. I think instead the way embryos initially develop is in a form that are anatomically and microscopically indistinguishable, but neither male or female.

In fact, during the first six weeks of human development there are no anatomic or microscopic distinctions between XX or XY embryos, but instead all the pieces are put in place during those first six or seven weeks of development for that embryo to ultimately develop as either a male or a female. And what follows after the first six or seven weeks is a series of decisions made within the embryo.

For example, the embryo must decide whether its embryonic gonads will develop as testes or ovaries. Once it makes that decision the embryonic gonads secrete hormones that determine the fate of the external genitalia. But the beginnings for both male and female structures are present in all human embryos and so it's really from a sort of a common a single model that female and male development follows.

Both the male pathway and the female pathway are very active and require highly orchestrated, highly integrated sets of events, extremely complicated biochemical cascades that we're only beginning to understand. And truth be known, the prevailing textbook models of how sex differentiation unfolds are extremely biased in favor of the male. So our present textbook understanding of sex differentiation in mammals is really a story of how does a male develop. The story of how a female develops has yet to be written.

How do we have a sense of our gender?

Sex and gender can be defined at many different levels. At one level we can look at the chromosomes, at another level we can look at do you make eggs or do you make sperm, at another level we can ask each person. Who do you say that you are? Do you say that you're a male? Do you say that you're a female?

In some sense at a biological level we'd like to understand how all these connections are established during the development of an embryo, the fetus, of a child, of an adult. We don't understand them. I think the simplest answer is that the notion of sexual identity is not at all understood at present. I think that our individual sense of sexual identity teaches us as much as anything we can read in a textbook at present about how it develops.

It remains a tremendous mystery. People are chipping away at this question of how sexual identity forms, but to be honest there remains a big gulf within the field of research between those scholars including myself whose work is more anatomically and chromosomally focused and the work that is more behaviorally and cognitively focused. I think a big challenge for the future is going to be to unite these different notions of what it means to be male or female, these notions of gender.

Is there biology to gender identity?

I'm absolutely convinced that there is a biology of gender identity, but the field of the biology of gender identity is really in its infancy. I don't know that those questions are inherently more difficult, but it's harder for the scientist to grapple directly with those questions because if you're looking at the anatomy you can see it and there's a kind of indisputable nature.

In understanding the development of anatomic differences between the sexes, in most cases we actually learn much of what we know from the study of individuals in whom there's some problem, some abnormality in sex differentiation. And the anatomic differences that arise are generally agreed upon. Whereas sexual identity is obviously something that exists in the mind of the individual and is harder therefore for the investigator to identify objectively in a sort of an externalized way. So I anticipate a time when the biology of gender identity will be united with the biology of anatomic differences but we are not there yet. We're quite far from that unification.

What did the John/Joan case show?

I think the John/Joan case demonstrates that gender identity actually does have biological roots and that with respect to gene identity we are not blank slates. We are not blank slates on which our parents and our environment create us sexually.

That's what in part makes me so confident that ultimately we will understand in biological and therefore in chemical terms gender identity. I think that gender identity is probably every bit as biologically or chemically determined and molded as are our anatomies.

Do we know why people are homosexual or heterosexual?

In addition to the question of gender identity-do we see ourselves as male or female-is the question of sexual preference, heterosexual/homosexual. There remains a large unresolved controversy about whether there are genetic roots to homosexuality.

An influential paper was published in Science in the 1990s which pointed to a link actually between the X chromosome and in some cases of male homosexuality. There have been disputes over the meaning and validity of this report. Other papers have been published that were not able to reproduce the results. The reality is that the question remains unresolved. My own guess is that there will in fact prove ultimately to be genetic roots to sexual preference as there will prove to be for sexual identity.

So these are all pieces of a broad tapestry-sexual preference, gender identity, sexual anatomy, fertility-all of these are pieces of this sexual matrix which I think will ultimately be understood very much in biological and therefore, in chemical terms. But this will require a sort of synthesis and unification that we are far from at present.

What are the unanswered questions?

Among the biggest unanswered questions in the biology of sex in humans one is where do where do females come from. I think the models of how sex differentiation occurs in mammals is extraordinarily male biased. It does a good job of explaining how a testes and a male are produced and models at present actually do a very poor job of explaining how an ovary is formed and how a female develops. That is I think the most obvious hole in our understanding of the development of anatomic differences.

Beyond that lie a great many biochemical details that are extraordinary but which at present lie in a big black box that is not in any sense described either in textbooks or even in the primary scientific literature. [There is] the need to unify our understanding of the genetic biological and chemical bases of anatomic differences with our understanding of behavioral differences and our understanding of gender identity, sexual preference, and so on.

The fields of sex determination and of gender biology cross into so many sub-disciplines of biology and they are far from being united. They're disparate patches of study that ultimately need to be woven together and the need to weave them together is most obvious in the minds of people who are outside of biology who see the big picture as the focus. That big picture needs to be reclaimed.


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