The small, stumpy Y chromosome—possessed by male mammals but not females, and often shrugged off as doing little more than determining the sex of a developing fetus—may impact human biology in a big way. Two independent studies have concluded that the sex chromosome, which shrank millions of years ago, retains the handful of genes that it does not by chance, but because they are key to our survival. The findings may also explain differences in disease susceptibility between men and women.
“The old textbook description says that once maleness is determined by a few Y chromosome genes and you have gonads, all other sex differences stem from there,” says geneticist Andrew Clark of Cornell University, who was not involved in either study. “These papers open up the door to a much richer and more complex way to think about the Y chromosome.”
The sex chromosomes of mammals have evolved over millions of years, originating from two identical chromosomes. Now, males possess one X and one Y chromosome and females have two Xs. The presence or absence of the Y chromosome is what determines sex—the Y chromosome contains several genes key to testes formation. But while the X chromosome has remained large throughout evolution, with about 2000 genes, the Y chromosome lost most of its genetic material early in its evolution; it now retains less than 100 of those original genes. That’s led some scientists to hypothesize that the chromosome is largely indispensable and could shrink away entirely.
To determine which Y chromosome genes are shared across species, Daniel Winston Bellott, a biologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and colleagues compared the Y chromosomes of eight mammals, including humans, chimpanzees, monkeys, mice, rats, bulls, and opossums. The overlap, they found, wasn’t just in those genes known to determine the sex of an embryo. Eighteen diverse genes stood out as being highly similar between the species. The genes had broad functions including controlling the expression of genes in many other areas of the genome. The fact that all the species have retained these genes, despite massive changes to the overall Y chromosome, hints that they’re vital to mammalian survival.
“The thing that really came home to us was that these ancestral Y chromosome genes—these real survivors of millions of years of evolution—are regulators of lots of different processes,” Bellott says.
Bellott and his colleagues looked closer at the properties of the ancestral Y chromosome genes and found that the majority of them were dosage-dependent—that is, they required two copies of the gene to function. (For many genes on the sex chromosomes, only one copy is needed; in females, the copy on the second X chromosome is turned off and in males, the gene is missing altogether.) But with these genes, the female has one on each X chromosome and the male has a copy on both the X and Y chromosomes. Thus, despite the disappearance of nearby genes, these genes have persisted on the Y chromosome, the team reports online today in Nature.
“The Y chromosome doesn’t just say you’re a male; it doesn’t just say you’re a male and you’re fertile. It says that you’re a male, you’re fertile, and you’re going to survive,” Bellott explains. His group next plans to look in more detail at what the ancestral Y chromosome genes do, where they’re expressed in the body, and which are required for an organism’s survival.
In a second Nature paper, also published online today, another group of researchers used a different genetic sequencing approach, and a different set of mammals, to ask similar questions about the evolution of the Y chromosome. Like Bellott’s paper, the second study concluded that one reason that the Y chromosome has remained stable over recent history is the dosage dependence of the remaining genes.
“Knowing now that the Y chromosome can have effects all over the genome, I think it becomes even more important to look at its implications on diseases,” Clark says. “The chromosome is clearly much more than a single trigger that determines maleness.” Because genes on the Y chromosome often vary slightly in sequence—and even function—from the corresponding genes on the X, males could have slightly different patterns of gene expression throughout the body compared with females, due to not only their hormone levels, but also their entire Y chromosome. These gene expression variances could explain the differences in disease risks, or disease symptoms, between males and females, Clark says.