Faulty "Mirrors" in Y chromosome Lead to Sex Disorders

Author:  Dunia Rassy
Institution:  London School of Hygiene and Tropical Medicine

A proofreading mechanism exclusive to the Y chromosome has revealed its dark side: it may be responsible for male infertility, sex reversal, and even genetic syndromes. David Page and his team at Whitehead Institute for Biomedical Research studied this mechanism in patients' DNA samples. Their findings were published on the September 4 issue of Cell.

In the context of human gender determination, the presence and expression of the SRY gene in chromosome Y marks the individual as a male. While chromosome Y is normally paired with the X chromosome, they do not exchange genetic information, unlike the behaviors of the 22 pairs of somatic chromosomes. The exchanges, called recombination, allow beneficial genes to be passed down from generation to generation and permit the removal of harmful genetic information. The existence of healthy males indicates that the Y chromosome must have an alternative method in keeping its genetic information viable. In 2003, Page found a recombination system in the Y chromosome that is based on genes having a mirrored-image of themselves. If a gene needs to be repaired the chromosome folds in a particular conformation such that the faulty segment and its mirrored-image pair up side to side. This leads to a process known as self-recombination. During self-recombination the intact mirrored image of a gene is copied to replace the damaged segment.

After dwelling into the matter of Y chromosome's self-recombination, Page's team discovered the system had a major downside. In some cases, mirrored-image genes can be copied incorrectly and produce a chromosome with two centromeres, called isodicentric chromosomes. During cell division, centromeres become crucial to the equal distribution of chromosomes between the two daughter cells. In an isodicentric chromosome, each centromere can be tugged in a different direction, thus breaking the chromosome. If cells forming the gender-specific organs lack the key genes in chromosome Y that direct masculinization, a great range of sexual disorders could be present in the individual.

The team screened DNA from 2400 patients and found that in 51 cases isodicentric chromosomes were responsible for failed sperm production. Eighteen of the 51 cases presented sex reversal: they were XY individuals that anatomically look like females. The Whitehead Institute team found that the larger the Y chromosome was after an incorrect self-recombination, the greater the likelihood of sex reversal. "We had predicted this correlation...but when we confirmed it with patient data, we were blown away," said Page.

Isodicentric chromosomes may be fairly common. "Beacause the Y chromosome is not essential to an individual's survival, these isodicentric Y's can persist," added Julian Lange, a former student at Page's lab who participated in the study. In fact, Page believes that these aberrant chromosomes may also be responsible for Turner syndrome, present in one out of every 2500 girls. Girls suffering this syndrome lack one of the two sex chromosomes, and are thus considered XO individuals. Symptoms may vary from girl to girl, but generally they are shorter compared to average in height and infertile.