Exploring weird Australian genomes

We now know about three billion base pairs of the human genome - at huge cost. But this is very boring information unless we know what it does. One of the questions I am most often asked is: “Well, we’ve got the human sequence now, why do we need other mammals? Particularly, why do we need weird animals from Australia?”

In fact this is going to help us find new genes and discover what they do, so we can understand human genetic disease and how to treat it, and maybe even make money in developing new drugs and a better traits for our domestic animals. It will also tell us how the human genome evolved.

I would like to explain what’s being done and how animals are related to each other. A number of different placental mammal species have been sequenced, including humans whose genome has been sequenced multiple times. We also have the sequences for chimpanzees, mice, rats, dogs, cats, and even the elephants are now lined up for sequencing. But these animals are actually all rather closely related.

They shared a common ancestor only 100 million years ago, and that isn’t enough time for the genome to have changed sufficiently for us to get the maximal information out of it. If we go to the other extreme and look at animals that are very distantly related - that is birds, frogs and even fish - they share a common ancestor with mammals 300 or 400 million years ago and that’s too far because now the sequence is so different, it’s actually hard to line up.

But Australian animals are right in the middle. Marsupials and monotremes last shared a common ancestor with humans about 200 million years ago, so they’re exactly in the right spot to give us maximal information to make comparisons. Right now the genomes of two marsupials and the platypus are being completely sequenced. This gives Australia a fantastic opportunity to make a major contribution to the understanding of the human genome by using our own mammals.

I wish I could tell you that Australia is rising to the challenge, but apart from small contributions to the cow genome project, Australia has hardly participated in the international comparative genomics project. Our one standout is the kangaroo, which is supported, not by the Australian Government, but by the Victorian State Government. The Australian Genome Research Facility is doing half the sequencing of this and the Baylor Genome Centre in Houston is doing the other half.

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.

There are 26 species of kangaroo and we chose to sequence the Tammar Wallaby, on which much of the classic biochemistry and physiology was done.

The ARC Centre for Kangaroo Genomics that I direct is doing the mapping and preparing the genome for sequencing. The kangaroo genome is about the same size as the human genome but it’s packaged very differently - into just eight enormously large chromosomes that are a dream to work with. The other good thing about marsupials is their chromosomes have not been rearranged much, so if you’ve seen one genome you’ve seen them all.

The very large kangaroo chromosomes can be cut out of a cell, arranged in a row and assigned numbers according to their size and location of the centromere. There are two copies of each chromosome, one from the mother and one from the father. There are seven pairs of what we call autosomes - that is ordinary chromosomes - and a pair that’s different in males and females; these are the sex chromosomes X and Y. So the Tammar is great because it only has eight pairs and they’re easy to distinguish from one another, compared with humans who have 23 pairs that are all rather small and dull.

The first thing you need to do when sequencing an animal genome is to make a map of it. There are two different kinds of maps you need to make. One is a genetic map made by mating animals with different characteristics - these can be anything, including fur colour, proteins, or sections of DNA. The other kind is a physical map where you’re actually looking at the location of particular bits of DNA on the chromosomes under a microscope. Once you have both maps you need to put them together. We already have a framework genetic map of the Tammar and are rapidly building a physical map.

All these genes exist in humans as well and we know where they are. So we can colour the bits of the kangaroo genome according to what parts of the human genome they represent. This is useful because we can read off one map and onto another. For instance, if we map a milk gene in the Tammar, we know exactly where that gene is going to be in the human genome and we can go in and look for it in the human genome sequence. So this comparative map is already extremely valuable to us.