A 300,000-Year History of Human Evolution - Robin May

So today what I want to talk to you about, um, is a blink of an eye. In evolutionary terms, 300,000 years. It's a, a kind of moment in time. Um, for most organisms on this planet, it wouldn't even be worth thinking about. It's such a brief, uh, dalliance. But we of course, as a species are incredibly young. We haven't been here for very long. Um, and at the rate we're going, we might not be here for much longer. Uh, uh, so we are a, a kind of in ourselves a very brief, uh, moment in history. Um, and so actually 300,000 years for us feels like a long time, even if in planetary terms, it's the blink of an eye. So the question is, with that very brief slice of time, can we learn anything useful about human evolution by looking at that, um, and what it might mean for our understanding of who we are today? The Gresham College lecture that you're listening to right now is giving you knowledge and insight from one of the world's leading academic experts, making it takes a lot of time. But because we want to encourage a love of learning, we think it's well worth it. We never make you pay for lectures, although donations are needed. All we ask in return is this. Send a link to this lecture to someone you think would benefit. And if you haven't already, click the follow or subscribe button from wherever you are listening right now. Now, let's get back to the lecture. And when we think about evolution, um, there's a kind of straightforward and simple rule, really, which is that evolution is basically about reproduction. Stuff that has an impact on your reproduction, and most importantly, on your offspring's. Reproduction is really important for evolution and stuff that doesn't is completely irrelevant. So, um, so if I look around this hall, uh, for example, there are some people here who are gonna be massively shaped by evolution because they're at the start of their potential reproductive journey. They may have children, they may not have children, um, they may have grandchildren, but all of those things are still for play. For if you are like me pushing the wrong end of your reproductive life, you're becoming significantly less and less important in terms of evolution. Um, and of course, once you've reproduced and your post reproductive, anything or nothing that happens to you is invisible to evolution. And that's an important point. I'm laboring that point because we often ask questions about why do we have this disease? Why is this problem come up now? And quite often the answer to that question is 'cause evolution doesn't care. It's irrelevant 'cause it has no direct impact on reproduction. So broadly speaking, evolution boils down to the question of how many offspring do you have and how many of those offspring go on to have offspring themselves. Um, and so you can compare that. This is a, a little example from, uh, the British royal family, for example. So here is Queen Victoria, um, surrounded by a couple of generations of her family. She was very evolutionary successful, right? There are a lot of offspring here. Um, and actually if you, if you're a kind of budding historian and you look at the royal families of Europe, you can see a sort of genetic legacy of Queen Victoria right across Europe. Um, that in evolutionary terms, very successful, uh, not so great over here. This is William and Mary from the glorious revolution. No children of their own. And in fact, uh, Mary's sister Ann, who took throne, had no children either. And of course, this is why the throne changed hands. Um, so evolutionarily speaking, that lineage essentially went extinct. Why am I putting out pictures of kings and queens here? The point about this is that if we are measuring evolution and measuring impacts, the really important thing to measure are these things here, the kids and their children and so on and so forth. And we need to think about that in terms of features, behaviors, things that change the survival or reproduction, um, of our children. So it all ultimately boils down, uh, to babies like this. Still cute one here. She's, she's not so cute anymore. She probably won't be very happy about this, uh, baby photo of my teenage daughter being on the screen. But nevermind, um, when, when it gets taken down on YouTube, you'll know she's filed an official complaint. Uh, so it's all about the survival and reproduction, um, of babies. And so if we think about evolution, the strongest forces in shaping all evolution, but in particular human evolution are, are those that impact on infant survival and ultimately on their reproductive, uh, success. So, um, if we look for example, at this data from the WHO from a few years ago now, uh, this is a pretty grim slide. This is a slide of, uh, what means that babies date survive infant mortality under five. Okay? The leading cause. And if you look at that data, first of all, foremost, I think it's important to say this is actually a tragic indictment of where we are today.'cause many, many, many of these things are preventable, um, and should not be causing infant uh, mortality, but they are because of inequality and poverty and all the other things that go with it, that notwithstanding in evolutionary terms, if we look at these leading causes of death, the majority of them are infectious diseases. Okay? So at a first approximation, your biggest risk if you're a newborn human infant on planet earth is something that will infect you early on. And if it infects you and it kills you, that's it. You're removed from the gene pool, your evolution, um, re contribution has finished. So we might expect then that if we are looking for evidence of what has shaped human evolution, that these