Sex, Genes and Chromosomes: Their Discovery, Function and Evolution Jennifer A. Marshall Graves Cambridge Univ. Press (2026)
“Sex is the most profound normal difference between human individuals,” explains geneticist Jennifer Graves in Sex, Genes and Chromosomes. In this definitive and wide-ranging book, she outlines the discovery, molecular biology and evolution of sex chromosomes as well as the determination of sex across vertebrates — including the charged public discourse around genes, sex and gender.
Graves knows this terrain well, having contributed to many of the discoveries that she describes. She offers fresh insights for experts as well as clear explanations for lay readers. Genomics is notoriously hard to describe, however, and she apologizes for the complicated vocabulary: “Sorry, but you really can’t get sex unless you understand ploidy, meiosis, and recombination.” Students, take note.
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In humans and most mammals, sex is determined at fertilization: if a sperm bearing an X chromosome fertilizes an egg that also contains an X, the result is typically female offspring; if it contributes a Y chromosome instead, the result is male offspring. But biology is rarely that simple.
Researchers know that it is the presence of the Y, rather than the absence of an X, that constitutes the first step in determining sex. Organisms with unusual combinations of sex chromosomes, such as XXY or XYY, develop as males, whereas those without a Y usually develop as females, including those with a single X, or even three or more X chromosomes.
There are exceptions. Male offspring with XX chromosomes can arise when a part of the Y chromosome is stitched onto X or one of humans’ other 22 pairs of chromosomes. And female offspring with XY chromosomes can arise when a part of the Y chromosome is lost.
Comparing those occurrences has enabled researchers to pinpoint the exact gene on the Y chromosome that determines sex — and that triggers the development of a testis instead of an ovary. In those exceptional cases in which parts of the Y chromosome are added or deleted, this gene is always present in an XX male and always absent in an XY female.
The decades-long hunt is one of the great detective stories of genetics. It illustrates how science advances through the systematic elimination of plausible but wrong hypotheses.
Making of a male
The first plausible gene candidate for triggering male development was zinc finger Y (ZFY). This gene encoded a protein that, by its structure, seemed likely to control the expression of other genes. However, in 1988, Graves’s laboratory ruled it out. The equivalent of the human ZFY gene in kangaroos, in which the Y chromosome is also sex-determining, did not map to the Y chromosome as it should have done if it was the signal for male development.
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Another gene, known as SRY (sex-determining region Y), emerged from subsequent studies as having the right characteristics: mutations in human SRY cause XY individuals to develop female physical traits. Proof came in 1991: mice that carried two X chromosomes would usually develop into females, but with Sry inserted into their genomes they developed as males with XX chromosomes1. The final test came in 2013, when an XY mouse in which the Sry gene was knocked out by gene-editing technology; developed as female2.
Such experiments show how extraordinary X and Y chromosomes are, Graves writes. And, beyond sex differences, they are crucial for human health, too. Genes associated with the X chromosome are linked with effects in the brain, and deficiencies can cause behavioural issues, cognitive impairment and eye abnormalities. Meanwhile, the structure of the Y chromosome is, in Graves’s words, “quite bizarre” and “atypical of the human genome in every way”.
The Y chromosome has large tracts of genetically silent DNA that consists of simple DNA sequences that are repeated (such as GATAGATAGATA) and are incapable of coding for proteins. Some males have more silent DNA than others, but with no evident effects. The Y chromosome also contains several copies of the same genes, often stacked close together. These can be arranged in what Graves describes as palindromic loops, which read the same in both directions (as with the word radar). Strange indeed.
Long-term losses
Evolutionarily speaking, Graves contends that the Y chromosome is a degraded form of the larger X chromosome, based on an analysis of sex chromosomes in a range of vertebrates. In some organisms, the X and Y chromosomes are equal in size and almost indistinguishable, apart from the male trigger gene. Graves paints a picture of how X and Y started around the same size, but the Y chromosome then becomes progressively smaller as genes are lost.
On the future of the Y chromosome, Graves projects that, at its current rate of gene loss, the mammalian Y would be depleted in around 8 million years. Graves asks: “Are we ultimately at the mercy of the crazy rule-defying sex chromosomes, which could potentially cause human extinction or speciation?” This question makes for interesting speculation, but because the human species is some 200,000-years-old, 8 million years is a timescale on which I find it difficult to recognize any descendant as human at all, irrespective of their chromosomes.
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