Cat genome sequence reveals cause of dwarfism

Our furry friends have had their most thorough genome sequencing to date. A cat called Cinnamon now serves as the reference genome, the cat against which to compare all other cats. And the team have already discovered new genetic variants that relate to humans as well. Leslie Lyons was part of a team of researchers, and told Phil Sansom the story...

Leslie - We have been able to complete the most contiguous genome assembly for the domestic cat, which rivals that of most any other species. So what that means is that we have most all the puzzle pieces of the genome lined up properly. And that gives us a great genetic resource to do all kinds of health studies and evolutionary studies in cats.

Phil - You'll have to explain this a bit to me, because didn't we have a cat genome before? And isn't a genome a genome?

Leslie - Right? Well, yeah, that's what everyone thinks: once you've sequenced the genome you're done. But no, genomes are quite complex, and so we do them at different levels of resolution, and it all depends on the technology that's available. And so now we have something called ‘long read technology’ which allows us to put the genome into larger pieces. So picture a puzzle: certainly the puzzles with the smaller numbers of pieces are easier to put together, and you get them more correct. Sometimes when you're putting puzzles together, you somewhat try to force a piece and you think that's the right piece. And then later as you do more of the assembly, you realise, "oh, I kind of forced that piece. That's the wrong piece. Let me put the right one in." That's what we're constantly doing with genome assemblies. We're constantly correcting things and making them more finished from beginning to end, so there's no gaps in the sequence.

Phil - What do you have here then that you didn't have before?

Leslie - We have a whole gene, as well as we probably have more of the fragments that are upstream of the gene. And that's like the regulatory sequences of the gene; that's what turns a gene on and off. And that is actually what makes species different. Most species all have about the same number of genes, and the same type of genes. However their regulation, when they get turned on and off during development, and how much they get turned on or off; that makes the difference between a cat being a cat, and a human being a human. For example, we have the gene to make whiskers, but we have a different regulatory element.

Phil - You're joking. I have a whiskers gene?

Leslie - You have a whiskers gene.

Phil - Is there some way I can activate it and become a cat superhero?

Leslie - Yeah. If we can get that regulatory element popped in, which now we can technically do with CRISPR and genome editing, we could probably give you whiskers.

Phil - Wow. Okay. Let's park that for another episode. In this cat genome, did you find bits like that? Little regulatory elements that control things that you didn't expect?

Leslie - Yes. In the new cat genome, we were able to find better regulatory sequences, and also sequences that are called structural variants. And structural variants are just larger DNA changes that are harder to see with the short read sequence. By being able to see these larger structural variants, we were actually able to find a disease mutation that we've been looking for quite a long time. And that is the dwarfism of munchkin cats.

Phil - What does a munchkin cat look like? Because I don't think I've ever seen one before.

Leslie - Yeah. So munchkin cats have a very small structural variant in the gene called UGDH. And this is what causes them to have short legs. So there's many types of what we call ‘disproportionate dwarfism’; If you've watched any of the TV shows like Game of Thrones, you'll recognise characters with disproportionate dwarfism. Cats have the same thing. Their torso is the right size, but just their legs are shortened. And so we found a brand new gene, which means this gene can now be investigated in humans as well.

Phil - Is it really the same between humans and cats?

Leslie - Yeah, absolutely. Most of the genes that we find in humans are what we find in cats as well.

Phil - Are munchkin cats, would you say, more cute than your average cat?

Leslie - That's a very personal opinion. So I think cats are just quite beautiful, moving artwork. There're many beautiful cats, and it's to each his own, really.

Phil - Do you mind if we look at a picture?

Leslie - Please do, there should have been a picture right in the paper too.

Phil - All right. Here's one, the legs are really short. That is quite cute, actually. This cat, is this the one that you got the really well sequenced genome for?

Leslie - Actually no. Cinnamon is the reference sequence, an Abyssinian cat called Cinnamon. And so that becomes our baseline that we compare every other cat to. That is our gold standard.

Phil - Well, thank you to Cinnamon for the gold standard.

Leslie - Yeah!