The Scientist 15[15]:18, Jul. 23,
2001
RESEARCH
The Sexes: New Insights into the X and Y Chromosomes
The distance between Mars and Venus might be closer than previously thought
By Bob Beale
Neutrality? The default starting point for human embryos may be a neutral one,
not male or female as previously thought.
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The cry of "It's a boy" or "It's a girl" marks the newborn
child's first and most basic label of personal identity. But researchers'
understanding of sex is undergoing profound and surprising changes due to new
insights gained from sociology, biology, and medicine. The differences between
females and males, once believed black and white--or pink and blue--now appear
like a blurred rainbow of confusion. Researchers are learning, for example, that
the Y chromosome has degenerated over the centuries. They have found that, in
mice, some genes involved in early stages of sperm production are on the female
X chromosome; and they have identified the gene that can produce ambiguous
genitalia.
Genetic studies are revealing that men and women are more similar than distinct.
So far, of the approximately 31,000 genes in the human genome, men and women
differ only in the two sex chromosomes, X and Y, and only a few dozen genes seem
to be involved. Moreover, it's now known that the Y has only about 30 genes and
many of those are involved in basic housekeeping duties or in regulating sperm
production. The X has hundreds of genes with a vast array of roles.
Strong evidence exists that these two chromosomes were once a matching pair of
Xs, says Jennifer Graves, a genetics researcher at La Trobe University, in
Australia. According to Graves, it's unclear why the male sex chromosome, the Y,
shrunk and shed most of its genes over time. Humans are not alone in this. The Y
chromosome's degeneration is well documented in fruit flies and "is clearly
an ongoing process in all animals," says Sherman Silber, a medical doctor
and director of the Infertility Center of St Louis.1
Past assumptions regarding these sex chromosomes are being challenged: It's
recently been discovered that in mice, nearly half of all genes involved in the
earliest stages of sperm production are found on the X. "Scientists and
non-scientists alike are comfortable thinking about the Y chromosome as a
specialist in male characteristics," says David Page, who headed the
discovery team at the Whitehead Institute for Biomedical Research in Boston.2
"By default, we've traditionally thought of the X chromosome as sexually
neutral or as a specialist in female characteristics," Page says. "Our
findings indicate that the X chromosome has a specialty in sperm production,
much like the Y chromosome does."
Sex-Determining Genes
Detailed molecular and embryological studies are revealing
how genes determine the anatomical sex of a fetus and how that process can and
does go awry. Andrew Sinclair, who now heads the Centre for Hormone Research,
University of Melbourne, was part of the British-based team led by Peter
Goodfellow, of the Imperial Cancer Research Fund, which in 1990 discovered a
crucial gene, known as SRY.3 It usually occurs only on the male Y chromosome.
Using this discovery, researchers at Britain's National Institute for Medical
Research then showed that a fertilized female mouse egg will become male when
injected with SRY. The animal in question, named Randy, was the first
sex-reversed mouse ever produced in this way, Sinclair says. The testes were
small but Randy otherwise grew up male in every discernible way, despite being
conceived as a genetic female. Placed in a cage with some females, Randy behaved
in a typically male-mouse way, mating up to six times a night. "He thought
he was male, they thought he was male, and we thought that was pretty good
evidence," Sinclair says. "It tells you that SRY is the only gene you
need on the Y chromosome to develop testes and become male."
But other genes complicate the process of sex determination. One known as DAX1,
for example, is thought to act as an anti-testis gene, promoting ovary
development. Another, called SOX9, combines with SRY to promote the formation of
testicular cells in a male embryo. A third gene known as WNT4 and found on
chromosome 1, seems to prevent the development of Leydig cells in male testes.4
Researchers led by Eric Vilain, assistant professor of human genetics,
University of California, Los Angeles, recently found that when WNT4 occurs
twice it can convert an embryo from male to female, often resulting in ambiguous
genitalia.5
Neutral Starting Position
It is often argued that being female is the default state
for mammals; that an embryo will develop in a female way unless male genes
impose themselves on the process. It now seems just as possible, however, that
the default state is merely a sexless one, a case of dual potential. In the
first six weeks after conception, a human embryo develops a simple gonad that is
neither a testis nor an ovary, but more of a neutral sex bud that can bloom
either way. The bud has two parts, the medulla and cortex. At about seven weeks,
when the fetus is thumbnail size, the SRY gene, if it is present, starts to work
its magic. It switches on and the cells in the medulla start to multiply and
form into a testis, while the cells in the cortex regress and virtually
disappear.
Every significant distinction between men and women apparently stems from that
event. As Graves puts it: "Of all the differences between male and female
mammals, the primary one seems to be the development of the testis in males.
Early in development the mammalian embryo is ready for anything. Male and female
embryos are morphologically indistinguishable ... and the embryo is equipped
with both male and female internal ducting." The development of the testis
triggers a cascade of hormone-controlled changes, so once this decision--testis
or no testis--has been taken, the sex of the embryo is determined. Within a week
the new testes soon start producing their lifelong supply of testosterone, which
floods the embryo and kicks off the development of typical masculine physical
traits. If no SRY gene is present, the embryonic gonad waits until the 13th week
of gestation to commit itself to femaleness. The medulla shrinks away and the
cortex develops into an ovary, which starts to produce estrogen and feminizes
the rest of the body.
The differentiation process in the womb can be affected,
however, by genetic problems, infections, or exposure to toxins, drugs, or
maternal hormones. In that context, it's remarkable to note that SRY's discovery
was made possible with the help of French scientists who identified four unusual
men who had sought treatment for infertility, Sinclair says. Chromosome tests
revealed that they were in fact genetic females, with an XX female
sex-chromosome pattern. Yet all four were anatomically male and had testes.
Further studies showed that they had a small fragment of Y chromosome containing
the SRY gene, tacked onto one of their X chromosomes. It was just a tiny glitch,
enough to reverse their sexual anatomy but not endow them with other male genes
to enable their testes to make sperm.
Many other such variants are now being discovered, along with true
hermaphrodites and pseudo-hermaphrodites. There are people with missing sex
chromosomes, extra sex chromosomes, or tiny genetic fragments tacked onto or
missing from chromosomes that seem to have nothing to do with sex determination.
Delving into the very fundamentals of sexual genetics and biochemistry and
making personal contact with people whose sex and gender are ambiguous has made
Sinclair see the whole issue in a fresh light. "I
think humans like things to be ordered, and they get bothered about gray areas
and when things become less clear-cut," he says. "But these days I
don't think so much in black and white about male and female. Now I think of it
all as being on a spectrum."
Bob Beale (www.bob.beale.org) is a freelance writer in
Sydney, Australia.
References
1. S. Silber, "The disappearing male," Proceedings of the 11th World
Congress in In Vitro Fertilisation and Human Reproductive Genetics, May 1999.
2. J.P. Wang et al., "An abundance of X-linked genes expressed in
spermatogonia," Nature Genetics, 27[4]:4226, 2001.
3. A. Sinclair et al., "A gene from the human sex-determining region
encodes a protein with homology to a conserved DNA-binding motif," Nature,
346:24044, 1990.
4. "Making Babies," New Scientist, 2290:367, May 12, 2001.
5. B.K. Jordan et al., "Up-regulation of WNT-4 signalling and
dosage-sensitive sex reversal in humans," American Journal of Human
Genetics, 68[5]: 11029, 2001.
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