How to make a koala

Yes, the koala is cute. But it’s also evolved a bizarre survival strategy. 20 million years ago, when marsupial lions roamed the undergrowth, its ancestor sought refuge in the canopy of a select few species of gum tree, spent most of its time sleeping, and became the world’s only animal able to survive solely on a diet of toxic gum leaves.

Now, the secret to this survival strategy has been revealed by reading its genome, an instruction manual written in 3.42 million letters of DNA and over 26,000 genes – a tad larger than our own which is 3 million letters, and at best 21,000 genes.

The Australian-led international team report the findings in Nature Genetics.

Though they haven’t yet fingered the gene for cuteness, the high-quality genome explains a lot about what makes a koala a koala and will help both zoo vets and conservationists protect this vulnerable national icon.

It’s not just Aussies who adore the cuddly koala. Phascolarctos cinereus, which translates to ‘ash grey pouched bear’, regularly makes the top twenty list of the world’s cutest animals.

But it wasn’t always so.

In the mid-19th century, an estimated 2.5 to 3 million were killed for the fur trade.

Though now protected, the current population, estimated at 329,000 animals, ranges from Queensland in the north down through New South Wales and Victoria, as well as the introduced populations of south-east Australia and its islands in Port Phillip Bay. The northerly populations are considered at risk as the Eucalyptus forests they depend on are vulnerable to clearing, fragmentation and fire.

On the other hand, the population around Victoria is at risk from low genetic diversity since it was largely restored from small numbers of island animals. When genetic diversity is low, the populations can be decimated by an infectious agent, currently the situation with the Tasmanian Devil and Devil facial tumour disease.

It was “conservation issues” that triggered the koala genome project, says Rebecca Johnson, a geneticist at the Australian Museum who co-led the project of 54 scientists from 29 institutions in seven countries. “I consider myself a professional cat herder”, she says but acknowledges, “there’s nothing like the koala to get people lining up”.

Nevertheless, reading the koala genome raised particular challenges.

For starters, there was a problem sourcing high-quality unfragmented koala DNA. Koala blood proved unsuitable because it carried DNA-damaging chemicals such as phenolics. Their only option was to use post-mortem tissue supplied by wildlife hospitals and zoos.

Three dead koalas provided the DNA. One had been hit by a car; the other two had succumbed to chlamydia infections.

But acquiring the tissue was just the first hurdle to overcome in this five year marathon.

As Johnson explains, reading the koala genome for the first time was rather like shredding eight volumes of an encyclopaedia written in ancient Sanskrit. You have to shred the genome to get it out of the cell and then feed bits of DNA code into sequencing machines. But reassembling the entire DNA code is tough. Especially because most of the bits look pretty similar.

However, the longer the shreds the more confidence you have that the final assembly is correct. The team were able to use longer shreds thanks to state-of-the-art “third generation” DNA sequencing machines which can tolerate being fed ‘longer reads’. Carried out at the Ramaciotti Centre at the University of NSW, it is the first mammal genome to be sequenced in Australia using this technology.

While the genomes of other Australian animals have been read, including the Tammar wallaby, Tasmanian devil and platypus, much of the sequencing was done by collaborators outside the country and employed older techniques. That means these reconstituted DNA encyclopaedias are far less complete than that of the koala genome. Indeed, its accuracy is considered on par with that of the human genome.

So how does a genome help save koalas? Many ways, it turns out.

For one thing, the genome has allowed researchers to more accurately assess the diversity of the country-wide population. The good news is the northern population is more diverse than thought. Furthermore, the population that extends across Australia’s eastern Eucalyptus forests shows small continuous variations, defining it as a single species.

Because Northern koalas are smaller, paler and less fuzzy than the southerners, there had been suggestions that there were two or even three separate subspecies. Given they’re not, that should reopen the debate about mixing the inbred southern populations with some fresh northern blood. “It’s time to have tough conversations,” says Katherine Belov, the University of Sydney geneticist who co-led the project. 

By revealing the secrets of their weird biology, the genome should also help those looking after koala health.

Koalas are being ravaged by chlamydia, a sexually transmitted disease that can be passed on to offspring and cause blindness and infertility. Vets treating the disease with common antibiotics like chloramphenicol find they need to use massive doses.

Now thanks to a collaboration with researchers at the Earlham institute in Norwich, UK, they know why.

Koalas carry multiple copies of genes for breaking down the drug, so-called members of the Cytochrome P450 family. These same genes are vital to the koala’s ability to survive solely on gum leaves, which are packed with toxins such as terpenes. Most animals, including us, carry copies of these types of genes to detoxify the inevitable nasties we encounter in our diet.

But the koala genome reveals multiple duplications and variations on the theme. Understanding the chemistry of how koalas detoxify chemicals should help inform which kinds of drugs will work best for them. 

Koalas are also notorious for being picky eaters, a great challenge for zoo keepers who need to supply a koala with over one kilogram of eucalyptus leaves each day. Now that pickiness has been traced to their large collection of genes for smelling and tasting bitter chemicals.

Another revelation from the koala genome sheds light on their distinctly ‘marsupial’ type of immune system, and may offer strategies for our own survival.

Like all marsupials, koalas are born at an extremely early stage of development. About the size of a kidney bean, the newborn is devoid of organs or an immune system. Immunity is provided by antimicrobial peptide molecules secreted in the mother’s milk. Belov has been fascinated by these peptides for decades, ever since she learned during her PhD that koala joeys do not suffer infections after surgery. While other marsupials contain only two sets of these genes, the genome revealed that koalas contain five.

Belov plans to test the antimicrobial activity of the newly identified genes by following the DNA instructions and making the peptides in a test-tube. Given the era of antibiotic resistance, she says, “it’s a great opportunity to develop new drugs.”

All parts of the genome have been scrutinized by aficionados. For LaTrobe University geneticist Jenny Graves, whose passion lies with tracing the evolution of marsupial sex chromosomes, the precise new koala genome makes a welcome addition.

And, she says, “I would still like to find the gene for cuteness.”

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