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Hey, everybody, this is Razib Khan here with the unsupervised learning podcast, and I am here with Dr. Jason munchie. South. And we're gonna be talking about rats. Jason, could you introduce yourself?
Yeah, sure. I'm Jason munchie. South. I'm a professor of biology at Fordham University in the Bronx, I also maintain a lab at the Lewis Calder center, about 30 miles outside of the city.
So Jason, we've known each other, you know, online for a while now. And so you know, I know you're the rat guy. But I know of you as the rat guy, I'm sure other people know and you know you in very, very different ways. But how did you get the rat evolution genomics beat because that's what I think of as your as your primary focus.
Right, that has become a primary focus, I'd say over the last five to 10 years. When I moved to New York, I actually was a tropical biologist. But when I moved to New York, I wanted to start some research on local systems. My first job was at the City University of New York. And I decided I was going to study small mammals in the city, particularly looking at the native small mammals that live in parks to try to understand, you know, if their populations are still genetically connected, if they're potentially exhibiting local adaptations to the parks, and that sort of thing. And I did a series of studies on on a native animal called the white footed mouse, which you may have heard of parrot miscast, it's similar to Yes, it's a related species where Hopi hopes or works on. But what I found over the years is that more and more everybody wanted to know what was going on with rats in New York City. This was really the animal that was inspiring people, both scientists, and you know, just people I would meet out or friends, you know, that are not scientists. And I started to think about, you know, well, how would we approach studying rats in New York City, because they're very different organism than that, you know, the native species were used to studying in little patches of forest and so forth. And so ultimately, I decided, Alright, we're just going to do this, even though I was hesitant at first, because studying rats in the wild is not a very common activity, or it hasn't been historically. But you know, we pitched this idea to the National Science Foundation. And it turns out, they really liked it. And they funded us. And then we just started spending a lot of our time working on rats in New York City and have expanded this to many other cities at this point.
Well, I mean, so you spend your time studying rats in New York City. So what's the what's going on? You just chilling out on subway subway terminals tracks.
That was actually the first thing we had to figure out, you know, was, where are we actually going to study rats, you know, a lot of people do encounter them in New York City. on the subway, they see him on the tracks, maybe occasionally on the platform, which inspires a lot of funny responses from people. But it turns out after talking to some of the the folks that work at the Department of Health, you know, the subway is not actually the number one reservoir for rats, most of them are living out on the surface, and they may build burrows in the soil, but there were kind of at surface level, and then you have another large population that's in the sewers. So we immediately knew we were going to have to be creative in how we obtained rats. So we eventually decided we were going to mostly do our work at the surface and try to catch whatever rats were there plus whatever was coming out at night from the sewers. on the subway, we have one data set from a subway line that we haven't published yet. But that presented a lot of logistical issues working down there.
Yeah, I can imagine. Um, so, you know, for the non American listeners, you know, rats in New York City are kind of a, I don't know, they're kind of a famous cultural just phenomenon. It's one of those things you get shared with on some viral, you know, kind of like city news, the giant rats are swarming rats and all this stuff. And so I'm sure you get a lot of rat related questions. But for the non Americans, can you just set the stage for why rats in New York City are a big deal? Like, for example, I don't know if this is true. I've seen multiple debunk gigs. You know, people say there's like 10 times more rats that humans in New York City, which I think isn't true, but if you could shed some light on that.
Yeah, sure. Well, New York City has a lot of rats. Nobody knows how many for sure. I actually tried to get the New York City Department of Health interested in doing long term population studies. To figure out, you know, estimate how many there are and whether the population goes up or down in any given year, but they didn't really want to do it. You know, it wasn't clear what the benefits of them would be to know if they're more or less rats, they're still gonna get complaints. I do think there are quite a few. I don't think the numbers of rats are anywhere close to the human population, which is over 8 million. You know, there have been attempts to estimate it that come up with, you know, a million or two, I think it's probably even less than that. Just anecdotally, based on how I see rat populations using New York City, I wouldn't be surprised that there are several 100,000. And you know, that I guess that raises the question of why are there so many rats in New York City, you know, assuming even several 100,000 is a lot of one animal in an urban area? And I'd say that? Well, the the simple answer is that it's because of us because of humans and what we do. But why is New York City potentially worse than other cities? Well, the main reason is the way we deal with garbage in New York City. If if, you know people haven't visited, and they haven't had the pleasure of experiencing this, you know, there aren't alleys in dumpsters in New York City in most places. So what happens is, restaurants and residential buildings and other businesses collect their garbage inside, put it in bags, and then they put the bags out on the street the night before it's picked up. And this happens on a schedule. So there's pretty much always bags of garbage sitting out on the street in New York City, and that is essentially a buffet for rats that is available and they likely can predict it, but they probably just know which night they're going to have. Which bags on which street? Yes, they also can take advantage of you know, all the overflowing trash cans just from you know, street level traffic and so forth.
What is it? What is going on with that system? I don't I've never looked into it. It's always strikes me as weird when I'm in the city to see that. Like, why don't they have bins for people?
Well, it's a good question. I think the city was just built up so densely that there weren't a lot of alleys. And it was too late to retrofit anything for alleys. Why they don't use bins is an interesting question. Basically, somebody would, you'd either have to force people to buy the bins, or you'd have to provide them. And you'd have to maintain them rats can be quite destructive. Like, you know, if it's a plastic bin, they'll just do the corners off near the lid or at the bottom. And so you have to constantly replacing them with their metal, they get dinged up and, and davidge and bent so that the rats can just find a way into the top, they're not sealed anymore. So that's kind of the the issue. And you'd also have to change the job of the sanitation workers who are used to doing it one way and following certain routes. And at certain times, you know, they've talked about actually, you know, having some areas with a lot of rat populations, put their bags out like at four in the morning instead of the night before, then you have to pay somebody to put it out at four in the morning. So it's just you know, the scale of the problem is really the issue, you know, you've got 8 million people and all of these old buildings, and nobody has bins and nobody wants to, you know, get up in the middle of the night and put their garbage out. So that's really why we're stuck where we're at.
