Ten years in the making, the sequencing of the tammar wallaby’s genome was published last week, and two UConn biologists in the College of Liberal Arts and Sciences are among the senior authors.

The tammar wallaby – a small kangaroo weighing about 30 pounds (the size of a large beagle) – is the first Australian marsupial to be sequenced. The genome sequence will provide scientists with new insights into the evolution of mammals, and into human reproduction and development. Because the kangaroo baby, known as a joey, develops outside the mother in a pouch, biologists can access information that could not be studied in utero on a human fetus.

One of the surprising findings in the sequencing was how many tammar wallaby genes are conserved, or look similar and seem to have similar roles, as human genes, even though humans and kangaroos diverged in their evolutionary path 150 million years ago, says Rachel O’Neill, professor of genetics and genomics in the Department of Molecular and Cell Biology, one of the principal investigators.

That makes the tammar an “awesome model,” she says, for studying the evolution of genomes and chromosome structure. Tammars also make good models for understanding more about mammalian reproduction, says Andrew Pask, associate professor of genetics and genomics in the molecular and cell biology department, also a principal investigator.

From this project, scientists will be able to learn more about milk production (the wallaby produces two different types of milk from four nipples); how mammals develop and grow; and how nutrition in early development can affect adult health outcomes, says Pask.

They will also learn more about what makes kangaroos hop, as they investigate further the HOX genes responsible for the tammar’s powerful hind legs.

The tammar wallaby was the first Australian marsupial discovered by Europeans. An excerpt from the Genome Biology paper records an early description:
“Their manner of procreation is exceeding strange and highly worth observing; below the belly the female carries a pouch into which you may put your hand; inside the pouch are her nipples, and we have found that the young ones grow up in this pouch with the nipples in their mouths. We have seen some young ones lying there, which were only the size of a bean, though at the same time perfectly proportioned so that it seems certain that they grow there out of the nipples of the mammae from which they draw their food, until they are grown up.” Francisco Pelseart, captain of the Dutch Indies ship Batavia, while shipwrecked off the coast of Western Australia, 1629.

The wallaby’s unusual method of reproduction, with the baby emerging at about one month – when it is a kidney-bean-sized fetus – and crawling up the mother’s tummy into the exterior pouch, also provides potential clues for the development of antibiotic-resistant drugs. The pouch is dirty and full of bacteria (“pouch jam” is the name given to the black material typically found in a kangaroo’s pouch), but the international team of researchers found novel proteins in the wallaby’s milk and secretions in the pouch jam that protect the baby, which has not yet developed an immune system.

“It’s a great model when you’re thinking about anti-microbials,” says O’Neill.

The wallaby baby also has a remarkable sense of smell – the study found it has as many as 1,500 olfactory receptor genes. These allow the newborn embryo to locate the mother’s pouch and the correct teat: only one of the four provides the milk it needs at the newborn stage.

The paper, with dozens of authors and researchers around the world associated with it – from Baylor College of Medicine in Texas, to Japan, to the UK – was published Aug. 19 in Genome Biology. The manager of the project and lead author is Professor Marilyn Renfree of the University of Melbourne, Australia. Four UConn graduate students are also authors on the paper – James Lindsay, Thomas Heider, William O’Hara, and Dawn Carone. Carone contributed to the work but is now a postdoctoral associate at the University of Massachusetts Medical Center.

The large consortium of researchers spread around the world used various technologies in sequencing the genome. For years, researchers in Australia have been mapping the tammar wallaby genome – both O’Neill and Pask, who overlapped as Ph.D. students at LaTrobe University in Australia – had worked on the map. But taking the bits and pieces of the map and placing them on “scaffolds,” or structures that allow scientists to assemble the full genome, began a decade ago.

UConn’s contribution toward the end of the project was critical, using a next-generation 454 sequencer purchased through a National Science Foundation grant to O’Neill and Linda Strausbaugh, professor of genetics and genomics, and director of the Center for Applied Genetics and Technology, where it is housed. Where older sequencers available at the start of the project could process 96 sequences overnight, the new generation can process billions of sequences in a few days.

Dealing with the resulting terabytes (1 terabyte is 1,000 gigabytes) of data then becomes a challenge, but a UConn supercomputer, the SGI Altix, nicknamed “The Dude,” which was obtained through a large equipment grant from the Provost’s Office a couple of years ago, made that possible.

“That supercomputer is gold,” says O’Neill. Even so, the UConn team worked “a lot of 100-hour work weeks” over the summer to validate the genome assembly, do all the annotations, and wrap up the project, while getting anxious calls from the researchers at other institutions.

O’Neill was surprised to find that the tammar wallaby’s genome was very compact – smaller than the human genome, even though researchers had expected it to be larger. That makes it ideal for studying, since the chromosomes are large and easily identifiable. The amount of non-coding RNA in the genome was also an exciting find, she says. Non-coding RNA is often involved in regulating protein pathways, but it doesn’t actually make a protein. It is the subject of a massive, emerging new field of study, she says, and the tammar wallaby findings will allow scientists to identify new non-coding RNA in humans.

The study also provides new information about a gene that is essential in human reproduction. It is essential for developing normal testes in all mammals, and the wallaby project will help determine what part of the development process the gene affects, Pask says.

About 26 scientific papers will be published as a result of the sequencing. Some are in progress; others have already appeared. While the sequencing is considered definitive, it will be tweaked on a fine scale and updated as studies continue.

Says Pask, “I think we’ve created a really unique resource that, hopefully, the scientific community will now utilize.”

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