The Scientist

The Y chromosome has a unique approach to ensuring its survival, but that self-preservation mechanism may cause a range of sexual disorders from male sterility to sex reversal, in which a person's genetic sex is opposite his anatomical development, according to a study published online today (September 3) in Cell.

Tug of war during mitosis can break the isodicentric chromosome in two Image: Tom DiCesare/Whitehead Institute

"Every time nature solves a problem, it seems to create one," said linkurl:Scott Hawley,;http://www.stowers-institute.org/labs/HawleyLab.asp a chromosome biologist and American Cancer Society research professor at the Stowers Institute for Medical Research in Missouri, who was not involved in the research. "[The] very same system that can protect the Y can, in rare events, do something really disastrous." The entire genome is constantly subjected to random errors during replication, the vast majority of which are detrimental to the overall fitness of the organism. These deleterious mutations are purged from the genome during sexual reproduction in a process known as recombination, in which homologous chromosomes exchange bits of genetic material. In essence, the chromosomes are swapping out their bad genes for good ones. For most of the Y chromosome, however, there is no homologous chromosome to trade with -- its 'partner' is the fundamentally different X chromosome. "The idea was that the Y and its genes reproduced asexually," said linkurl:David Page,;http://www.wi.mit.edu/research/faculty/page.html a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Mass., and the corresponding author on the Cell study, "[which] really hampered this purging function." The result would be rapid accumulation of mutations that would one day eliminate the Y chromosome altogether, possibly in as little as 10 million years or less. But in 2003, when the first full sequence of the human Y chromosome was published, biologists identified large sections of DNA that were mirror images of each other. These large, palindromic regions of the Y chromosome provided a possible answer to the age-old question of how it gets rid of accumulating deleterious mutations -- by recombining with itself. Swapping a mutated allele out for a good one from the other side of the palindrome could, for all intents and purposes, fix the problem. Analyzing the Y chromosomes of nearly 2,400 male patients with previously identified sexual abnormalities, Page and his colleagues identified 51 Y chromosomes that showed characteristic signs of having undergone this self-swapping, or recombination, of genetic material. "This study actually provides evidence that recombination in the [palindromes] does occur," Hawley said. The researchers noticed these particular Y chromosomes because they had a peculiar structural anomaly: two centromeres, instead of the normal one. The centromere is the region of the chromosome that is pulled during mitosis, and having more than one can result in cellular confusion during nuclear division. "Chromosomes just can't have two centromeres," Hawley said. "It's like having two people in the car trying to decide which direction you're going." This double duty may cause breaks in the Y chromosome as the two centromeres are pulled in opposite directions, or loss of the Y chromosome altogether. These so-called isodicentric Ys are an unfortunate side effect of recombination within a chromosome, according to the study. After breaking the DNA to swap the genes in need of repair, the pieces could be put back together incorrectly, resulting in one chromosome that has no centromeres while the other has two. The resulting mitotic instability can result in a staggering array of clinical outcomes, Page said. "The same chromosome disorder [is] showing up in men who make few or no sperm but are otherwise healthy, and individuals who have various anomalies of sexual development at a broader anatomic level," he said. "This is what really blew my mind." The mechanism of gene swapping, however, has yet to be confirmed. While these results support the idea that the Y chromosome can recombine with itself to facilitate its own survival, the actual process has not yet been visualized. "What I hope to do in the future is to actually observe these things," Page said. To this end, he is working on sequencing the Y chromosome of other mammals in which detailing these processes may be more feasible.
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