Well, so, you know, we're talking about rats. But let's let's talk about what we're talking about, I think, you know, we're mostly talking about like the Norway rat, correct. We're not talking about black rat, we're not talking about? There's I mean, there's there's rats in India that are pretty common in domestic areas, like the bandicoots or something, I don't know. Can you talk a little bit about the type of common rats that are present around humans? And I know that I, you know, my understanding is the black rat was earlier in Europe, and then it was replaced by that, quote, Norway rat, which is actually from Eastern Asia, I believe. Can you talk a little bit about the phylogeny? Like the Natural History of the rat?
Yeah, absolutely. So there are several commensal rodents that live with humans, and then evolved to live with humans. And commensal, you know, derived from Latin literally means eating at the same table. So these are rodents that live off of our food sources and live in and around our homes. And the main, the main ones are the house mouse, which came from Central Asia is all over the place now. And then several species in the genus Rattus and Rattus is primarily an Asian group. There's 60, some species in the genus. And there are three or four major species that live with humans. So there's Rattus norvegicus, which is the Norway rat, which is the one we have in New York City, Rattus Rattus, the black rat, Rattus 10, azumi, which is, you know, kind of an offshoot of the black rats confusing taxonomy. Then Rattus excellence, the Polynesian rat, which is moved around with Polynesian peoples as they they colonize those islands. And there's also as you mentioned, there's there's the bandicoot rats in India, which are actually a different group. And yes, it's it's relatively well known at this point. That the Norway rat Rattus norvegicus, evolved in eastern Asia, probably in northern China, possibly in parts of eastern Russia and parts of Japan as well. And it's, we don't know exactly, you know what their natural history was before they became a commensal with humans, but they likely lived in grasslands and savannas, eating seeds and fruits and all sorts of things. Unlike many other rodents, Rattus norvegicus also knows the brown rat needs to drink water every day. So it's likely that their distribution was and still is limited by being near freshwater sources. And when you see them in other parts of the world, they often naturalize along rivers and streams, when the brown rat became commensal, with humans is not entirely understood. But it's likely began pretty early on when agriculture was developed in China. And that was a long time ago, we're talking you know, 11,000 years ago, maybe earlier, when people started domesticating, growing millet in China, they switched to wheat about 4600 years ago, due to a number of factors, including climate. And so it's likely during that period that the brown rat began to live around humans in their agricultural settlements and began eating grain, and evolved to be, you know, living with us. And as a past, you know, the other major rat, you mentioned the black rat, you're right that it evolved in. It's not that it evolved in India. And then it spread. It actually spread much earlier outside of India, probably in about 3000 years ago, maybe earlier, they were already in the little box in the Mediterranean. And it's not that they spread, you know, over overland, but along coastal routes, maybe on some ships. And then when they got to the Mediterranean, they spread to Europe, initially with the Roman Empire. And then when the Roman Empire began to contract, their numbers declined quite a bit, then they rebounded again, as medieval economies began developing, about around the 1200s. And so the black rat has a long presence in, you know, Western Asia in Europe. But it actually began to decline when the brown rat arrived. So we think what happened with the brown rat or Rattus norvegicus, is that it spread out in northern China down into Southeast Asia, relatively recently, probably less than 1000 years ago. And it's thought that that happened is in Asia, they were recovering from this climate anomaly. And people began spreading down into Southeast Asia. But once they got to Southeast Asia, they spread quickly along coastal routes, into the Middle East, and then into Europe. It's unclear exactly when they got into Europe, they were definitely there. By the early 1700s, maybe earlier, not all of the archaeological remains have been tested. So we don't actually know which ones are the black route and the brown rat. But once the brown rat got to Europe, the black rat declined pretty rapidly. It's not entirely clear why. But it's thought that you know, the brown rat is more cold hardy, and maybe has a competitive advantage over the black rat, they use slightly different habitats. So the brown rat will burrow in the ground, whereas the black rat, sometimes burrow, but it's fine living in trees or rooftops and, and attics, and things like that. But the brown rats seem to win that competition, you do find both species and some cities, particularly those cities that don't have harsh winters, and those that are subtropical or tropical. Like if you go to New Orleans, CLC, brown rats, you know, running around on the street,
in the French Quarter, but then you'll also see black rats, you know, in bushes and stuff in other parts of the city. So they can coexist with a brown rat seems to have this big competitive advantage. So the overall scenario brown or the black rat expands earlier, gets into a lot of Europe and other places, but then declines when the brown rap also expands much later.
Yeah, I mean, it's it's weird to me to think that the rise of agriculture in the Levant you know, you had these grand juries, and it wasn't rats, it was probably mice. Right? That were the main pass.
Yeah, so that so the house mouse has a long history with humans. And it's a complicated story, because there are a couple different species that hybridize and so forth. in those early agricultural areas, but yeah, that's the species that in the Middle East, like, you know, in that area, where we that was one of the early centers of agriculture that the the house mouse mus musculus became the major pest. And then, in India and Asia, you have these rats that became more important.
And so, you know, just, you know, before we jumped to the genetics, in terms of behaviors from from what I've heard and read, you know, the rat is, this way, it's kind of like, doesn't it Kind of excludes the mouse in certain ways. Like they're pretty aggressive towards mice and cats don't really intimidate a lot of rats. As much as you know, mice are terrified of cats for obvious reasons. But with rats, it's not the same. Is that correct?
Yeah, that's, that's basically correct. So you can have brown rats or black rats and house mice occupying the same areas, but they won't, but they'll subdivide the habitat. So you'll, you know, the mice will avoid rats, presumably, because the rats will kill them. If they're too near, and will, you know, and eat the babies out of their nest and so forth. I have found locations in New York City, where house mice and rats seem to coexist peacefully. But the only places I've seen that are were like near dumpsters and things where there's just so much food available, there's probably no reason to compete or fight. And then the only other places I've seen in New York City where you have mice living outside is where rats have been eliminated. So that indicates they can coexist if there's like super abundance of resources, but usually the mouse is excluded if the rat is there. And so that what basically the way they subdivide an urban habitat is the house mouse's inside buildings. And then the rats are primarily outside or in, you know, subterranean infrastructure. They have different biology, I mentioned the brown rats need to drink water every day that house mice don't really they can kind of just live you know, in a you know, a cabinet or something and just have access to food. They don't really need to drink water. Oh, wow. So
in the wild is because they get the water from the seeds or whatever that they eat.
