Sunday, November 10, 2013

What has cheap genome sequencing done for dog science lately?

So you have the full sequence of a couple few dog genomes, and a wolf genome to boot. (Yes, these days sequencing is cheap enough that genomics researchers can do this. There are more errors in these less expensive, “shallowly sequenced” genomes than the one that we use for the standard canine reference, but even with errors, you can still get the whole genome to play with.) So you have these genomes. And you are curious about domestication. What makes a dog different from a wolf? These genomes each are made up of millions of nucelotides, so when you do a straightforward comparison between dog and wolf, you get hundreds of thousands of differences in nucleotides, ranging from single nucleotides that are different to long stretches where chunks of the genome are repeated in one species but not the other. And what to make of the differences between pairs of dogs — are those important too? It can seem an overwhelming problem.

Luckily, in addition to having fast and cheap access to full genome sequences, we also have powerful computers for analyzing these sequences (and one of my favorite parts of my PhD program is that I get to use my programming skills in addition to my biomedical skills). What people do is think of patterns that suggest that certain areas are the interesting ones, and tell computers to look for those areas. It turns out that if you have a couple of genomes of animals of the same species, you can compare them to find regions where there is very little variation between animals. This suggests that this area is important — everyone has to have exactly the same sequence here, because anyone who has any differences is less fit and less likely to survive to pass on their genes. This is called a selective sweep, because at some point in the past, this change swept through the genome and everyone eventually got the identical copy of this region.

For an added bonus, if you have the ancestral species — in this case I am obviously talking about wolves, which are ancestral to dogs — you can compare this region in that species. If you find that this region is the same in all the dogs but different in the wolves, you have an area which is highly suspicious for being involved in domestication. So you can ask a computer to go find some of these low variation regions for you,

There are a lot of statistical tests that you can do to convince yourself that this area has sufficiently low variation to be interesting, but that area doesn’t, and it has been my pleasure this week to be reading about those in great detail. (Being a grad student rocks, but then sometimes there is statistics.) But the most recent papers I have been reading have pretty much done away with statistical tests to convince themselves that certain areas are involved in domestication. What they have done is to use stats to find areas that are just potentially interesting, and then they actually go look at the areas and see what they see. What known genes are in that area? Anything that could have to do with domestication? Yes? So let’s see how that gene differs in a whole bunch of dogs and wolves. The same in all the dogs, and different from that in all the wolves? Awesome. So what does this gene actually do? Can we understand how the genomic change between dogs and wolves — the mutation — changed the protein? Did it change the protein’s function? Or maybe dogs make more, or less, of that protein. Labs have just been selecting specific genes from these areas and investigating them intensely and seeing what they find out.

The best example of this approach (and the one I find the most interesting, because it was done in dogs, not pigs or chickens like the other papers I have been reading) was published early this year. You have probably heard it if you are interested in dog domestication, because it made a big stir by declaring that dogs had evolved to be better at digesting starch than wolves.

Axelsson E., Ratnakumar A., Arendt M.L., Maqbool K., Webster M.T., Perloski M., Liberg O., Arnemo J.M., Hedhammar Å. & Lindblad-Toh K. (2013). The genomic signature of dog domestication reveals adaptation to a starch-rich diet, Nature, 495 (7441) 360-364. DOI:

But when you read about this paper, did you know how they figured out that dogs are better at digesting starch? They did one of these low-variation genomic scans. They found some interesting regions. They looked at what genes were in these regions. They found a lot of genes involved in digestion, so they decided to chase that first. (They also found some interesting genes that work in the brain, and hopefully we will see a followup paper on that soon.) They focused on a few genes and tried to figure out what they did and how they had changed between dog and wolf. In at least one case they found that dogs just expressed a lot more of a particular protein than wolves do, and that protein is involved in digesting starch.

There are a lot more regions to look at in dogs, and there are some interesting things to hunt down in tame foxes, too, of course. We are in a fascinating time for genomics. The technology is becoming so inexpensive that we can actually look at the code of genomes belonging to individual animals more more readily than we could just a few years ago, and this is a game-changer. There should be many more discoveries to come soon about the mechanics of canid domestication!

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