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BIOLOGY

Sex Redefined: The Idea of 2 Sexes Is Overly Simplistic

Biologists now think there is a larger spectrum than just binary female and male

By Claire Ainsworth, Nature magazine on October 22, 2018

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Credit: Gary Waters Getty Images

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As a clinical geneticist, Paul James is accustomed to discussing some of the most delicate issues with his patients. But in early 2010, he found himself having a particularly awkward conversation about sex.
A 46-year-old pregnant woman had visited his clinic at the Royal Melbourne Hospital in Australia to hear the results of an amniocentesis test to screen her baby's chromosomes for abnormalities. The baby was fine—but follow-up tests had revealed something astonishing about the mother. Her body was built of cells from two individuals, probably from twin embryos that had merged in her own mother's womb. And there was more. One set of cells carried two X chromosomes, the complement that typically makes a person female; the other had an X and a Y. Halfway through her fifth decade and pregnant with her third child, the woman learned for the first time that a large part of her body was chromosomally male. “That's kind of science-fiction material for someone who just came in for an amniocentesis,” says James.
Sex can be much more complicated than it at first seems. According to the simple scenario, the presence or absence of a Y chromosome is what counts: with it, you are male, and without it, you are female. But doctors have long known that some people straddle the boundary—their sex chromosomes say one thing, but their gonads (ovaries or testes) or sexual anatomy say another. Parents of children with these kinds of conditions—known as intersex conditions, or differences or disorders of sex development (DSDs)—often face difficult decisions about whether to bring up their child as a boy or a girl. Some researchers now say that as many as 1 person in 100 has some form of DSD.

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The gonad is not the only source of diversity in sex. A number of DSDs are caused by changes in the machinery that responds to hormonal signals from the gonads and other glands. Complete androgen insensitivity syndrome, or CAIS, for example, arises when a person's cells are deaf to male sex hormones, usually because the receptors that respond to the hormones are not working. People with CAIS have Y chromosomes and internal testes, but their external genitalia are female, and they develop as females at puberty.

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Studies of DSDs have shown that sex is no simple dichotomy. But things become even more complex when scientists zoom in to look at individual cells. The common assumption that every cell contains the same set of genes is untrue. Some people have mosaicism: they develop from a single fertilized egg but become a patchwork of cells with different genetic make-ups. This can happen when sex chromosomes are doled out unevenly between dividing cells during early embryonic development. For example, an embryo that starts off as XY can lose a Y chromosome from a subset of its cells. If most cells end up as XY, the result is a physically typical male, but if most cells are X, the result is a female with a condition called Turner's syndrome, which tends to result in restricted height and underdeveloped ovaries. This kind of mosaicism is rare, affecting about 1 in 15,000 people.


The effects of sex-chromosome mosaicism range from the prosaic to the extraordinary. A few cases have been documented in which a mosaic XXY embryo became a mix of two cell types—some with two X chromosomes and some with two Xs and a Y—and then split early in development. This results in 'identical' twins of different sexes.

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