Yeah, that's right. A lot of rodents are pretty hearty to arid areas. But the brown rat is not one of them. They do need quite a bit of water every day.
Okay, so basically, the rats in Phoenix, they do not exist outside the city.
Yeah, that's a that's a fair assumption, you know, they they're probably you're not going to find them in the middle of desert unless they're near some sort of water source. Okay.
I've read that there are no brown rats in Alberta. Is that true? And why haven't they made it there?
It's it's an interesting claim. You know, it's this comes from the government of Alberta. And they've claimed for years that they're like a rat fee province. And basically, when the you know, when the rat, I don't remember exactly the dates of this, but sometime in the 1950s, the government decided they were going to eliminate rats. And they had some fairly robust pest control programs that reduced the numbers greatly. And they claimed to be rat free. And but I'm certain there are some rats there, it's you know, coming in on shipments of lumber or other types of materials. But they do try to control them, they have one thing in their advantage is that while the brown rot is cold hardy, there are limits to that. So areas that get really cold and are relatively dry, anyway, are not great rat habitats. So they, again, if they're, you know, if you have really harsh winters, that will cause a lot of overwinter mortality. And if they don't have ready access to water, that's going to hurt them as well. So I think they have kind of a head start in Alberta anyway, because it's pretty cold, dry, harsh environment.
So we're gonna be talking about rats as we proceed. You mean mostly the brown rat, right?
Yeah, so we've done a little bit of work on black rats, but the private primarily my lab has worked on the brown rat. So if I say rat, that's, you can assume that's what I mean.
And so, um, before you started doing your work, was there a lot of rat evolutionary genomics? I mean, genomics as a field is pretty new anyway, but
not really, there have been a few attempts at looking at relationships among rat populations around the world using mitochondrial haplotypes, which is not really genome scale, it's just they use one or two genes for the mitochondrial genome. So we're talking about, you know, like 400 base pairs a sequence that can be quite useful because it's unit parentally. inherited doesn't undergo recombination, but the there are limits to what you can infer. And there was at least one study on a city scale in Baltimore that looked at how rats in Baltimore were related using microsatellites, these little neutrally evolving repetitive regions of the genome. But other than that, there hadn't actually been a lot of population genetic research on wild rats there. There was kind of a golden era of urban rat research in the 40s and 50s, out of Johns Hopkins, primarily focused in Baltimore, and they publish a lot of great population ecology and behavior. And yeah, actually, you asked about cats and they actually did some of the early studies that showed that cats aren't very effective predators on rats just because they only remember Small individuals, and they can't really tangle with the big one very well. But there was that kind of golden era of, I would say more sort of population ecology research, but not a lot of genetics. And there hadn't really been much, you know, like some wild populations at all.
So I, you know, when was the what was the first rat? Norway rat, brown rat reference genome published?
Oh, that's a good question. I don't remember exactly. It was one of the earlier reference genomes, I want to say like in the early 2000s, maybe, okay. I have to look back, but we're now up to like version seven. Okay. The reference genome,
okay. And it's about it's the same size, I'm assuming as a human genome, like all mammals, right? It's about similar size. Yeah, it's about 2.7 billion base pairs. And so you got the genome of this story, right. So I, but but I'm assuming it was actually a lab rat, right. lab rats, these white rats. So these lab rats? Are they all brown rats?
Yeah, so that the lab rats that you see the white ones, the black and white ones, in some of them are gray, are domesticated. Rattus norvegicus, the brown rat. And we actually dug into this history a bit, and we tried to understand where you know, some of this domestication happened. And the history is really fuzzy, the records aren't very good. It does seem that by the like, mid 18th century in Europe, the people had domesticated brown rats, and they had, you know, domesticated them to where they change, you know, you see the white coloration. And they show that kind of domestication syndrome, where they become tame, and not very aggressive. And there's probably a lot of those classic changes that you see in other species. And then, you know, when the when the rat became a very common lab organism one wasn't until a bit later, the story in the United States was that sometime in the late 18th century, they had colonies at the University of Chicago. But it's not clear like To what extent they were maintained that they were using rats from Chicago, they may have just imported them all from Europe. And then, in 1906, there was a guy named Henry Donaldson, who was at Chicago who brought some of those rats to the Wistar Institute in Philadelphia. And then when he got there, they established outbred an inbred strains of rats, they were using some wild rats for the outbred strains, then they, over the years shipped out hundreds of 1000s, if not millions of rats, and people created all sorts of new strains. And sometimes they would breed them with local wild rats, and sometimes they would breed them with other lab rats, but the history got lost. And so, you know, these hundreds of strains were created, about 50% of them show ancestry with the Wistar Institute rats. But, you know, that's about all we know about their history, but, but they are all descended ultimately from wild brown rats.
Okay, okay. Is there? Is there a reason why the black rats were never used as a model or brown rats better?
I don't know. I assume it's just that, you know, the brown rats were available in Europe at the time, because by then the black rat had already declined. So I, you know, I don't actually know that anybody's tried to domesticate the the black wrap. It wouldn't surprise me if you could do it relatively easily given their similar behaviors, but I don't know.
