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Jenny Jumps for Marsupials

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By John S. MacNeil

If there’s one thing Stephen O’Brien can tell you about his colleague Jenny Graves, a comparative genomicist at Australian National University in Canberra, it’s that she’ll tolerate excruciating pain in the name of science. O’Brien, who runs the laboratory of genomic diversity at the US National Cancer Institute, accompanied Graves on a trip into the outback several years ago to round up and study koala bears. After breaking her leg on the first day, Graves stuck it out rather than cut short the expedition.

“She’s hobbling around with a broken leg while these Crocodile Dundee characters are busy running around jumping up trees and searching for koalas,” says O’Brien. “It was quite an image.”

When not capturing koalas (a feat that O’Brien says entails shaking a Union Jack flag attached to a pole in the animal’s face to scare it into descending the tree while your mate catches it in a sack), Graves spends her time championing kangaroo genomics — tammar wallaby kangaroo genomics, to be precise. The mini marsupial, which grows to a height of only 18 inches, has provided a crucial link in scientists’ understanding of mammalian evolution, and soon may be the first of the order Marsupialia to have its genome sequenced.

Graves, in fact, is widely regarded as the mother of marsupial genomics. Raised by scientists — a soil physicist dad and geographer mom — Graves began to take an interest in biology late in high school. In college, she discovered the world of cell biology during a sophomore year abroad at UC Berkeley where she came under the sway of Dan Mazia, her physiochemical biology instructor.

When she returned to the University of Adelaide, Graves chose kangaroo chromosomes as the subject of her undergraduate research project, showing that just as in humans and mice, X chromosome inactivation is involved in the process of sex determination in kangaroos. The study morphed into a master’s thesis on DNA replication in kangaroo cells.

After returning to Berkeley to earn a PhD on mammalian cell genetics in Mazia’s group, Graves took a faculty position at La Trobe University and moved to Melbourne, accompanied by her new American husband, John. (They met performing the roles of Maria and Tony in a scientific take on “West Side Story” at Berkeley called “Nucleoside Story.”)

The X and the Disappearing Y

Back in Australia, Graves says she initially didn’t want anything to do with kangaroos, but a colleague recommended that she pick up on her work in Adelaide and investigate cell hybrids as a means of mapping genes onto the tammar wallaby and human X chromosomes. While some of her peers argued that marsupials were too distantly related to humans to make any meaningful comparison, Graves found them to be just the right genetic distance from humans to ask essential questions about mammalian evolution.

“It turns out they’re just like ‘Goldilocks and the Three Bears,’” Graves says. “They’re not too far [apart], so you can actually line up [the genomes], and they’re not too close, so they actually are significantly different. It’s these differences that have become very fascinating, because they’ve allowed us to do a lot of genetics of extremely fundamental processes that are pretty much the same between man and mouse, but different in kangaroos.”

Graves’ kangaroo gene maps have led to several insights into how the process of sex determination evolved in humans, such as showing that DNA methylation is important in the inactivation of human and mouse but not kangaroo X chromosomes, and in identifying the gene involved in sex determination in humans, known as SRY. Graves’ sex determination work put marsupials, and kangaroos in particular, on the map.

Graves has also gained notoriety for a theory that the male chromosome, which contained as many as 1,500 genes 100 million years ago, is shriveling. Today the Y is a mere 41 genes long and shrinking. “They’re getting lost at a great rate,” she says, “so I’ve been predicting for some years that the Y chromosome is running out of puff and is going to disappear in about 5 million years. That’s been dubbed ‘Jenny’s feminist theory of the Y chromosome!’” she says. Yet even without a Y chromosome there’ll still be men. “It’s likely [the Y chromosome] will only disappear if some other gene takes over its role,” Graves says.

Adds O’Brien: “Jenny’s very fond of making the metaphor that the Y chromosome is a very tiny little thing in marsupials. [At a meeting] she’ll emphasize how little it is until everybody is crawling under the table!”

Bring on the ’Roo Genome

By the late 1980s Graves was known for marsupial gene mapping, and was invited to the Paris meeting of the International Workshops on Human Gene Mapping. After working with the comparative gene mapping committee for several years, she began to realize that sequencing a marsupial genome would help fill in more of the pieces in the “giant jigsaw puzzle” of comparative gene mapping.

In February this year she submitted a white paper to NHGRI detailing the reasons why US sequencing centers should prioritize the kangaroo genome, and in mid-July Graves met with Eric Lander and other Whitehead Institute higher-ups to vet the various organisms under consideration for sequencing. Says O’Brien, who also attended the meeting: “One of the species everybody agreed on was a marsupial, and we all looked to [Graves] to find out which one it was, and she said, ‘Well, it’s already been decided. In Australia it’s going to be the tammar wallaby!’” Her role in the actual sequencing will be limited, Graves admits, but she plans to make use of the data by helping establish a DNA microarray and functional genomics resource center at the University of Melbourne, and physical mapping and map integration effort in her lab at ANU.

Outside of work, Graves is an accomplished choral singer, and spends long weekends at her home outside Melbourne, where her husband, a transportation planner by day, has a vineyard. Her 96-year-old father lives next door on one side, and her sister and her family on the other. From Tuesday to Friday Graves commutes by air almost 400 miles north to Canberra, and oddly enough, she says, her family “didn’t all want to move!”

NCI’s O’Brien isn’t the kangaroo queen’s only fan. Jim Womack, a veterinary pathobiologist at Texas A&M who first met Graves 20 years ago, praises both her contributions to comparative genomics and her collegial manner. “Jenny’s one of those people who shares everything,” says Womack. “She’s a lot of fun to be with, and she loves to talk science.”

 

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