Human Sex Chromosomes Are Sloppy DNA Swappers

Variety is the spice of life—especially when it comes to genetics. Our species needs DNA to intermingle to create genetic diversity, which is key to population-wide health and hardiness. As cells divide and grow, all 22 pairs of chromosomes in a human can perform genetic swaps along their entire lengths, except for the sex chromosomes. Because X and Y differ in size and in the genes they carry, these two genetic bundles remain aloof.

But research has been showing how the sex chromosomes do sometimes trade genetic data in select spots—and it seems their swapping is sloppier than originally thought.

A team led by Melissa Wilson Sayres at Arizona State University offers new details about what happens when X and Y chromosomes swap DNA during the cell division that gives rise t eggs and sperm. Intriguingly, their work confirms that when the sex chromosomes converse, a particular gene that is critical for male development sometimes gets accidentally moved around. The results could help explain why some people have female DNA—a pair of X chromosomes—but develop physically as male.

Millions of years ago, our X and Y chromosomes were roughly equivalent and were able to freely swap genetic material. In most cases, evolution favors this exchange of DNA between chromosomes because it boosts diversity. But today, the X chromosome is much longer than the Y chromosome, and only two small matching regions remain at the tips. “We often talk about how different X and Y are,” says Wilson Sayres. “But there are two regions in which they are identical,” called pseudoautosomal regions. This is where the X and Y chromosomes can partner and swap DNA.

Previous work by geneticists David Page at MIT and Bruce Lahn at the University of Chicago showed that, millions of year ago, segments of the X chromosome got cut, flipped and reinserted. The result of this mutation, called an inversion, is that the X and Y chromosomes could no longer interact in the inverted region. Analyses from Wilson Sayres’ lab also previously showed that inversions on the X chromosome have happened up to nine times in our evolutionary history.

These inversions "were favored by natural selection because they prevented the male-determining gene to recombine onto the X, and allowed X and Y to evolve independently,” says Qi Zhou, a postdoctoral fellow at the University of California, Berkeley, who studies the evolution of sex chromosomes in fruit flies and birds.

Because the process of inversion cuts genes in half, scientists can see the pseudoautosomal boundaries on the chromosomes simply by looking at the DNA sequence and identifying the chunks of truncated genes. So Wilson Sayres wondered whether genetic swapping happening inside the pseudoautosomal regions might leave a distinct signature of diversity with sharp borders. “Because recombination is happening in the pseudoautosomal regions, there should be increased diversity there relative to the other parts of the X chromosome,” says Wilson Sayres.

To test the idea, she and her undergraduate collaborators at Arizona State analyzed patterns of genetic diversity across the X chromosomes from 26 unrelated women. To their surprise, the team did not observe a clear border. “Diversity decreases at almost a linear rate across the pseudoautosomal boundary, which suggests that recombination boundaries are not very strict,” says Wilson Sayres. Instead, it seems that when pseudoautosomal regions trade snippets of DNA, nearby pieces of the inverted region sometimes get taken along for the ride. The team is presenting their results this week at the 2015 meeting of the Society of Molecular Biology and Evolution in Vienna.  

The finding “is really important, because one of the genes on the Y chromosome that is very close to that boundary is SRY, the Sex-determining Region of the Y,” says Wilson Sayres. SRY is a gene that is key for initiating testes development in males. “If the boundary is not set, you can pull the SRY gene over onto the X chromosome," she says. In that case, an individual with an XX genotype, which is typically female, may instead develop as male. XX male syndrome, also called de la Chapelle syndrome, occurs in 1 of 20,000 people who appear outwardly male. Individuals with this rare condition are usually sterile.

“Lots of mammal species have SRY, and it is at very different places on the Y chromosome, because the inversions happened many times independently in different lineages,” adds Wilson Sayres. “It’s just bad luck that, in humans, the SRY gene happens to be close to the inversion boundary.”

A 2012 study by Terje Raudsepp at Texas A&M University and her colleagues had already suggested that errors in X-Y recombination can move SRY to the X chromosome in humans and chimpanzees. The new work boosts that result and shows a probable mechanism. Also, because the swapping region boundaries are so fuzzy, it's likely that XX male syndrome is not a recent "fluke" phenomenon in modern humans but has occurred for at least thousands of years. “XX males likely occurred with this frequency throughout human evolution,” says Wilson Sayres.

The new analysis also shows an unexpected peak of genetic diversity in an inverted section of the X chromosome that, in humans, was copied and added to the Y chromosome. One of the genes within that peak is called protocadherin 11, a gene thought to be involved in brain development. “People usually assume that this region is X-specific, but actually we show that there is swapping between X and Y in that region,” says Wilson Sayres. This is important because “the X-transposed region looks like a new third pseudoautosomal region. This could lead to a new process for male-biased genes from the Y to hop onto the X, where they don't belong, leading to additional sex-chromosome genetic disorders.”

“The work by Dr. Wilson Sayres’ group certainly adds to the depth of analysis of the curious features of human sex chromosomes,” says Raudsepp.