And so I'm domestic rats, I guess these pets that I see around? Are they from a particular lineage? Are they independent domestications. Or
they, they were also like, they were part of the early domestication in Europe, you know, it was actually like, especially in the UK, it was a common hobby to breed animals. You know, there were the fancy pigeons that Darwin talked about in his writings. And then, in the late 18th century, people were breeding rats to create fancy rats. And you can still buy the fancy rat breeds, which have various traits there. There tend to be more like the black and white ones, but there are various colors and morphs and so forth. Where they actually came from, it's just not entirely clear. When we looked at the genetics of this, it seemed that overall lab rats and pet rats were heavily bottlenecked not surprisingly, because when they were domesticated, they were at least partially inbred, if not intentionally inbred. And so you only have a very small portion of genetic diversity from Asian your European wild rats represented in any of the domesticated rats. It's probably an opportunity, you know, in the future, you know, to identify net wild populations with different traits and try to breed those traits into the lab rat, although it hasn't really been attempted on a wide scale yet.
Yeah, and let me be let me be clear for the listener who I'm talking about this extensively rats, I mean to Not the same extent, but, you know, like mice, rats, or rodents that are used as model organisms to study all sorts of biological issues. So I think rats are actually pretty big in neuroscience, you know, you look at their brain, you could cut their brain, I don't think mice are that big neuros, that's rats are big. And then in genetics, they're more expensive than miso. You know, they're used for some specific things, but they're obviously way less expensive than primates. And, you know, you can't do certain things with humans, right. And so, you know, rats are a model organism, and they're a mammal, they got a decent sized genome, just like us, you know, their organs are small, but you know, they're, you know, they're within the same plane. So this is why I'm just kind of curious, because sometimes, the lineage you select for your model kind of matters a lot. And we didn't really think of it when these sorts of things were happening decades and decades ago. And now we have to redo it, I think people would be a little bit more careful in their selection of lineages and whatnot to get the appropriate diversity. Not that it matters that much, because they're not human. But I don't think it's something that people would ignore necessarily today.
I agree with that completely. And it's true there, there are different fields that use the lab mouse versus a lab rat. And unfortunately, for our purposes, the lab rat isn't used as heavily in population genomics. So there aren't as many there's a good reference genome, but there's not like a haplotype map. And, you know, some of those other deeper resources are missing, there isn't really a good snip chip yet. But I think those are on the horizon. Oh, there are a few, a few labs out there that are attempting to compare wild and lab rats directly in behavior and other traits, and maybe, you know, breeding, creating f ones and things. But not a lot of that has been published yet.
Well, so what is um, I mean, I can kind of guess from our earlier discussion, but But what is like the phylogeny, the relationship of rats across the world is every rat lineage outside of northern China, kind of a branch of the Chinese rat, so then it's kind of just, you know, kind of, like humans have this phylogeny out of Africa. Everyone's nested in Africa, and the new world is nested in East Asia. arats exactly the same.
It's it's a similar kind of story. You know, when we started our work in New York City, one of the questions I wanted to answer is, you know, where did rats in New York City come from? And we realized, you know, we might not be able to answer that if we don't have a good idea, just the general relationships amongst rats all over the world. So I contacted dozens of people all over the world back in like 2012, and asked them to send me whatever they could. And so I had people sending me, you know, years and bits of liver and toes, and all sorts of things, from rats, they collected mostly for public health purposes, you know, to monitor disease, and so forth. And we were able to get genotype information on those rats, you know, over 30,000, snips, low sigh, which was pretty decent. And what we found is that the samples from northern China and those actually had a genome that was already published for a different study. Those are the most genetically diverse samples. And that's kind of what you expect for the center of origin of the species. And also the older, the older studies have been done a microbe mitochondrial haplotypes, they have more haplotype diversity, if you look at whole genomes, they have more heterozygosity across the genome. So it does seem that you know, that's the center of origin, it's where you have the most diversity still. And then it does seem that first out of China out of northern China, they diversify down into, or they move down into Southeast Asia, and you see cliental variation from northern China down into Southeast Asia. And then from there, the story gets a little simpler, because rats moved out very quickly. And you can see a pretty strong signal of that. So after Southeast Asia, they moved along this kind of like coastal route into West Asia and then into Europe. And what we see in the genetics is that there are two different groups in Europe and Northern European group in a Western European group, that are fairly clearly distinct with some admixture or some ancestral variation. And then it's those Western European lineages that essentially seeded rat populations around the world, beginning in the 1700s, essentially, as a side effect of European imperialism. You know, because these rats can survive long ocean voyages, though, you know, they'll just live in the hole and eat whatever food down there. And so they made it and then in the on the ship docks, and they just, you know, come out with a cargo or walk right off the ship into the city, or into the port. And so out of Western Europe, you see ancestry with populations all over the world, North and South America, all over Africa, Australia, New Zealand, etc. and lots of islands. And so, you know, there's kind of a big bottleneck. They're as they got into Europe. And then it was just a few lineages that got spread out. from Western Europe, you do see a little bit of a few areas that have evidence of mixed ancestry. So New Zealand, South Africa, the west coast of North America, they show some evidence of mixed ancestry and that Western European group of rats, but also some Asian ancestry. So there may have been some rats moved out of Asia directly into those places, and they, you know, they ad mixed with rats from Western Europe. So those are particularly interesting. But, you know, most places that we looked at, particularly cities only have one dominant, you know, evolutionary lineage of rats, it seems that, you know, they get introduced to a new place, they reproduce quickly, and then they they probably basically exclude new migrants from getting into the population having a big genetic impact.
Yeah, so it's a first rounder effect. Okay, so, you know, we've been talking about the phylogeny, you know, the relatedness, the origin, the natural history, but, you know, I want to talk about adaptation and selection. So you have a paper, you're an author on a paper, genetic adaptation in New York City rats, and it just came out, actually, it was published this year, in January, it's in genome biology and evolution. And, you know, I know you've done work in this area earlier, can you kind of talk about, you know, what character so with humans, you know, people are interested immune system digestion, all these things, actually kind of notice some of the same issues in the rats. But um, can you talk about functionally, what would be interesting about rat adaptation and selection? Like, what are they adapting to, you know, reproduction? Cold weather and cold weather areas? Really bad processed food? I don't know.
