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Leslie Lyons – Exploring the Feline Genome | Our Longevity Futures | Ep.13

23 September 2021

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Over the last 150 years, our life expectancy has grown, from 40 years in 1850 to over 90 years today in some countries. This can be attributed to advances in medical science, improvements in public health, and equitable access to healthcare, especially for maternal and infant care.

What will the future hold for our world? Will we be overwhelmed by a ‘silver tsunami’ of retirees with poor health, or will we use the latest research findings to rejuvenate the elderly and extend their lifespan?

Our Longevity Futures is a show where I, Chris Curwen, speak to scientists, engineers, entrepreneurs, doctors, politicians, and community activists who are giving the world the hope that we can all live longer and better, and improve our health.

In today’s episode of Our Longevity Futures, we are delighted to speak to Prof. Leslie Lyons.

Leslie is an associate Professor at University of Missouri College of Veterinary Medicine. She also is the director of the 99 Lives Cat Genome Sequencing Initiative, which is a project that will read the entire DNA sequence of each of the 38 cat chromosomes and of which the data will be used to identify DNA mutations causing interesting traits, like different coat colors and ear and tail types, or health problems.

Here are some of the highlights for my conversation with Leslie:

Chris: Are you a dog or a cat person?

Leslie: I have to say, I am a cat person. I was raised with cats and we always had at least one cat running around the house. Never any dogs. I certainly know a lot about dogs as there’s a lot of good canine geneticists that we interact with and we try to share information between species all the time. So cat, dogs, horses, they’re all companion animals. And we try to learn on other all the time, but definitely more cat person. Cats rule.

Chris: Can you tell us a little bit more about your background and how you actually got interested in the field of feline genomics.

Leslie: Yeah, actually, so cat’s kind of picked me in the end. I was trained at the university of Pittsburgh in Pittsburgh, Pennsylvania in human genetics. And so it was during that time that I was learning about human genetics, I saw that many groups were doing the same thing and being highly competitive. And I thought ‘what could a different niche that I could do that would be very helpful to human medicine, but perhaps a bit different’. And I started to realize that people did the exact same things that you do in humans, but it could be cows or dogs or horses or some other species. So I started investigating and talking with investigators that were working on different species. And that was known as comparative genetics at the time. And somewhat still is. It’s very similar to comparative medicine, comparative genetics. And I considered working with cattle and fish and cats. And after I got my PhD, I ended up working with cats because I joined the lab of viral carcinogenesis at the national cancer Institute in Frederick, Maryland.

And they were still doing a lot of human genetics, which I wanted to maintain some of those ties. I wanted to learn more about evolution, and their organism that they were studying happened to be the cat. And then also my skills were in disease, gene mapping and trait mapping. And that was something that needed to be added to that laboratory as far as the cat work.

And so it all fit together. I didn’t really choose that because of cats, but I chose the career and cats were the model organism that were being used. But actually since then, usually your postdocs, that’s what your career is going to be, and since then we haven’t looked back. It’s been all cats.

Chris: Has it ever been tempting to jump back across to human genomics?

Leslie: Not really because I’ve been able to work with many different species. So we have publications on a variety of different species. I work closely with the horse community and also with the dog community here at University of Missouri and the things that we do in cats relate back to humans. And so in effect I actually do work on humans. The whole idea is the cat is a biomedical model for human disease, for certain diseases.

And so I do hope that. The things that we discover in cats are then applied to human medicine as well. So I’m not really out of human medicine, but I attack it from a different approach.

Chris: Could you tell us a bit about the 99 lives cat genome project, and what the aims of the project are?

Leslie: Yeah the 99 lives, cat genome initiative or project, whatever you would like to call it is really an effort that I started to push along. Once I got here to the University of Missouri in 2013. At that time. Also, the cost of sequencing was drastically dropping for humans and then also for other species. So a key thing that happened was Illumina came out with an instrument called the X10 and that allowed sequencing cost or dramatically dropped from two about $5,000 to $3,000 per mammalian genome.

