The evolution of the sex chromosomes: step by step

October 28, 1999

Men and women, according to popular self-help books, hail from different planets, but what really separates them are radically different chromosomes -- with two Xs you're a female, with one X and a tiny Y, a male. No other pair of chromosomes is nearly as diverse. How did the sex chromosomes become so dissimilar?

In the October 29 issue of Science, Bruce Lahn, Ph.D., assistant professor of human genetics at the University of Chicago and an expert on the evolution of the sex chromosomes, and his colleague David Page, M.D., of the Whitehead Institute, report that the X and Y chromosomes -- which arose from a pair of identical, non sex-determining chromosomes (known as autosomes) -- diverged from each other over the course of about 300 million years by going through four discrete stages rather than in a smooth transition.

"By fossil digging on the sex chromosomes, we were able to reconstruct the four events that drove sex chromosomes into their distinctive X and Y forms, and to date when these events occurred during evolution," says Lahn. "The farther back in time we look, the more similar X and Y appear, boosting the theory that they arose from a pair of identical autosomes."

Sex was not always determined by DNA. In many reptiles, the temperature at which the eggs are incubated determines the sex of the offspring. But when warm-blooded mammals with internal reproduction arose, sex determination by temperature became problematic. Shortly after mammals branched off from reptiles, approximately 300 million years ago, a regular pair of autosomes began evolving into what would become the modern X and Y chromosomes.

Many genes on the human Y chromosome have homologues (analogous genes) on the X chromosome. The presence of these X-Y genes reinforces the idea that the Y chromosome developed from an X-like ancestor.

To Lahn and Page, these X-Y genes serve as the "fossils" they can use to help reconstruct the evolutionary history of sex chromosomes. By comparing the number of mutations between the X form and the Y form of a pair of X-Y genes, Lahn and Page came up with rough estimates of when they were last alike, giving them a 'geologic' snapshot of sex chromosomes.

"The reconstruction of the defining events of human sex-chromosome evolution is analogous to the reconstruction of the evolution of species, except that we are looking at changes of a pair of chromosomes over geologic time rather than changes of whole organisms," says Lahn.

According to the reconstruction by Lahn and Page, the first step towards sex determination via DNA occurred roughly 300 million years ago when one of the autosomes mutated and acquired the SRY gene -- Sex-determining Region Y -- which is the master switch for creating a male. "The SRY-bearing chromosome became the Y chromosome and its SRY-deficient partner became the X chromosome," says Lahn.

Over time, X and Y stopped recombining -- the process of swapping bits of genetic material between a pair of chromosomes during the formation of eggs or sperm. Recombination is essential to maintaining genetic identity between X and Y. Without it, the two chromosomes would diverge into distinct forms. But, says Lahn, recombination between X and Y was suppressed in a step-wise fashion during evolution, so that discrete chunks of chromosomal material suddenly were unable to recombine. Today, the human X and Y chromosomes hardly recombine at all.

Lahn and Page believe that four chromosomal inversion events were responsible for the start-and-stop evolution of the X and Y chromosomes. Inversions occur when a large chunk of DNA gets turned upside down on the chromosome.

For autosomes, where there are two identical copies of each chromosome, the one with the inversion would be eliminated over the course of evolution, in a process known as "genetic drift." But when this happens to the X-Y chromosome pair, simply eliminating the chromosome with the inversion is not an option, since both X and Y were needed to ensure the presence of two sexes.)

Instead, each inversion drove the sex chromosomes farther apart as they evolved. Each piece of the chromosomes that inverted added to the length of DNA that could no longer align and recombine. On the Y chromosome, this led to degeneration and shrinking, since deleterious mutations were able to build up faster on this non-recombining chromosome. By contrast, the X chromosome retained its genetic integrity and size, since it could continue to recombine with its partner (the other X) in females.

"This manner of expansion is in contrast to the view that X and Y diverged in gradual increments, and is consistent with the notion that evolution occurs in leaps and bounds," Lahn says.

University of Chicago Medical Center

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