Yeah, that's a good question. And this, this paper actually had a fairly long history, we thought about doing this study, shortly after we looked at the global phylogeography of rats, because we found that, you know, most cities had a single population, and aren't receiving a lot of gene flow from other populations. So you thought, Okay, well, this, they're pretty diverse. So maybe they're actually experiencing some local adaptation. And maybe we can see signatures of that in the genome of rats in different cities. We didn't, we only had funding to really work on one city initially. So we chose New York City for because that's where you're located and read easy access to the samples. And I was interested in whether, you know, rats in New York City would show local adaptation to eating highly processed foods, that's one thing, whether they would shows any kind of signatures of selection associated with, like living in a new environment, you know, like moving through, like, some of these rats live in completely unnatural environments, like sewers, and subways, where they're just living on our built substrates, you know, concrete and iron, and so forth. And then also, they're exposed to a bunch of pollution in the city, like a lot like humans and other organisms. And they're also we deliberately try to kill them with poisons, and traps and other things. So I thought, you know, there might be signatures, selection associated with those traits. While I was thinking about this, I actually got an email from a group of grad students and postdocs at Stanford, that had just been, you know, kind of brainstorming at a lab meeting. This was Dimitri Petrus lab about, you know, interesting things they could look at. And they had to independently it on this idea of looking at the genetics of New York City rats, and then they found some story about my work and just, you know, sort of gold called me. And we ended up you know, talking about doing this study together. And, you know, it was a long kind of road because there were multiple children born amongst multiple people, lots of different jobs, switches and so forth. But we ultimately got this published. And, you know, we we use some of these new techniques that they had developed arvo harbach, and Lenny pendings. And Sylvester and not just a group. And we, we found some interesting signatures in the genomes of New York City rats.
Wait, so it does this date to like, more than five years ago, but I don't know. You know, I know some of these people. I remember meeting them in the Bay Area in the mid the mid teens, I guess, when they were at Stanford, and now it's 2021. Is that how long you're talking?
Yeah, I think so. So from the initial idea, we had the initial idea, then we sequence the genomes, and then, you know, there was a couple years of analyzing and then, you know, some longer to write up than we thought, because everybody like all of those people are now remarkably, you know, there are graduate students at the time, like our bells, actually down the road from you. at UT Austin just started.
Yeah, yeah, I noticed that. So, uh, okay. So, you know, you got the sequences, they're all in New York City. Like, you know, what's the questions you're exploring? What's the methods that you're using?
Right. So they were developing, they have been developing a method or a series of methods to identify selective sweep. That can accommodate detection of both hard sweeps and soft sweeps. And by a hard sweep, that's kind of a traditional selective sweep, where you have a single haplotype that is favored by selection and thus becomes very common. And you see that as a signature in the genome where many individuals in a population have the same sequence over some block of a chromosome. And a soft sweep is where there are two or possibly even more haplotypes, that sweep that are favored. And so you'll see it as you know, two different sequences become prominent in the population. And they they've been developing techniques that can distinguish between that based on these haplotypes that you find in a population, you can compare like pairs of individuals, and see whether you're having one or more haplotypes, becoming more common than expected. We had to adapt this method, they did this not me, this is more their specialty, we had to adapt this method for rats to use genotypes rather than haplotypes. Because our data were not phased, we could have phased them using some statistical procedures that aren't all that great. But, as I mentioned earlier, rats lack a haplotype map and similar resources so that it's somewhat hard to phase, you know which allele occurs on which chromosome. So they adapted these methods to genotype. So we looked at multi site genotypes rather than haplotypes. And look for these signatures of hard or soft sweets. And we did this in a sample of 29, New York City brat genomes, we sequence them to about 15x coverage, but most of them were more than 15x. And then we also compared our results to analysis of genomes from northern China that had previously been published, with the idea that, you know, if this was something that was happening, specifically in New York City, you shouldn't see the same signature and these genomes from China. And most of the sweets who identified You know, when you look at the Chinese genomes, they had much more diversity at these locations indicating that selection was not operating on the rats in China in the same way.
Well, so I do want to just back up one moment, because we met, we mentioned this a bunch of times, and some of the listeners might not know. So haplotype is basically like you have a segment of the genome. And that segment of the genome has particular variations as positions in sequence. And that's basically telling you what's ancestry back to a common ancestor. It's just a chunk of the genome that's, that's inherited together. And recombination slowly breaks apart these associations, but a second Association. And so when you're looking at, you know, associations that are found together a lot, that's a, that's a good sign that selection, grabbed a chunk of the genome and swept it upward. And you were talking about hard sweeps and soft sweeps. You know, this is why you study model organisms, hard sweeps, and soft sweeps are a huge thing in human population genomics in terms of trying to understand how adaptation and selection happened. And, you know, one of the issues I think, is, you know, the, the, the effect of looking for the keys under the lamp. Until recently, you really couldn't detect soft sweets very easily with genomic data, because there was no genomic data. Right?
Right. And, you know, I come from a non model organism background. And I've done a decent amount of population genomics, but usually on species that don't have good resources. And so it's kind of it was us meeting in the middle, I'm working with all these people that work under Safa and humans, and I'm working on all these weirdos and I start working weirdo organisms, and I start working on rats. And they're kind of a little bit disappointed in the resources available. And I'm like, Wow, look at all the resources we have. But it keeps getting better. And we have more power to do these types of studies on more species as we get these resources.
So what was a I mean, just overall in your career studying natural selection in rats, you know, because you weren't, I mean, you weren't a rat guy from like, day one. What has been your the most surprising result that you've seen consistently?