infectious forces will be the place where we are most likely, uh, to find that evidence and, um, to a first approximation, then infection is a big evolutionary problem. And things that overcome infection are big evolutionary successes. So can we learn about those processes over the last 300,000 years by looking at human evolution? And, uh, to quickly recap, for those of you who didn't see the previous lecture, um, and with the caveat that these dates change all the time, this is an incredibly fast moving field. People discover new fossils, new DNA all the time. Um, so with the caveat, this is probably wrong already and definitely will be by the time I finish this lecture. Um, this roughly speaking is how we think of the evolution of our own species, homo sapiens. So you roll the clock back, say 600,000 years. Um, this hominin species homo heidelbergensis is roaming Africa. Um, it spreads out from Africa to Europe where it devolves into the species we know of as Neanderthals. It migrates across to Asia and becomes this enigmatic species, uh, about which we know very little other than their DNA sequence and a few tiny fossils and called the dead sa. And then subsequently about 300,000 years ago, that, uh, that species that has remained in Africa has evolved again into what we would call anatomically modern humans migrate outta Europe again and meet all these other species around the world, um, and go on to populate the entire planet as we know it today. Um, and this graph, which I shared last time, lifted from the Natural History Museum, um, shows us up here, homo sapiens at the top corner. And the fact that we now know that up until about 50,000 years ago, we shared at least parts of the planet with these other species, certainly the de Saban and als, and who knows possibly other species too. So the key and important fact about this is that we have a species anatomically modern humans that evolved in Africa, that migrated out, they came into Europe. Um, and uh, we have this, uh, delightful phrase. The geneticists like to use add mixture, which basically means mating with other people. Um, and so admixture occurred, mating occurred between these, um, ancient but modern anatomically homo sapiens and Neanderthals in Europe, and then again, uh, with this group called Denis over in Asia. And so modern humans are this blend of these hybrid, uh, existences and you can find out much more about that, um, from various sources online if you want. What, why am I telling you about this? I'm telling you about this because this gives us a powerful tool to understand much more about how evolution has shaped modern humans. Because we can look at these hybridization events or these ancient matings between homo sapiens and other species, um, and we can look at the exchange of genes and we can ask which of those genes have had an evolutionary consequence for us as a species, and what does it tell us about the last, uh, 50,000 years? So let me explain what I mean by that. So here we have, um, this ancient, uh, mating event. Um, and this is a, this is a PG lecture, so I'm going to show skeletons. So here we have, uh, homo sapien skeleton. On the other side we have a neanderthal skeleton, very similar bit stockier, more chunky, various anatomical differences that mean you can distinguish it, but broadly speaking, similar when any two organisms mate, and hopefully you might remember this from your school, uh, biology lessons. Um, each of us carries two copies of each of our chromosomes. One inherited from my mum and one from our dad. When you produce sperm and eggs, they separate each sperm or egg getting one or the other. And then when you make somebody else, one of theirs comes together with one of yours and you get a new combination. Hopefully that's not new to anybody listening to this. When this ancient Neal and homo sapiens mated exactly the same process happened. So one homo sapiens chromosome was in a sperm or an egg, they mated with this neandertal, one of their chromosomes came together and you end up with this two one from each parent just like anybody else, the offspring of animating that includes all of us in the room and all those listening. So you have two chromosomes when you produce your own sperm eggs, those two chromosomes that you've got, one from mom and one from dad, do a process called crossing over. So before you produce sperm eggs, they come together and they exchange bits of DNA between each other. And so what you end up with when you produce, for example, an egg cell is not a cell that has just your mum's chromosome or just your dad's, but they have a chromosome that has, for example, been inherited from your dad, but with bits of your mum's or vice versa. And this is one of the processes by which we get variation. And this is why we don't all look like an exact clone of our grandmother or our grandfather. Uh, but even though you've got part of their chromosome, because there's been a genetic reshuffling, that process happened also 50,000 years ago when homo sapiens and Neanderthals mated. And so what you end up with in the first and second generation of this cross are chromosomes that are a blend of the homo sapiens, DNA and the Neanderthal DNA. So, uh, in this color scheme they look like this. They've got, they're not regularly striped obviously, but um, but they have some genes from the homo sapiens parent and some from the Neanderthal parent. And the important point is that to a first approximation, that process of shuffling is random. So what you should expect is that these offspring have a random inheritance of genes that were either sapiens or neandertal. Now that offspring is gonna go away and they're gonna have their own offspring and so