So mammalian genomes have 2.4-3 gigabases of DNA and to be able to sequence those genomes at a high enough test of coverage that cost had to get down to about that. And so then we realized ‘Hey, it’s at a cost that the normal person and researchers can really start sequencing cats’, and nine cats didn’t seem like enough, nine lives. So we made it well, let’s set a goal that we can be a little ambitious, let’s do 99 cats. And there’s the 100K project and the 10K project for other species. And so with cats, we just changed it up a little bit. So I’ve just pushed that forward and in the end we have now 30 different institutions, 50 different collaborators from all around the world, contributing genomic sequences to the 99 lives cat genome project.

Chris: How far through the project are you?

Leslie: yeah so all the genomes have been sequenced and we try to keep high, what’s called depth of coverage, for these genomes so that we know we have very accurate data. So we reached that goal within a year or so. And now we have more than 400 cat genomes. And in fact, we just did a doodle poll, and so the whole consortium is going to get together and regroup and say ‘okay, what’s our next goal? What should we do now?’ Should we start forming little subgroups that are working on specific diseases, such as diabetes or FIP or amyloidosis or hypertrophic cardiomyopathy. So we know those are questions that are out there for cats. And can we do a better job at the consortium, with people all kind of work together.

And so we’ll be asking some of those questions at a consortium meeting a little bit later here in probably September, October.

Chris: What results has the project already thrown up?

Leslie: One of the biggest things is we can find things faster and just if you’re a humans and you’re doing whole genome sequencing to try to figure out why a young child might have a health problem, doing whole genome sequencing, you have about a 50/50 chance of finding the mutation that you think is going to be causal right off the bat and really rapidly. And so that’s what we’ve been able to do with cats. So I think there’s at least a dozen papers now that have the 99 lives consortium in the author line of different diseases that have been identified and working on a host of them right now.

And we find traits, as well, so most recently mutations for what’s called the ticked pattern in cats. A cat that looks like an Abyssinian is ticked, it has no Tabby stripes on it. And so my group and another group Dr. Greg Barshes group with Chris Kailyn has also done excellent work on the tick locus.

And so, we find fun things, coat colours, which in the end are very interesting from the point of biology of how patterning works in animals. But then also we find inherited diseases and the goal is to do precision medicine. You send us DNA from your sick cat. We find the mutation and maybe once we know the DNA mutation, you can target a therapy towards that mutation that would be a better treatment than just treating symptoms. And so we hear a lot about this in oncology, where they do targeted therapies and targeted vaccines for certain receptors. While we want to be able to do that for almost any disease, whether it’s in humans or whether it’s in cats.

Chris: What are the kinds of diseases that stand out, as particularly common in cats when compared to other species? And also, what diseases are then actually particularly rare when in comparison, and why are these?

Leslie: Now understanding why we probably don’t have good answers to that. And maybe that’s where we want to get to. So something, for example, that is more, let’s say rare is, when cats normally die of old age they’re generally dying of renal failure.

So that’s very common, or a type of cancer called lymphoma. So you think ‘oh cancers are common in cats’, but actually not as common as in dog. So yes, cats die of old age associated lymphosarcoma, generally intestinal lymphoma sarcoma, but they don’t have a lot of the other cancers that we find in humans and dogs.

So dogs are more of a model for cancers where cats are actually more of a model for let’s say like infectious diseases. Cats have coronaviruses and it was because of cats that we did know, not just because of them but they certainly helped, to understand that the nucleuside analogs, remdesivir, actually work and fight off infections of coronavirus.

So we knew that a couple years before humans even saw COVID, we were using GS analogs to fight off feline, infectious peritonitis. Yeah, and it actually cures it, so that drug actually has provided a cure for what was a 100% lethal disease. If a cat got FIP it was done for.

Other diseases, a polycystic kidney disease is a very common human disease. You don’t hear much about it, but it’s more common than Duchenne, sickle cell combined. And so a lot of older people succumb to renal failure because of PKD and cats have that as well. And that’s something we’re actively studying; can changing the diets put cats on a more ketogenic diet and will that help reduce cyst volumes. And more we’re finding that’s true and the thing is cats naturally should be on a ketogenic diet, right. So only since the fifties or so have we been putting a lot of carbohydrates in their diets. But now we’re seeing. It might be as simple as changing the diet, and that might be the best therapeutic for polycystic kidney disease.

