MRC National Institute for Medical Research, London
Science for Health
Replaying the evolution of mammalian sex determination
22 December 2010
Males usually have one Y chromosome and one X chromosome, while females have two X chromosomes. A single gene on the Y chromosome is responsible for triggering the development of testes in the early embryo, and once these begin to form (rather than ovaries), the rest of the embryo also becomes male. This gene is called Sry. Just a short burst of Sry is all that is needed to boost the activity of a related gene, Sox9. Sox9 is not located on a sex chromosome, but on one of the pairs of normal chromosomes (autosomes). Sox9 then does all the hard work to drive testis formation and to maintain testis function throughout life.
Despite such a key role, Sry is found only in mammals. Other vertebrates, such as birds, reptiles, frogs and fishes, all have different ways of triggering which sex an embryo will become, although Sox9 is thought to be critical in all of these for making testes. It was thought likely that Sry evolved from another closely-related gene, Sox3, which is located on the X chromosome in mammals but on autosomes in other vertebrates. Until now there has been no proof to back this idea.
Sox3 normally functions in the development of the nervous system. While exploring this role of Sox3 Paul Thomas' group at the University of Adelaide showed that some mice carrying an extra copy of Sox3 gave rise to males with two X chromosomes. They had no Y and therefore no Sry gene, but had developed testes and other male characteristics – although they were sterile due to the absence of other Y genes required to make sperm.
Robin Lovell-Badge (pictured) and his group in NIMR's Division of Stem Cell Biology and Developmental Genetics originally discovered both Sry and Sox3 about 20 years ago. He has had a long-standing collaboration with Paul Thomas' group in Adelaide. Together they have now shown that the extra copy of Sox3 had (by chance) integrated next to a gene that was active in the very early gonad before it begins to form either an ovary or a testis. This neighbouring gene (which is autosomal) appears to have influenced Sox3 to become active at the same time, and this was then able to boost Sox9 levels sufficiently to promote testis development.
Further collaborative research with Professor Andrew Sinclair at the Murdoch Children's Research Institute in Melbourne and Professor Eric Vilain at UCLA (the University of California in Los Angeles), has also shown that changes associated with the human SOX3 gene are present in individuals who are XX males – indeed these changes may account for at least 20% of otherwise unexplained cases of XX male sex reversal.
Cases of XX male sex reversal are particularly intriguing and are poorly understood. These findings are of clinical importance with respect to diagnosis, counseling and treatment of sex-reversed patients. While little can be done at present to correct the problem, knowing its cause is very important, so as to determine how the patient is managed subsequently.
It is now very likely that something similar to what has happened in the XX male mice and humans we describe also occurred in our early mammalian ancestors: a chance chromosome rearrangement or mutation that gave rise to Sox3 activity in the early gonad. This then replaced the sex determining switch that had been operating in these animals, and led to the evolution not only of Sry, but of the X and Y chromosomes. Just think of all the trouble this little gene has caused!
Robin Lovell-Badge
Click image to view at full-size
XX Tg/+ gonads have a normal male appearance and express the Sox3 transgene at 13.5 dpc. XX, XY and XX Tg/+ 13.5 dpc gonads shown in lateral and medial views and analysed for Sox9, Amh expression and EGFP fluorescence in unfixed tissue. Scale bar, 250 μm.
Original article
Edwina Sutton, James Hughes, Stefan White, Ryohei Sekido, Jacqueline Tan, Valerie Arboleda, Nicholas Rogers, Kevin Knower, Lynn Rowley, Helen Eyre, Karine Rizzoti, Dale McAninch, Joao Goncalves, Jennie Slee, Erin Turbitt, Damien Bruno, Henrik Bengtsson, Vincent Harley, Eric Vilain, Andrew Sinclair, Robin Lovell-Badge and Paul Thomas. (2010).
Identification of Sox3/SOX3 as an XX male sex reversal gene in mice and humans
Journal of Clinical Investigation, epub ahead of print. Full-text
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