The unique mechanism behind the evolutionary survival of the human Y chromosome may also be responsible for a range of sex disorders, from failed sperm production to sex reversal to Turner Syndrome.
Roughly six years ago, David Page's lab at Whitehead Institute for Biomedical Research reported the discovery of eight large areas of mirror-imaged genetic sequences, or palindromes, along the Y chromosome. Because the Y chromosome essentially has no partner with which to swap genes, a process that between ordinary chromosome pairs leads to genetic diversity and the exchange of good genes for damaged ones, it relies on its own palindromes to swap genes with itself. The Y, as it turns out, folds itself in the middle of palindromic regions, thereby pairing identical sequences to allow for potentially beneficial genetic exchange.
At the time, the finding provided explanation for why, despite much-heralded reports to the contrary, the Y chromosome is not doomed to extinction. Now, the Page lab has discovered that the Y's process of self-preservation can randomly go awry, with considerable clinical consequence.
"This is the sequel to the Y chromosome palindrome story," says Page, Whitehead Institute Director and a Howard Hughes Medical Institute investigator.
The latest chapter of the story, whose conclusion is published in the September 4 issue of Cell, began with the intriguing hypothesis that perhaps the Y's process of self-recombination can inadvertently turn the entire chromosome into a palindrome—literally, a mirror-image of itself. The result would be a so-called isodicentric Y chromosome (idicY), an abnormal structure with, as the name implies, two centromeres.
"We began to think seriously about the centromeres and the activity around them. Two centromeres render the chromosome susceptible to damage," says Julian Lange, first author of the Cell paper and a former graduate student in the Page lab. Because of the Y chromosome's well known roles in sex determination and male fertility, Lange began to speculate about the potential clinical impact of the transmission of an idicY during fertilization.
"Because the Y chromosome is not essential to an individual's survival, these isodicentric Ys can persist," says Lange, who, after completing this research at Whitehead, became a postdoctoral fellow at Memorial Sloan-Kettering Cancer Center. "They can be found in the population."
And Lange found them, in the DNA samples of 51 patients screened from a field of nearly 2400 individuals who had come under study over the course of many years because of failed sperm production, structurally abnormal Y chromosomes, or sex reversal. Through sophisticated genetic analysis, it became clear that idicYs were responsible for spermatogenic failure in many of the male patients.