on and so forth. And what you should expect if all of those genes are essentially completely neutral, they have no impact, is that over time the distribution of neandertal genes and homo sapiens genes will remain random across your chromosomes. And that means that if I was going to look today at all of you sitting here listening to this and to sequence your DNA, which is of course possible, what I should see is a totally random distribution of neanderthal genes across your genome. But that's not what we see actually. So what we generally see is something that looks a bit more like this. Broadly speaking, most of your genome is a random mixture of neandertal, um, and homo sapiens. So if you are a European, for example, like me, then you've got about 2% Neanderthal DNA. And that is roughly speaking, distributed pretty evenly across your chromosomes with the exception of occasional patches where you see either no DNA at all from a neandertal, you have only homosapiens DNA or the reverse. You are highly enriched for financial DNA in that area. Why do we see that? We see that because that is a hallmark of the fact that this is no longer a neutral bit of DNA, it's no longer a neutral gene, what it means. So in this example here, for example, here you have a blue patch, which is only homosapiens DNA. So what that means is that the, the equivalent Neanderthal D gene has been selected against, it's been a bad idea over the last 50,000 years to have neandertal DNA in this bit of your chromosome.'cause whatever the gene was you inherited there was not helpful and it has been selected against. Conversely, if you have a patch like this, we have more neandertal DNA than by chance. That means something that Neandertal great-great-great, great, great, great, great great grandparent gave you, was useful and it has been retained despite this random process. So we can look in modern human gene names in all of your gene names and we can look for patches that look like this. And when we see them we can say, okay, something here has been important over the last 50,000 years. What is it? And what might it have done? And that's exactly what um, various groups have done. And this in particular is work with Josh Akey, um, and Serena Tucci and others, um, where they have looked in modern genomes. And what they've done particularly well in this is they have looked in two distinct populations, modern Europeans, people living for example, in London today. Um, and uh, modern Asians living in various parts of Asia. And the point about turning two populations is what if there is a gene that has been selected for, because it benefits modern humans broadly, it should be in both of those populations. And if there's one that's particularly specific, I dunno, it helps you navigate the tube in London, for example. Uh, then it will only be in the European population, not the Asian or vice versa. So when we do that, that is exactly what you see. So here on this graph at the top, what you see is a chromosome. This is chromosome seven, human chromosome seven. And the little red and blue lines are indications of where there are neanderthal bits of DNA still in that, uh, chromosome. And what you see is that roughly speaking, most of the chromosome, they're pretty random except that it's pretty clear. I think that here is a patch where we don't have any Neal DNA. Why is that? That must be the assumption is that's because whatever was on that chromosome from Neal was not helpful, was not good. Um, and that's actually disadvantaged people carrying it in the sense that they have not reproduced as well as the rest of us, and they have been lost from the population. And when we look in that region, one of the genes that's in this region turns out to be this rather delightful one called Fox P two. And Fox P two encodes a protein, which you can see here spinning around, uh, which we have known about for some years, because this protein is incredibly important for language. So modern living humans, for example, who have mutations in this, uh, protein often have very severe, uh, learning defects around language and communication, speech defects, um, and are not, uh, very successful in being able to communicate. If you look ancestrally, modern humans have evolved this gene much faster than chance. It suggests the gene itself is under very strong selection to do something. And it's different to other primate versions of this gene, for example. And it's different to the Neandertal version. And so the assumption we have here, which I think is a pretty reasonable hypothesis, is that the Neandertal version of this gene did not allow you, uh, to do what these people are doing here, did not allow you to participate in communication, uh, in the same way that modern homosapiens did. So for example, if you were a hybrid from this Neanderthal homo sapiens cross 50,000 years ago, you were probably struggled to communicate with other members of your species. Um, and for those of us who've had a very nervous first date, we know that communication is quite important, uh, for reproduction. So if you couldn't communicate, you probably didn't reproduce very well. And so those genes have been lost from the population. So this is one example of a Neanderthal gene that we haven't got anymore because it wasn't advantageous. Can we find examples of genes that are the opposite, where that Neanderthal history has benefited us and because we can, um, and so we can look on chromosomes for the opposite patterns, and now we're looking not for those gaps, but for places where the red and the blue genes are very, very dense, more dense than the rest of the chromosome. And you can see here on chromosome three, um, one neat example