INTERVIEW: A Graves future for the marsupial genome

The world now has detailed gene catalogues, maps and DNA sequences for two distantly related eutherian mammals: the mouse, Mus musculus, a rodent, and a large-brained African primate, Homo sapiens. Where to now?

Prof Jenny Graves believes that, to achieve the maximum yield about the deep genetic history of the world's mammals, it should be a marsupial -- specifically, a kangaroo.

Graves, the Australian National University molecular geneticist, will present the case for a Kangaroo Genome Project in her plenary lecture at the International Congress of Genetics in Melbourne next July.

To understand where humans came from, and the unique sequence of genetic events by which we became human, we need the genome of another mammal as a template, says Graves.

If you want to learn as much as possible about your forebears, Graves says you apply the use the same protocol that Goldilocks used for the three bears' porridge -- not too hot, not to cold, but just right.

Our closest relatives, chimps, bonobos and gorillas, are way too hot. Humans have one chromosome fewer than the ancestral great-ape count of 24 chromosomes, but the genes on those chromosomes are arrayed in almost identical number and order.

Even the mouse is too hot, despite some 80 million years of separation. But the chicken, a descendant of meat-eating raptor dinosaurs, is too cold -- the reptilian lineages leading to mammals and birds diverged during the Permian, some 220 million years ago, and bird genes now carry bird-specific regulatory sequences -- the DNA 'switches' that control gene activity.

The eutherian/marsupial mammal split occurred in the early Cretaceous, around 140 million years ago. And that's just about right, says Graves. "Among mammals, it doesn't get much wider than humans and kangaroos. One of the most efficient ways of finding genes is to do comparative sequencing between distantly related species."

Graves has worked on kangaroo genes for years -- her ground-breaking work on the genetics of sex determination in mammals drew heavily upon human-kangaroo comparisons.

One fundamental difference between eutherians and marsupials, says Graves, is that while females of both lineages always have one of their two X-chromosomes inactivated in every cell, in marsupials, it is always the paternal X that is switched off.

In eutherians, it's random -- some tissues have the maternal X inactivated, while in other cells have all the genes on the paternal X switched off -- the tortoiseshell colouration pattern of some female cats is due to random inactivation of X-linked pigment genes expressed in adjacent patches of skin.

Comparisons of the genomes of distantly related species, Graves says yields information about events like gene duplication, gene loss and chromosome rearrangements that have occurred over vast timescales -- geneticists can back-track through these events to chart how the genomes of species have evolved, and to predict where genes of interest should be found.

Graves' ANU group is collaborating with a team at Cambridge University to sequence large chunks of marsupial chromosomes carrying multiple genes.

"We're about to publish our first sequences in Genomics -- we found everything we predicted, and more," Graves says. "When we lined up a corresponding chromosome segment for human, mouse and marsupial, we found the mouse and marsupial have five genes, where humans have only four. That tells us the fifth gene was lost at some time during human evolution.

"The gene simply isn't there - it has just been flipped out."

If the gene was surplus to human requirements, but essential in other non-primate mammals, studies of its role in mouse and marsupial should illuminate a significant difference between humans and other mammals.

Graves says her plenary talk will argue for the first marsupial genome project to be based in Australia, rather than in the US -- and that it should involve the kangaroo -- a thoroughly modern marsupial, rather than North America's primitive Virginia opossum.

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