Thursday, 16 October 2008

What Makes a Man

Or rather, what makes someone genetically male?
Our results reveal potentially important SRY regulatory elements, mutations in which might underlie cases of idiopathic human XY sex reversal.
That's from New insights into SRY regulation through identification of 5' conserved sequences by Ross D.F.G, JBowles J., Koopman P., and Lehnert S. in BMC Molecular Biology 2008, 9:85 (14 October 2008).

The problem is that XY sex reversal happens a lot, and we're not sure why. Many women are born apparently "genetically male", with 46XY chromosomes. But actually genetically female.
A majority of gonadal dysgenesis cases cannot be attributed to mutations within or immediately 5’ of SRY, or to any other gene known to have a role in sex determination. We hypothesise that this is because SRY’s regulatory regions are uncharted, therefore providing no means to check specific areas for mutation.
Worse, the SrY complex, the thing that makes men male, is very variable between species. You can't automatically assume that what is true in, say, horses or monkeys is true in pigs or humans.
SRY carries out a similar function in all mammals in which it is present, but displays a high degree of variability between species. This situation is thought to result from the location of SRY on the Y chromosome, exposing it to a higher rate of mutation compared to autosomal genes, thereby leading to DNA degradation and even loss.
The usual experimental animal used for genetic research, the traditional white mouse, isn't useful in this case.
As with the SRY coding region, sequences beyond the transcription unit of SRY are very poorly conserved between species, a situation that has contributed to an almost total lack of understanding of how the expression of this gene is regulated. Comparative genomics is normally a powerful tool for identifying biologically important gene regulatory regions, based on the conservation of functional regulatory modules being under selective pressure during evolution, but this method has shown only limited success in studies of SRY to date. Although mice are most useful for a range of developmental and functional genetic studies, their utility in comparative genomics is limited by their unusually high rate of sequence drift, thought to be linked to their short generation time.
So what about other mammals? The experimentation shows that cattle, pigs, goats and sheep are better experimental animals to use. In fact, almost anything other than mice!
Progress in identifying potential gene regulatory motifs through comparative genomics relies on the availability of genome sequences from a range of non-murine mammals. A study analysing non-coding sequences in 39 bovine, human and mouse gene orthologues revealed 73 putative regulatory intervals conserved between bovine and human genes, only 13 of which were also conserved in mice. Further comparative genomic analysis of these regions showed that the homology to human is highest in bovine, and weakest in the mouse.
In the present study we generated novel bovine and caprine SRY 5’ sequence data in order to conduct comparative genomic analysis of 5’ sequences from human, bull, pig, goat and mouse Sry. In this way we identified four novel sequence intervals that may be important for the correct regulation of SRY expression and therefore for correct function of SRY in mammalian sex determination. The identification of these candidate regulatory regions provides a focus for efforts to discover new mutations associated with human idiopathic XY sex reversal.

This almost certainly has nothing to do with my own case. One would have to postulate a selective advantage to defective genes containing corrupted SrY complexes during cell turnover, in conjunction with all sorts of hormonal weirdness from a separate cause.

However, it does provide an important clue as to why little progress has been made on finding out how SrY works. It means that we will now no longer be trying to push water uphill.

This is not so much a new piece in the puzzle, as a better set of specs to enable us to find new pieces.

It also has given me some new ideas to explore in genetic algorithms maybe 10 years down the track, after I have my current PhD finished. There's all sorts of interesting twists and turns that Mother Nature uses, some of which may be forced on her due to physical chemistry (and likely counter-productive), but others actually non-obvious optimisations.


Lloyd Flack said...

Ah, While I haven't had anything to do with them the authors all work in the same building as mu but on a different floor. There have been quite a few seminars on sex determination anomalies.

It does look like it is not just SRY and SOX9. The idea of being female by default is not quite right. There appear to be genes that are involved in active feminization. Perhaps it is best to consider the default as something inbetween that suoerficially looks more female.

Lloyd Flack said...

Something I just thought of. People here might be quite interested in an unusual case of human sex reversal such as yours. They might be interested in looking at your genetic make up for clues not only to your case but to more general problems. Now it would normally be too expensive for you to have any genetic tests done for yourself. I could make enquiries her about whether they would be interested in looking at any cell samples of yours and possibly other members of your family.

Zoe Brain said...


Er, yes please. Thanks, Lloyd.

Lloyd Flack said...


I spoke to Peter Koopman, the head of the relevant section. He is interested.

I gave him your ANU phone number and email address. He said he'd follow it up.