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Y oh Y are some men infertile?

Nearly 3% of men are sterile. This can be caused by environmental or genetic factors. The environmental causes are relatively well understood, but much less is known about the genetic ones.

Men - and males of other mammalian species - have both X, and Y chromosomes, unlike females, who have two X chromosomes. The major function of the Y chromosome is to determine 'maleness'. One of the hallmarks of being male is the production of sperm, and the Y chromosome contains a number of genes for the constituents of sperm.

If any of these critical genes are disrupted, sterility can result - either from defective sperm, or the complete lack of them - although males with such mutations might be otherwise healthy. One of these conditions is 'azoospermia', in which a male makes no sperm. Mutations that remove large pieces of DNA within the Y chromosome - known as 'deletions' - have been associated with azoospermia, but precisely which gene or genes within a particular region cause the defect was unknown.

David Page and his colleagues of the Massachusetts Institute of Technology, Cambridge, Massachusetts, have now located the first 'azoospermia gene' on the Y chromosome. In Nature Genetics1, they describe their identification of the gene, 'USP9Y', within one of the large regions of the Y chromosome previously implicated in azoospermia.

While screening a large population of infertile men, the researchers noticed that one of the men had a mutation in USP9Y that stopped the gene from functioning. The mutation was not seen in the man's father (nor could it have been, because the father was clearly fertile) or in his fertile brother, indicating that it had arisen, afresh and strongly suggesting that the gene caused at least some cases of sterility.

But finding a mutation in one man was not sufficient proof that a defective USP9Y gene causes sterility, so the researchers confirmed their finding in an unorthodox manner: they re-analysed the results of an earlier study. A sterile man in the previous work had a mutation in the same gene, but at that time, it had been uncertain where the precise boundaries of the gene were. Page and colleagues mapped the region more precisely, and were able to re-interpret the old data.

The technique that Page and his colleagues used here, correlating chromosomal defects with particular diseases or conditions, is known as 'cytogenetics'. R. Scott Hawley of the University of California, Davis, California, hails the study as "the most elegant application of cytogenetic mapping I can ever remember seeing," and as a good example of "how one should do genetics."

Given the number of infertile men who do not have defective copies of USP9Y, there are clearly many other genes on the Y chromosome and elsewhere which are essential for sperm production, which, when mutated, can lead to sterility. USP9Y is another contributor to a process that involves many genes, but which is only now starting to be understood at the genetic level.


  1. Sun, C., et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nature Genetics 23, 429, (1999).

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Ronemus, M. Y oh Y are some men infertile?. Nature (1999).

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