Why the Y chromosome can trigger sex disorders
Dutch and US researchers have discovered that a weak Y chromosome could trigger a number of human heath disorders including Turner syndrome (Gonadal dysgenesis) and failed sperm production. The results of the study were published in the journal Cell. Research on the mystery behind the Y chromosome's role in sex disorders kicked off a few years ago, when the David Page lab at the US-based Whitehead Institute for Biomedical Research reported the discovery of eight large areas of palindromes, or mirror-imaged genetic sequences, along the Y chromosome. This sex chromosome, the researchers had reported, cannot swap genes with another chromosome because it has no partner. Gene swapping helps secure good genes, and the problem with the Y chromosome is that it can only exchange genes with itself, so palindromes play a major role in this process. The Y chromosome folds itself in the middle of palindromic regions, effectively pairing identical sequences in order to make the most of a good genetic swap. But while the Y chromosome tries to preserve itself, the Page lab discovered that a glitch could impair the process. 'This is the sequel to the Y chromosome palindrome story,' explained Professor Page of the Department of Biology at the Massachusetts Institute of Technology (MIT), and Director of the Whitehead Institute for Biomedical Research. Flash-forward six years from the initial discovery, and the findings of this latest study suggest that the Y chromosome's process of self-recombination can turn the entire chromosome into a palindrome quite unintentionally. The researchers call this 'isodicentric Y chromosome' (idicY), an abnormal structure with two centromeres. Each normal human chromosome has a single centromere which is located near the middle or end of a chromosome. We need centromeres to ensure proper chromosome segregation. 'We began to think seriously about the centromeres and the activity around them,' said lead author Dr Julian Lange, a former Page lab member. Dr Lange started mulling over the possible results of an idicY being transmitted during fertilisation. 'Because the Y chromosome is not essential to an individual's survival, these isodicentric Ys can persist,' Dr Lange, who is currently at New York's Memorial Sloan-Kettering Cancer Center, pointed out. 'They can be found in the population.' For this study, DNA (deoxyribonucleic acid) samples were taken from 51 patients screened from a field of around 2 400 people who had been evaluated over the years for a variety of health concerns like structurally abnormal Y chromosomes or sex reversal. The researchers found that idicYs caused spermatogenic failure in many of the male patients. But of the 51 patients, 18 were anatomically female even though they had two copies of the male-determining SRY (Sex-determining Region Y) gene on their idicY chromosomes. The Page-Lange team speculated that the instability of the idicYs themselves led to the feminisation of these subjects. With this in mind, the researchers searched for a link and discovered that the larger the Y chromosome, the greater the chance of sex reversal. 'We had predicted this correlation, which relates to the overall distance between the centromeres,' Professor Page said. 'But when we confirmed it with the patient data, we were blown away.' Researchers from the University of Amsterdam in the Netherlands co-authored this paper.
Countries
Netherlands, United States