Cats have lots of hypertrophic cardiomyopathy. These are the type of cardiac diseases that when you hear about an athlete that suddenly it succumbs, drops over, from a heart attack, these are hypertrophic cardiomyopathy. And so cats have lots of that.

Cats have lots of diabetes. So just like us there drink eating too many carbs, sitting around in the house, not getting enough exercise and becoming obese, and then they have obesity associated diabetes as well.

What we’re trying to promote is that, now that we can do genomics, for almost any species, let’s pick the right animal for the right disease. So the mouses is wonderful, we’ve come a long way with mice, but we need to realize that they’re not always the best answer to everything. So they’re not particularly the best thing to study polycystic kidney disease, for example. But a lot of research has been done on mice PKD.

Chris: It’s similar with Alzheimer’s.

Leslie: Yeah, exactly. So let’s start learning because now we have these genomic tools, these whole genome sequences of any almost, any species. Now let’s use the right model for the right disease, become more efficient with our science and get to our therapeutics.

Chris: What disease is the cat model the best model to use to study the disease?

Leslie: Cats are absolutely for example, the right model for polycystic kidney disease. A cat’s kidney is large enough that you can do a CT or an MRI and not only measure the kidney volume, but you can determine the cyst volume as well, which that’s really hard to do with a teeny little mouse kidney. And the thing is to figure out if your therapeutic is working, you want to see the cyst volume go down, as well as the kidney volume. So you can’t do that with imaging, with the mouse, but you can do that with the cat. So the cat is a slightly better model for polycystic kidney disease. And that all depends on other diseases and what specialty that you’re working on that the cat might be better, or maybe the dog might be better. Type two diabetes the cat is a pretty good example.

Chris: Why are cats prone to only certain types of cancer?

Leslie: We haven’t really investigated that well yet in cats. And the two things we have to realize is there might be an ascertainment bias in cats. So like dogs are always thought, ‘oh, they have all these cancers’. There’s far more breeds of dogs, so there’s more inbred populations. And each one of those inbred populations will have their own health concerns.

They tend to be a lot of different cancers for dogs. So there’s more breeds. There’s also more vigilance. More of our dogs are fancy breed dogs where most of our cats are just random bred cats. They’re not of an inbred variety. And so we just we say dogs have more cancers, but maybe that’s just also partly an ascertainment bias.

And then then the second thing also is that, remember I mentioned that, we have a 50/50 chance of finding our disease mutations. That’s because, maybe a good proportion of disease mutations are in the coding part of genes, that’s what we are good at. But we’re discovering that the ones that we can’t find are potentially copy number variants or structural variants that are outside of the genes, we used to call the junk DNA.

Now we’re discovering that’s important DNA and now they’re calling it the dark matter. And now we’re discovering that the 3D structure that the DNA makes as it folds is actually part of the regulation of genes, and that is what turns genes on and off to some extent as well. So it’s becoming very important to look outside of the gene, into that dark matter, and maybe that helps explain some of our cancer issues and dogs and other species as well.

So why cats don’t have as many cancers? Potentially just an ascertainment bias, but potentially, maybe their genome is slightly different and wouldn’t it be cool to find out why they don’t have cancers as opposed to why many animals may have a cancer such as humans and dogs.

So the reason why they don’t is just as important as the reason why they do.

Chris: What are the dynamics of cat telomeres?

Leslie: We’re just getting to the point where we can answer that. So the mouse, second to human, has a very good genome. And so their telomeres structures, how long each telomere is, and telomeres are the caps of the chromosomes. And they pretty much tell the chromosome, okay, you’re running into this repeat sequence and there’s not going to be any genes there. This is the end.

But now we’re discovering that, maybe some of that repeat sequence wears away, and when it wears away, does it actually wear away into the next coming gene? And does that affect some of our aging process? So the thing is we don’t know that yet for cats, we know they do have telomere repeats. But now with the new ultra long contiguous cat genome reference assembly, that is now coming out, so we’re going to change the reference assembly for the domestic cat. Cinnamon, the Abyssinian, is going to be retired and this fall a new cat is coming in. The cat’s name is not as nice, it’s grumpy the cat, and so maybe we’ll come up with some pseudonym for grumpy.

