Jenny Graves is talking about sex - again

Not only is Jenny Graves one of Australia's most influential scientists, but she is also gaining a wider reputation in the non-scientific world for her ability to convert difficult scientific concepts into language non-scientists can grasp.

Earlier this year she was awarded the distinguished Macfarlane Burnet medal for biology by the Australian Academy of Science, an honour handed out only every three years. In her Macfarlane Burnet lecture, delivered in May in Canberra, she delighted the audience with an hilarious speech explaining how studying the genes of some of Australia's most distinctly odd animals has widened our knowledge of human genetics, particularly the evolution of the sex chromosomes.

She certainly delighted those members of the audience fortunate enough to own two Xs. Tracing the evolution of the pitifully small Y chromosome with its 45 genes, she told the audience it was time to reconsider its future.

"There are two models for the Y chromosome," she said. "The model we were all brought up with was the Y as a macho little thing because if you have a Y you're male and that's it. But it turns out that's only because the Y chromosome has the SRY gene on it. The other theory is that the Y is a selfish sort of entity and it grabs genes from other parts of the genome that are handy in males.

"But our work on comparative mapping says that the Y is merely a wimp, a relic of the X chromosome. It started off being identical to the X but over millions of years it has been losing genes and there are hardly any left. This, of course, makes men very anxious."

And it's on its way out, she says. It may take 15 million years for the Y chromosome to disappear, according to Graves, but it's going to happen one way or another. "It could be tomorrow or it could be never - I think we'll probably have wiped ourselves out long before 15 million years is up," she says.

"But it's good to dream and it's funny to think that things are happening out of our control that might have very dire consequences on humans; well, the males anyway."

Next thing you know, all the women in the audience have broad smiles on their faces and the blokes are shifting uncomfortably, unnerved by the prospect of their fundamental redundancy. It certainly gets their attention.

History of research

A keynote speaker at the upcoming International Congress on Human Genetics, Graves has been studying Australia's marsupials for more than 30 years and now, through the ARC Centre for Kangaroo Genomics, heads the research into the genome of the Tammar wallaby, a gentle and pliant animal that has taught us about more than just genetic evolution. By studying this wallaby, her lab has racked up the discovery of 13 human genes - human genetics labs would be more than proud to claim just one.

One of the most important discoveries was that the gene commonly thought responsible for male sex determination, ZFY, wasn't the real deal. In humans, this gene is found on the Y and has a homologue on the X. Studying wallabies, however, showed that the ZFY is on chromosome 5 and is not the male master gene.

That discovery was made in Graves' lab by her PhD student Andrew Sinclair, who made a further breakthrough when he moved to London's Imperial Cancer Research Fund to work with Peter Goodfellow and located the real male sex-determining gene, SRY.

Back in Australia, Graves' team found another gene involved in the male sex business, RBMY, which is critical for spermatogenesis.

"RBMY's homologue is the RBMX," Graves says. "Supposedly there wasn't an X version and it was quite important to discover that there was one, because for a start it showed us that even genes that have important functions in making sperm do come from genes that have been sitting around on the X chromosome for millions of years. They are not new genes. They have just been tweaked so that they do something different."

One thing they may do is assist in embryonic brain development and this is where is gets interesting.

"We were very interested when we discovered this gene because it mapped right in the middle of a region that is deleted in some families that have X-linked mental retardation," Graves says. "So we knocked it down in the zebra fish, which is a very easy thing to do in a zebra fish embryo, and their brains just don't develop properly at all. They kind of rot away."

So if there is a link between a sex-determining gene and brain development, does that mean that men actually do think with their testicles? "That's a good question."

---PB---

Brains and balls

With the SRY gene found to be expressed in the brain, it's probably not there for no good reason, she says.

"There are a lot of genes on the X chromosome that are involved with both brain and ball - we call it the brains and balls hypothesis - and people have wondered about it for years. It seems very strange that there doesn't seem to be much in common with brains and balls but there is probably a different explanation.

"My explanation is that these genes have started off producing very useful sorts of proteins but they've been pulled and tugged in quite different directions. One direction that they've been pulled in is doing something useful for males. This is an old theory but a gene on the X chromosome will be expressed in males but not in females because men obviously only have one X chromosome so there's not another one to mask it. It's always been thought that you very rapidly select for genes on the X that would have some advantage for males, like more sperm or bigger sperm or more aggression.

"But it also turns out that there are many genes on the X chromosome that have something to do with intelligence; there are lots of X-linked mental retardation genes, for instance. So there are also selections for genes on the X that have something to do with making us smarter. It's not my original theory but the idea is that it is females that have selected smart males. And doesn't that make sense to you? Not only smart males but males that can paint on the cave wall.

"The theory is that it is female choice that has led to an incredibly rapid development of the brain. That is one of the big mysteries - how the human brain doubled in size in so short a time - and I think it's all female."

So, will the Y chromosome disappear? "I have predicted that at the rate it's going the Y chromosome will disappear in something like 15 million years. Will the possession of sex and spermatogenesis genes save the Y? Probably not.