I think what's really surprised me with rats. First, I was pretty surprised that there isn't evidence of ongoing gene flow between cities that there seems to be this kind of like, founder population that that takes over. And some of the fine scale population Jacks we've been doing is yielded some interesting results. You know, I thought rats would be kind of these big pan miktek populations or maybe just show like some isolation by distance within cities where the farther they are, you know, apart the more different they are, but we find like real kind of like there's somewhat subtle but recognizable breaks in the populations in individual cities that correspond to like certain neighborhoods with a don't have a lot of rats where it's really clean and there's a lot of pest control are due to infrastructure like roads and rivers. It was a pretty surprising to me that uh, you know, the way we build a city can influence you know, Basically what the structure of genetic variation is amongst rat populations in space, and you think about that longer term, we may be able to design cities that kind of hem them in or prevent them from spreading everywhere. I was also wasn't sure what we'd find when we actually, you know, sequence these genomes. And, you know, I was a little bit worried wouldn't find anything. I mean, that's an interesting result in and of itself. But, you know, I was hoping we find, you know, at least some evidence of local adaptation. And we did find, you know, I'd say more low sigh, showing up in these sweeps than I thought. There were a few genes involved in pathways for metabolizing endogenous compounds or toxins from outside, particularly in these CYP genes. And these are known in rodents, they've expanded to gene family that expanded across rodents. And it's often associated with novel diet. So like when a species moves to a new diet, especially if there's some toxic items in the diet. Yeah, you see evolution in these genes, we found that in rats, it might be related to new diets, it might be related to, you know, dealing with poisons, we're not sure. There were some other genes along those lines. And then, you know, maybe the ones I find most interesting, but they're also the ones we don't know that much about yet. And it's going to require a lot of work to really figure out what they do, are some of these genes involved in the nervous system. And there's one called cat no one see, that we found is an outlier, you know, undergoing sweeps and in rat populations. And that's that gene has been repeatedly associated with psychiatric disorders in humans, it's one of the strongest candidates we have for a number of psychiatric disorders. And, you know, it's one of those ones that, you know, there's the nucleotide changes, but its expression and so forth, can be modulated by early life, stress and other stressful events. And it's associated with a number of anxiety like traits and other behaviors in humans. And we see this as a fairly strong sweep in New York City rats, it makes you wonder, you know, what, how is their behavior changing? Way, way, way? Are you saying rats in New York City are neurotic? You know, that's, that's kind of I, as a, you know, when you're doing these kinds of studies, you have to be very careful, you don't want to make claims based on a statistical result, right? Say, like, Oh, we found a sweet is in or near this gene. So it does x. But, you know, you use this to generate hypotheses. So when we see genes like this, you know, if I start to think about hypotheses we could test, you know, and that's one one potential hypothesis, right, then in a stressful environment, where there are lots of things trying to kill you. You know, some sort of anxious like behavior or something like Neo phobia, like fear of new objects in the environment might be favored. And anecdotally, we see this variation in the population, you know, just we've trapped hundreds of rats in New York City. And imagine going to a new place where you haven't trapped before. And there's a bunch of rats in there kind of an undisturbed colony. If you put like a box with traps in their environment, you'll catch a few like, usually young ones, like the first night or two. But then it takes like a week to catch the big adults. And, you know, one hypothesis for why that is, is that they're essentially Neo phobic. So you put a new object in their environment. And they avoid it until it's been there for a while, and they kind of get over their fear. Rats are naturally very curious. It's one of their, you know, traits that correlates with with their broad success around the world, probably. But there's also it's, it sounds paradoxical. But it's probably good to be curious, but also neophobic. So to be interested in objects in the environment, but also be very cautious. And you know, so that's kind of the hypotheses where these results lead.
What's the one thing that I that does come to mind is that New York City, I mean, large cities in general, but New York, in particular, in the United States, at least, like Indian cities are just off the charts, as you probably know, this, they're very loud. Whereas like, you know, if you're in like a regular college town up there, there are rats, but they don't have to deal with the same level of ambient sound. And I just wonder how that affects their stress level, just awareness of their surroundings?
Yeah, I think it's absolutely true that there, you know, is some sort of baseline exacerbation of stress levels and rats in loud, urban environments. You know, one one place that in particular, I've thought about this is in the subway, because you literally have rats wandering around the tracks, while trains are going on top of them. And they're just, you know, in the little space between the train and the bottom of the tracks, and that's incredibly loud and they're hearing this all day, I wouldn't be surprised if they're mostly death after a while. In which maybe they is fine with them because they can you know, survive mostly through Sans and a little bit of sight but you have to imagine that's an incredibly stressful and also I know for me, Working in the subway a bit, you know, you blow your nose at the end of the day, and it's full of black like steel dust from the tracks, and they're living down there full time. So you have to imagine these kinds of environments and pose a toll. You know, same thing with similar things with the, you know, the rattling in the sewers, or even a, you know, at surface level, depending on where they are, you know, they're going to be, some of the most successful colonies are going to be in places where people don't want to be for very long. And that makes you wonder, you know, to what extent they are, are they just suffering like physiological abuse? And, you know, it just decreases their quality of life and reproduction? Are they adapting to this? And, you know, these genomic results can give you sort of a first glimpse of like, maybe where to look next, it doesn't answer the whole question.
Yeah, I mean, one thing that I think about is, if these rats are indigenous to New York City, like they arrived, say, I don't know, in the colonial period or something like that. The city has changed a lot. It's grown. It's gotten more industrial, it's gotten louder. It's gotten, I mean, arguably dirtier. I mean, it was always unhealthy. But kind of like, you know, horses are different than cars in terms of the exhaust. So, I mean, I can imagine some sort of in situ selection happening in these populations, just because the nature of the evolution of the city, which I mean, what's the route generation time?
Well, it's not completely stable, but they could likely have, you know, three or four generations in a year. So we're talking about on the matter of a few months.
Okay. So I mean, in the centuries that New York City has been a thing could be 1000s of regeneration types.
Yeah, that's right. And in one way we have, that we're trying to use that kind of ideas that, you know, there are a number of rat skulls and skins kept at the museum natural history here. And we actually got permission to sample like little dried up crusts from the skulls, and so forth. And then we're going to try to, you know, shotgun, sequence those to see if, if some of these genes are different, you know, 120 years ago, compared to today, that project got a bit derailed by COVID, because we couldn't really get into the museum for a long time. But uh, one of my collaborators is doing that sampling, Yvonne hekla, she's been there and, and sampled some of the schools and the next step is going to be sequencing. Some of those, like 120 year old rats, and I think that's something that you're gonna see a lot more of with rats is kind of picking up steam using these museum specimens, or archaeological remains.