But we have this wonderful sequence that goes telomere to telomere and Bill Murphy’s group at Texas A&M is working hard on making sure that sequences all put together well. And one of my questions to him was, do we read into the telomere of each cat chromosome and how long are some of the centromeres as well? Those are repeat sequences as well. So soon we’ll be able to answer that more on a different cat basis and monitor that as cats get older.

But first we need to know what baseline is, because grumpy the cat wasn’t a neonate, it was a cat that was several years old. So we’re going to have a genome assembly that represents a cat that is a few years old, and then we’ll be able to go from there.

Do we see longer ones in younger cats? Do we see shorter ones in older cats? And now we’re setting up the tools so that we can start looking at things like.

Chris: I imagine most of these cuts that you are sequencing are domesticated cats. Is that correct? Or is it cats of all sort of variation?

Leslie: Unfortunately, but fortunately, we have included many of the wild felids, so I’ll refer to cat’s as random bred domestic cats are fancy breed cats. Then there is a species called wildcat. Wild felids that are in these survival programs can also get inbred and have health problems. So we’re studying, and we’ve already solved an inherited blindness in black-footed cats. We’re working with polycystic kidney disease and palace cats. Lions have a vitamin D deficiency issue that causes their skull to malform as they grow as cubs.

Fishing cats have transitional cell carcinomas. Black-footed cats again also have amyloidosis. And snow leopards have a multiple ocular defect that we’re also working on. So not only are we working on domestic cats, the normal average ally cats, moggy but fancy breed cats, but also wild felids as well.

Chris: If you compare the genomes of domestic and more wild cats, what parts of the genome have been altered in response to actually living with humans? Have you looked at these sort of evolutionary changes in the cat species?

Leslie: We would love to do that project actually, but it’s rather hard to do because the progenitor for the domestic cat, which is the African Wildcat, still exists. We can go out and get samples of African wild cats, and we would be able to compare them to domestic cat. And there’s also European wild cats as well, but they are not the exact progenitor, they’re a step away. They are different sub species of wild cat. But the problem is if you go out and get a sample of those cats today, they’ve been what we call intergressed. They’ve already bred with domestic cats accidentally and so it’s really hard to get a real nice clean signal.

So that’s where we have to go back and try to do ancient DNA studies. And there’s a couple of groups, one group there at Oxford and one group in France that is very actively looking at ancient DNA, but it’s hard to get ancient enough because we need to get ancient DNA that would be greater than 8,000 years ago, because that’s about when cats became domesticated and we want a signal that has no integretion, there’s no mix of the domestic and the wildcat.

We are working to do some things like that, we have in the last genome paper, there was some information on neurological genes that are seem to be common in the domestic cats. But that’s all very large clouds of data, instead of pinpointing saying exactly here’s the gene that causes cats to be domesticated. That’s what everybody would love to have.

And who knows? There’s probably more than one. Cats were probably domesticated differently in the far east as they were in the mid east or in different parts of the world. So you never know if you just have only one gene or. Parts of the world. There might be different genes that are selected for domestic.

That’s probably one of the goals, the next goals for 99 lives: can we get more focused on that aspect, but finding those clean datasets is. We can get wild cat samples, but they’re modern wildcat samples. And then you’re never sure whether they’re going to give you the right signal or not because maybe two generations ago, those cats interbred with just feral domestic cats and stuff.

But we’ve done a lot of looking at feral cats around the world. And we know that at the fringes, the cats are genetically different. So Southeast Asian cats are very different from Western European cats. And just like you saw in Morocco, that’s how we’ve collected some, our cats just go and offer the cats of the streets and the Medina, just offer them some tuna fish and they come running.

Chris: Is there a drastic difference in lifespan between domesticated cats and feral cats?

