Monday, 30 October 2006

The Uncanny XX-Men

From Nature :
How can a person with two X chromosomes be a man? In more ways than one...

The battle of the sexes continues to rage — right down to the level of our genes.

A gene has now been discovered that, when mutated, turns girls into boys. The finding advances, but also complicates, our understanding of how sex is determined by our genes.
As if it wasn't complicated enough...
In people, almost all men carry two different sex chromosomes (XY) and women are XX. But there are some (extremely rare) exceptions to this rule. It is possible to have XX men, for example.
And X0 women, and XXY men, and (very rarely) XXY women, and a whole host of others, XY/XX, XY/XO mixtures, and this is just for humans who are mentally normal. XXXY, XXYYY etc and Bad Stuff (tm) happens in neural development.
This female-to-male sex reversal almost always happens when a
certain gene called SRY, usually carried on the Y chromosome, accidentally ends up on the X chromosome inherited from the father.

Other genes have been found to muddle up sexual identity, making the resulting child neither fully male nor fully female.
As regular readers of this blog are no doubt aware. Then there's environmental issues in the womb, where the genes are fine, but a chemical is introduced, or things just go slightly amiss for one reason or another. It happens.
But in most cases of anatomically complete XX men — who have functional testes, but without a Y are infertile — SRY is involved. For this reason, it has long been called the gene that defines 'maleness'.[1]

But now Giovanna Camerino of the University of Pavia in Italy and colleagues have found another gene that is equally important to the process.

The team studied a family in which four brothers were each XX. None carried the 'male' SRY gene. Instead, the team reports in Nature Genetics [2], they each have a mutation in a gene called RSPO1.

It seems that sex is determined in humans by a cascade of genes. At a crucial junction in this process lies a gene called SOX9, which in males is switched on by SRY, causing testis development. In females, the researchers now suggest, SOX9 might be typically switched off by RSPO1, which, via other genes in the cascade, leads to the development of ovaries. In the brothers, it seems the mutated RSPO1 gene could not fulfil its switching-off role, leaving SOX9 on and leading to male development.

This theory fits with animal studies: mice with two X chromosomes that have their SOX9 expression turned back on form testes.[3]

The idea stands in contrast to previous theories that said that female development was basically the default that happens in the absence of genes to direct maleness. "What is really important is that suppression of male and induction of female development is an active process," says Andreas Schedl of INSERM, the French National Institute of Health and Medical Research in Nice, who is a co-author on the paper.
"RSPO1 clearly plays a key role in this process." The identification of this gene, he says, may be as important to the field as the identification of SRY.

1. Koopman P., et al. Nature, 351 . 117 - 121 (1991).
2. Parma P., et al. Nature Genet., doi:10.1038/ng1907 (2006).
3. Vidal V. P., et al. Nature Genet, 28 . 216 - 217 (2001).
Another piece in the puzzle. Not an expected one either, hence more valuable than most.

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