Mm hmm. Well, so, in the results that you have, in this paper, you know, there's three different categories of genes as a pop topic processes, animal organ morphogenesis, and axon guidance. I'm assuming the axon guidance is this kind of like bio behavioral stuff that you're talking about? Okay, I can see that. Why would animal organ morphogenesis be affected? Or they get bigger or smaller? Like what's going on there?
Yeah, unknown. You know, when we look at the the individual genes, like the names of the genes, those are the the gene ontology categories. So, you know, all these genes that have been studied in like knockout studies in mice or other organisms, they, they they get a number of categories assigned to them based on what they do, or what we think they do. And that's one of those, you know, that's, that's one of the criticisms of these kinds of studies is like, you end up with these terms, and you don't necessarily know what, you know, what they mean, or, or what traits they're affecting, if they're not the one of your a priori hypotheses. So I would say with that one, I don't really know. I mean, there could be some kind of, it could be an overall growth effects. We've done some studies on morphology that show like changes in school size, you know, so there might be overall like morphological changes with organ morphogenesis itself. You know, I don't know for sure. I could come up with stories, but I don't want to like tell too many stories that we can't really back up.
Yeah, why we what's going on with rat skull? sighs I mean, you know, human skulls have been shrinking since like, 40,000 years ago.
Yeah, so the skull size. You know, we did an earlier study, where we were looking at White footed mice in the city. And we found that the skulls were actually getting smaller. Were like the tooth rows were getting shorter, and some of the other traits were shrinking. The the changes in the rat skulls were pretty, like, they weren't huge. It's not necessarily something that you would notice just looking at a rat running around in the street, but it was, you know, it was statistically significant. And, you know, some of these tests, you can run that that look at whether it's just kind of like neutral changes, like drifting around or if it's selection indicated that this shape variation and crania is a, you know, potentially due to directional selection. And I just wanted to make sure I get the traits right. Here for which one show Lutron showed significant change. So contemporary rats had, you know, essentially their their noses getting longer. And they also have shorter to throws just like we found in the in the white footed mice. And the tooth result is particularly interesting, what we hypothesized with the wife that Of Mice is that they're eating, like a higher quality or softer diet in the city, we thought maybe they're eating. And we're doing some dioceses now in the parks, that they're eating, like softer foods or seeds from new plants in the city. And so they don't have to, you know, chew as much. And we think that's what has happened with rats as well. Like, if you go from eating like hard seeds and environment to eating like rice, you know, cooked rice and, you know, bagels and, and things like pizza and things like that, then that might exert selection on, you know, on two sides. So you're putting in less resources to grow in these large teeth. The longer nose issue, we don't know exactly what's going on there. You know, one, one thought that from mammals in general, is they get these longer noses when they're adapting to colder environments. It's not that you know, the air warms as it goes through those longer terminals. But that's, you know, we don't know that for sure. I think the diet one is more likely to be be something that we could test.
What do you do you see selection in spermatogenesis stuff like you see in humans or rats, so well adapted already to that sort of, like high reproduction that you don't see it?
We didn't see that in our results, we did actually find that for urban white footed mice. Okay, which live in in denser populations, when they're stuck in these little parks and their competitors are all extra baited. But we didn't actually find that with clear, as clear a signal with, with rats. But yeah, I think that that could happen. But like, as you mentioned there already so adapted to rapid reproduction, that, you know, maybe you won't find that. So he's one of the primary effects.
So this study is based on New York City, right. And, you know, you're already seeing kind of, like population differentiation within the city. I mean, it's a big city. You know, but you already seen population differentiation in the city, I'm assuming you're going to be sampling other cities in the United States, you know, maybe in different environments. Like, I'm assuming, for example, that if you did a comparison with rats in Miami, you would see substantial differences, just because the climate is so different. I mean, is that your intuition or expectation?
Yeah, and we, you know, for our sort of neutral population genomic studies, we're looking at the, you know, how rats and their genes are distributed across cities, we, we have actually done multi city studies, we have collaborators that helped us and collaborated with us on multiple cities, we've done Vancouver, in British Columbia, New Orleans, Salvador, Brazil, so we have kind of a range of temperate to tropical cities, that's one area, you'd think that would result in local adaptation, you know, adapting to fairly different climates, you know, the place like Salvador, Brazil, doesn't really have a winter, as we think of it here in New Orleans has a very mild winter. And then, you know, thinking longer term and larger scale, when we have the funding to actually like sequence genomes from all over the world and actually start to look at lots of populations. I think there'll probably be changes, like a lot of changes, and due to local adaptation and environment like climate, possibly, like local incidence of disease, we know there's a lot of variation in disease in rats across cities. And then also things like diet, you know, if rats are eating primarily human diets in cities, you know, humans don't eat the same thing every in every place. So you might see differences depending on what specific carbohydrates are eating or what other foods they have access to whether they have access to more protein, and, and so forth. You know, some of the genes we found in our sweeps in our sleep analysis, were related to metabolism of sugars and carbohydrates. You know, we see this even in humans, right, you know, that you see selection on like cable lipoproteins and things that we've similar similar pathways effects potentially affected in rats, probably because they're eating a lot more simple carbohydrates than they would otherwise. We saw similar effects in the white footed mice we looked at which may also be eating some human foods or other subsidies or providing them
yeah, that's, I don't know, I always think because they're commensal because they live with us. And they're always around us. I mean, they're adapted to us. It's always funny to think about the hooks of like, how they would adapt to human, you know, foibles and cultural evolution. It's like, Oh, well, you know, these rats have like, you know, I don't know bigger teeth because this population has less processed food. There's more fiber, you know, they gotta chew more. I don't know. Whereas like, you know, another population is like they're all eating spam. You know, I mean rats. You know, rats are omnivorous, but they like grain and they like me, right? And sort of stuff like that. Yeah, preferentially, I have a horse before I let you go, you know, I actually just thinking of like, you know, these brown rats are pretty recent. And like, you know, in films about the Middle Ages, there's always like rats all over the place. I think they're, they're black rats, right? For the bubonic plague. Yeah, but for the brown rat. I can see what it's so common in a city and even in like college towns, I still see rats and like in Berkeley, you know, there was a serious problem with rats and bushes. rats running around. I don't know if it's still a problem. But are they really strongly affected by Urban locality, size and density? Because, you know, this focus on water and other things? It seems like
it seems like the cities are pretty good. Like New York City has puddles all over the place in random places, and
there's, you know, hydrants, fire hydrants that people are let go in the summer. So I can see that they'll be able to find water there. But I'm in small towns, yeah, there's water. But then like, you know, where do you find the trash? And it seems like it's could be a harder life there. So I mean, what do you know about that?