Leslie: So that’s a little hard to put a number on because that would mean someone has to be watching a group of cats for quite a long time to see what did they die of and how long did they live, when were they really born? And that’s a little tricky to do, but certainly if a cat is in a household it’s going to have far more protection and certainly cats, at least in the United States, if they’re feral cats they are killed by prey, coyotes, by dogs.

I mentioned two reasons for cats to lose their lives, so that’s renal failure and lymphosarcoma. One of the other major killers is being hit by a car. If you’re a household cat and not going out much then you at least have a better chance at living longer. And my cats have generally lived about 14 years and have succumbed to renal failure each time.

But certainly I would think with better protection, nutrition, a more consistent nutrition. I don’t want to say it’s necessarily better because a cat might be out there eating bunny rabbits and mice, and lizards, and bugs by far might be the better nutrition for a cat. But having a consistent diet, we do know our pet foods are nutritionally sound.

It should be living longe in our house, but it’d be interesting to go into the literature and see how well we can document that. But I’ve definitely seen many cats make it into their the twenties.

Chris: Does the shared environment between domesticated cats and humans help to translate the medical findings in cats to human biology?

Leslie: Yes, certainly. I, these are things when, even when we’re doing the sequencing projects, these are the things we have to ask about every cat. What is their household environment? Are we for sure looking for something that is genetic or something that is somewhat environmental.

So what kind of exposures are they getting? Even what kind of stresses they get. Cat get a lot more stressed than we think they do. And so it’s very difficult to actually go away for a week and put your cat in the kennel, where that’s easier to do for a dog. The cat needs to stay at the house where people come in and feed them.

There hasn’t been a lot of longevity studies yet accomplished in cats. But I think we’re moving to the point of where now we can, when we see the successes of the golden retriever project, and now that we can do web based tools and web based interactions with the lay public, so something we would call citizen science.

Really, we just need to start launching things like that. Can we start understanding what is common about cats that are living to be 16 years of age and longer, as opposed to what’s probably about the normal live span of 12 to 16 years for domestic cats. Those types of studies can and should be able to be launch.

Chris: How much our our genome do we humans share with cats?

Leslie: Certainly if we look at the coding part of the genome, but however, the coding part of the genome, the part of the DNAs translated into actual proteins, so the actual genes, that’s actually a very small part of any mammals genome, so less than 10%. So when we look at genes, some genes between a cat and a person can be 100% exactly alike. Where others can have a lower percentage of similarity. On average, we’re probably looking at about 85% similarity between a cat and a human, and dogs about the same. And mice are actually even a little less as compared to humans.

Perhaps the cat is the right model to help us to understand structural variation and regulatory variation that is outside of the genes and makes up 90% of the genome and will help us understand disease better in that.

Chris: What do you see as inevitable in the field of pet longevity over the course of the next 5 or 10 years?

Leslie: Inevitable is one that I certainly want to make sure does happen is that cats will be part of precision medicine. We’re trying to do that now, so that if your cat has a health problem it can come in, get the genome sequence done, we find the cause of your cats problem, it gets the right therapeutics so that you can have better longevity and a better quality and quantity of life for that individual animal. So that’s the immediate goal and that’s what I hope is occurring within my lifetime as well.

But there’s also things where we’re going to discover more things about cat nutrition that will keep our cats healthy and strong, and maybe try to learn what’s going on with renal failure, perhaps get cats to live longer in that regard as well. And then hopefully we’ll also understand what’s going on with the overall biology of longevity. What genes are involved? Is it all about telomeres or are there other genes as well? What kind of nutritional, should a cat be drinking a glass of water every night and that’s why they live longer or something like that. Those are more speculative, but definitely precision medicine aspect.

Let’s not forget just the behavioural aspects as well. We’ve certainly seen that just having pets, their longevity and their quality of life as well. And so does that go both ways, does a good human companion for a pet, for an animal, help them with their longevity also. Do when a cat lays on our lap, does it lower its blood pressure? Like they lower our blood pressure something we have to investigate

We really appreciate Leslie for taking the time out of their day to come and talk to us. A massive thank you from Chris and everyone on the Gowing life team. You can keep up-to-date with everything that Leslie is doing here.

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