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Low Y Chromosome Genetic Diversity Linked to Effects of Natural Selection

NEW YORK (GenomeWeb Daily News) – The human Y chromosome is marked by low genetic diversity that is consistent with the effects of natural selection, researchers from University of California, Berkeley, reported yesterday in PLOS Genetics.

The researchers compared patterns of variation on Y chromosomes from eight men of African descent and eight men of European descent. Through population genetics simulations, they noted that the variability they saw on the male sex chromosomes didn't match with a purely neutral model of selection. Rather, models including purifying selection and a low male effective population size were consistent with the patterns seen.

"We show that a model of purifying selection acting on the Y chromosome to remove harmful mutations, in combination with a moderate reduction in the number of males that are passing on their Y chromosomes, can explain low Y diversity," first author Melissa Wilson Sayres said in a statement.

The Y chromosome contains just a little more than two dozen genes, having lost some 90 percent of the genes it used to share with the X chromosome — the X chromosome and Y chromosome stopped recombining their genes about 200 million years ago.

This Y chromosome gene loss has prompted speculation that the chromosome could waste away to the point of being lost, as it has been in some other mammals. One estimate said that the Y chromosome could disappear within 5 million years.

The X chromosome still recombines with other Xs and has not experienced decay.

A study published in Nature in 2012 from a Whitehead Institute for Biomedical Research-led team, though, calculated that the rate of gene loss and genetic decay of the Y chromosome has leveled off and that the male sex chromosome has been fairly stable for tens of millions of years.

In this new study, Wilson Sayres and her colleagues also found that the number of spots on the Y chromosome that appear to be under purifying selection outnumber the number of Y-linked coding sites, indicating that the highly repetitive ampliconic regions of the chromosome may have functional significance.

"Our study demonstrates that the genes that have been maintained, and those that migrated from the X to the Y, are important, and the human Y is going to stick around for a long while," Wilson Sayres added.

To study the Y chromosome, Wilson Sayres and her colleagues turned to a set of publicly available, high-quality whole and mitochondrial genomes from 16 unrelated men generated by Complete Genomics.

After normalizing the sequence data to account for differences in mutation rates at different spots in the genome, the researchers found that the diversity on the Y chromosome is lower than what would be expected based on the diversity present at other regions of the genome. They noted that the pattern was present in men of both African and European ancestry, though the level of Y chromosome diversity was even lower in the African men.

To determine why the Y chromosome has such unexpectedly low levels of diversity, Wilson Sayres and her colleagues constructed a number of population genetic models that examined the possible influences of reproductive success differences between males and females, purifying selection, and positive selection on the Y chromosome.

Differences in male and female reproductive success could influence the expected effective population size of the Y chromosome and the expected variability of the Y chromosome, and in one model, the researchers inspected how skewed sex ratios affect Y chromosome diversity. While they found that a decrease in the male effective population size did decrease the expected diversity of the male sex chromosome, the predicted diversity of the autosomal, X, and mtDNA were not consistent with the observed data.

Purifying selection could also be a culprit leading to low Y chromosome diversity, and the researchers used forward simulations to model how background selection could affect diversity at neutral sites under varying degrees of reproductive success. Modeling purifying selection on new nonsynonymous mutations, though, indicated that such an effect could not reduce diversity at the linked neutral sites to the levels observed.

However, the researchers noted that none of the models that assumed an equal sex ratio could lead to the low levels of Y chromosome diversity seen. They posited, then, that together, a reduced effective male population size and such purifying selection on nonsynonymous mutations could contribute to decreased diversity. The model, though, still predicted diversity levels higher than those observed.

Purifying selection, they reported, is working on more than just those new nonsynonymous mutations. Using a novel approximate likelihood approach, the researchers estimated the number of sites on the Y affected by purifying selection, and found that as many as 30-fold more sites than there are coding sites on the Y chromosome could be subject to selection.

"This suggests that content recruited to the Y chromosome after X–Y recombination was suppressed, including the high-copy-number ampliconic regions, as well as any transcription factor binding sites, may be subject to purifying selection that, due to the lack of homologous recombination, acts to reduce diversity on the human Y chromosome," Wilson Sayres and her colleagues wrote.

Still, they noted that positive natural selection could account for the low diversity observed. The researchers analyzed the folded site frequency spectrum for SNPs on the Y chromosome. The pattern observed, they said, was consistent with either purifying selection or positive selection, and due to the low abundance of such SNPs, they were unable to further clarify that finding. Additionally, a neighbor-joining tree of unrelated Y haplotypes wasn't indicative of a selective sweep, but again, they could not rule it out.

"While a combination of factors influence genome-wide estimates of diversity, and variance in male reproductive success still affects patterns of autosomal, X, Y, and mtDNA diversity, selection clearly affects levels of diversity on the Y," the researchers said.

A number of the newer, repeated ampliconic genes on the Y chromosome have been linked to male infertility. "These ampliconic regions that we haven't really understood until now are evidently very important and probably should be investigated," Wilson Sayres added.

In addition, Rasmus Nielsen, the paper's senior author, noted that the Y chromosome is commonly used to track ancient human movements and evolutionary history. These findings, he said, will help refine such estimates.

"[Wilson Sayres] has shown that this strong negative selection — natural selection to remove deleterious genes — tends to make us think the dates are older than they actually are, which gives quite different estimates of our ancestors' history," Nielsen said.