Yeah, I mean, definitely, I think large cities with very high human population density are, are pretty much prime rat habitat, we've done a lot, some collaborators and I have done a lot of habitat suitability modeling across cities, that try to understand what factors promote rat populations in different places. And it seems that like some simple stuff you predict is really important, like population density. Another thing that's important across cities is like the, the age of the buildings that are there. So older cities have more rats. And that's just because the buildings are, you know, they just start to crumble a little bit, right, as they get older, and they, they have entry points for the rats, they have more places they can nest and get inside and so forth. So I think, you know, pretty much the best trap habitat is with has a lot of people and a lot of old buildings that aren't very well maintained. You also see strong correlations with socio economics, but that's kind of an umbrella variable for a whole bunch of other things that are going on in urban neighborhood, you know, buildings that aren't taken care of, and all sorts of things like that, you know, where people have less control over the material conditions of their lives, maybe, um, you know, in these smaller cities, I think rats will be and you see this in bigger cities, too. But I think the effect will be magnified in smaller cities where rats will be more of a local issue, like very localized, like, let's say, you, you have, like a street with a bunch of bars, like bars that serve food. And it just gets like trashed every weekend, and there's tons of garbage put out every night behind the bars, like you're gonna have rats there. But then if you go into like, the more residential neighborhoods without a lot of, you know, food service, and you know, where people are taking good control, they're crap, they're trash, there just aren't gonna be rats there, because it's not a good habitat for them. And people, if they see a rat, they're gonna put out traps, and they're gonna try to kill them. So I think in those smaller cities, it'll be more like smaller pockets of rats, where the conditions are really good.
Well, I mean, you know, we're recording this tail end of COVID epidemic in the United States. So you know, I do need to ask you the question, I am curious. So there's all this stuff about how restaurants were closed, and they weren't throwing their trash out, and the rats are going insane, and they're cannibalizing each other, and they're swarming on the streets. And, you know, they're attacking diners who are eating all fresca. I'm sure you saw the show. I saw the stories about, you know, I know that they're, like fascinating stories for people. But do you think that there was an exaggeration? Or is there truth to that? Like, what did you see? I mean, I'm assuming you were in lockdown. But you know, you have some intuition about rats more than regular people.
Yeah, so yeah, you're right. I wasn't on the ground in the city as much. Not very much at all. During COVID. I moved out of the city a few years ago, so I wasn't even in my old neighborhood. But I was constantly getting calls from media and and other people about this issue. A group of us actually tried to look at like the 311 complaint data. And where that was happening to see if there was kind of a shift in where the complaints were coming from, like, were rats leaving the areas where restaurants were closed, and, like going to nearby residential neighborhoods, like desperate for food or something. That was kind of the narrative. Yeah, I didn't see a real strong effect. We have a preprint up. You know, it's not like it's not a huge effect there. There was some evidence that, you know, rats shifted location, a little bit, but I think, especially in New York City, a lot of those restaurants were pretty good about like switching to delivery and stuff so they didn't really go under so they were still you know, serving food and putting out garbage. So I don't I think some of that stuff, you know, it's also kind of like a, like a bias from people being at home, you know. So there's Yeah, they're at home all day, and they're walking around on their block, like every day. Usually they're just going to work. Yeah. And they're seeing rats more, I think.
Yeah. Yeah. Yeah, we have, you know, we had an issue in our backyard.
And it was like, I think it was because the neighbor had an open compost pile that they that they were, they were munching on. And so they would just wander around the neighborhood. And, you know, I mean, they're mostly nocturnal, right. But sometimes they get pretty bold during the day, what's up with that?
Yeah, that can vary. Sometimes, that's actually evidence that there's a really bad problem. And the weaker rats are out during the day just trying to get some food, because like, rats don't like to be out in the middle of the day, usually. Because they're, you know, they'll get eaten by hawks or dogs or whatever. So it could be in a sign that there were, you know, a lot of rats in that area. And so some of the, like, weaker ones were coming out during the day. Okay, I see that, you know, you see that in some of the worst infested parks in New York City, or DC or other places I've been, that, you know, you know, it's really bad when there are rats out during the day. But I think there's also just some variation, like some rats just don't care as much, you know, and if it's like, not a threatening environment, you might see them every now and then this out. Awesome. Well,
um, you know, I'm not I'm not a big fan of your of your model organism. I'm not gonna lie. I'm not gonna lie. Not a big fan. But you know, I'm glad there's enough for you to study. I hope there's enough for you to study through your career, but then maybe we could figure out a, you know, solution to this at some point, I don't know, I would probably, it's as simple as having like, very, very durable bids, would would fix this problem in I think, like, 75 80% of the United States.
I agree. And, you know, you often hear people talking about like, Oh, we need to develop gene drives to sterilize them all. Or, you know, design drones that will like, just operate autonomously and kill them in the environment. But really, it's just like you said, it's simple changes in human behavior would go a long way to controlling rats, like you remove their access to food. You're gonna have a lot less rats.
Yeah, that's got me. That's the issue. I mean, when you have pasts, it's because you're, you're allowing them to eat and thrive and survive. So it's not you. That's not us. You know, it's not about the rats, the rats, the rats do what they will, you know, it's on us to, like, take care of our stuff and not be slobs, right. Oh, yeah, absolutely. All right. Thank you, Jason. I will see you online. Yeah, thank you so much. received a lot of fun. Yes, podcast for kids. David