"We know that some genes needed for making sperm in mice have been lost from the primate Y. If this gene can be lost in other species, why not the SRY gene itself? If it becomes inactive and then gets lost there is no reason to keep a Y chromosome at all - it can just disappear."

More weird animals

In addition to looking at kangaroos and what they can tell us about the redundancy of the male, Graves has been delving into the very weird and wonderful world of the platypus, and here the research has thrown up some distinctly interesting possibilities.

"I have been fascinated with platypuses for nearly 30 years because they are really weird animals. The platypus is not content with having one X and one Y - it has to have five Xs and five Ys. We think this happened completely by accident but once it happens it's very hard to go back. What you can do is keep on adding more and more chromosomes to this chain, this X, Y, X, Y chain. We think this is probably what has happened in platypus and probably in the echidna as well.

"The bizarre thing is that it actually seems to work pretty well. Baby platypuses get born and they seem to know whether they are supposed to be male or female. Probably at miosis all these line up and all the Xs go one way and all the Ys go another way so a sperm has either got five Ys or five Xs."

The link between platypuses and birds, and platypuses and mammals, however, is where it starts to get very strange.

"We got a real surprise when we got a look at the genes of these Xs because at one end was a bird Z. We didn't think it had a link to the mammal X but now we think there is some connection. We can't tell without more study but our best guess is that there must have been some interaction between those two sex-determining systems.

"Originally we probably had the same sex-determining systems as a bird does and that has swapped its gene onto another chromosome and swapped and swapped again. The embarrassing thing is that we don't actually know what gene causes sexes in platypuses because there is no SRY - there's something else somewhere."

Another embarrassing thing is that it is American and not Australian researchers who have taken the platypus and run with it, she says. "It has been sequenced at Washington University in St Louis and while we did have a big input into that project, it was not our money. I'm glad it's being done but it's a bit embarrassing. We don't have ownership of it. Thank goodness for the kangaroo genome project or we wouldn't be able to hold our heads up high at all."

This is one of her bugbears, shared with many other Australian researchers: that we haven't carved a niche for ourselves in the genetic mosaic, save for our precious kangaroo. "It is the kangaroo genome project that is saving Australia's reputation in the genomics community and giving us a seat at the genomics table," she says.

Plenty of good science to talk about

Exhibiting at the ICHG is an institution deeply involved in the kangaroo genome project and one that is leading the way in genomic research in this country, the Australian Genomic Research Facility (AGRF).

Comprised of three different nodes, the AGRF is doing the actual sequencing of the Tammar wallaby genome, in association with the Baylor College of Medicine's Human Genome Sequencing Centre in Houston. The director of the AGRF, Dr Sue Forrest, says progress is increasing at an encouraging rate.

"The project involves doing a two-times coverage of the wallaby genome and that will give us a good basic blueprint to work from," Forrest says. "We are doing half of it and Baylor College the other half. We've finished just over a third of what we need to do. The last few months have seen everything functioning fabulously and it's probably the most productive pathline that exists in the country. The team is really excited."

Work on the wallaby genome is predominantly being carried out at the AGRF's Melbourne node, which also specialises in microsatellite genotyping and expression arrays. The Brisbane node focuses mainly on sequencing and single nucleotide polymorphism (SNP) detection.

"Where the SNP market is growing is in a lot of sectors besides human testing," Forrest says. "So people come to us to have a set of genetic markers designed specifically for that species or region of the genome. It's a customised service."

The Adelaide node works on plant growth and DNA and RNA extraction, leading into other services for researchers.

Bioinformatics in particular is a growing area that the AGRF can assist with. "We are providing bioinformatics services very close to the service edge. We are not developing new things but we are taking the tools that have been developed and letting the researchers get the most benefit from their data. Some of the more academic groups think 'this is taking up my time, I could be doing other things' ... so that's where we can help."

One of the most important roles that Forrest fulfils as the director of the facility is publicising its services. "What we often find is that we might have a certain group of the scientific community that might use us regularly but they might only know that we do sequencing, for example. Now that the scientific questions have changed they are not aware of all the things we can do."

Forrest believes that of the best things to happen in years for Australian science is the startling number of scientists being recognised publicly for their work, particularly through the increasingly popular Australian of the Year awards. In the early '90s there seemed to be a plethora of sporting identities claiming the gong, with the odd actor thrown in. Then Peter Doherty came along.

Doherty got the award in '97, Gus Nossal in 2000, Fiona Stanley in 2003, Fiona Wood in 2005 and this year it was Ian Frazer. Forrest describes this as fantastic.

"Years ago I gave a talk to the (Victorian) State Government and said if we could have - it was the day the Olympic team came back in 2000, unfortunately so because there was no one at the briefing - I said if we could have a cavalcade going up Collins St with flags waving and there were scientists sitting in the car, I would be thrilled. To have Fiona Stanley, Fiona Wood and Ian Frazer, all so eloquent ... we've got to bring science to the people, we've got to take off the lab coat so we are engaging in sensible conversations. And there is so much good science to talk about."