here, but what's clever about this example, I hope you can see this, is that there are lots of red lines there. So, uh, these are the ones derived from modern Asian humans. So lots of people in Asia carry this Neanderthal gene, but it's missing from European populations. So the assumption here is that whatever this gene is, whatever this DNA region is here, it has been helpful, it's been kept, but only if you are have a lineage in Asia. So there's something here that is in some way that we don't quite understand, beneficial for survival and reproduction in that part of the world, less beneficial in Europe. And it turns out, when you look at this region, uh, of DNA, there are several genes in here, but there's a little cluster here called, uh, HYAL hyaluronic, um, acid genes. And these genes encode proteins that are incredibly important for rebuilding cellular structures after DNA damage. And in particular, after DNA damage caused by sunshine caused by ultraviolet irradiation. So for example, if you have a poorly functioning version of this gene, uh, you burn incredibly easily, you get very bad sunburn, quite rap rapidly. And so the hypothesis here is that back 50,000 years ago, we picked up this version of a gene, uh, from the anatol crosses. Uh, it confers better protection against ultraviolet radiation. If you are in a gray, misty, northern Britain, that is pretty irrelevant. Um, but if you are in a sun baked Asian desert, for example, really quite important to be able to survive sunburn. Um, and so this gene has been retained in the populations that needed it and not, uh, in the pale, kind of rainy populations of Europe, um, like the one we're standing in today. So that's an example that goes, uh, the other way. And then, uh, perhaps the neatest example that I really like in this study, um, is the one here which applies equally to all modern humans. So now we are looking for a region, this is on chromosome 12. Um, and there is a region here, hopefully you can see it very, very densely populated with Neanderthal DNA, uh, in both populations. So in both European and Asian populations. So here in this region is something that we inherited from Neanderthals. It's turned out to be really useful for all humans, or at least all of the ones that we've sequenced. And it's been kept at very high frequency. And this little gene cluster here contains three genes all very closely related called the OAS genes. And these genes are very, very important because they drive an immune process. And what they do is they detect and respond to viral infections. And it's a very clever system because what this gene does is it keeps back, it keeps under control the very powerful weapons that you use against the virus to avoid them doing damage when you're not infected. When a virus appears, these genes respond and they drive the production, um, of one of these antiviral, uh, weapons that we have, um, called RNAs. And this essentially is a degrading enzyme, something that chew up viruses. And as you may know, viruses come broadly speaking in two flavors. There are some that have a genome that is made of DNA, like, like our genome, but there are many, many viruses that have a genome made of RNAA related but different molecule. Um, and so because our genome is made of DNA but a virus, what is made of RNA that gives you a tool to destroy a virus by targeting the RNA, and that's what this tool does. So when you detect a viral infection, these OAS genes turn on this weapon, this RNAs weapon, the weapon is produced and it comes and it degrades the virus you're infected with. So this seems like quite a good thing to have. And so the hypothesis, maybe the neandertal version of these genes, um, is a bit better at dealing with viruses. And so that's why we have kept it so well, and that is exactly true. In fact, it turns out you can do these experiments in the lab if you have the neandertal version of these genes rather than the homo sapiens version. Um, you are much better at controlling a whole variety of, uh, viruses, actually particular things like hepatitis c tick encephalitis and West Nile virus. And one of the interesting things about this is the virus group that the, that you are particularly good at controlling if you have these genes all belong to a group called the flay viruses. And so to me at least, that is quite compelling evidence that at some point between that mating the Neals 50,000 years ago and today we have been through quite a strong selective pressure in which flay viruses were a really big problem. And so what happened was people who did not have this extra protection succumbed, died, didn't inherit their genes. Those people who carried this extra neandertal uh, gene were able to survive those, uh, pandemics if you wanna call them that, um, and give their genes on. And that's why we see those genes today. The last twist in this rather neat tale, I think, is that these neonatal genes that we inherited have apparently helped us survive at some point in the last 50,000 years. But even more importantly, they've also helped us survive in the last five years. Because you may know that during the covid, uh, 19 pandemic, there was intense interest in what made individual differences in our response to the virus. And we will all know people who got Covid to 19 and carried on as if nothing had happened. They were completely fit and well. And unfortunately many of us will also know people who were very severely ill or perhaps died. Um, and the question became quite often, why is it the two people who are superficially very similar may respond so differently to that virus? And so many groups looked at this by sequencing DNA in those different people and asking what genes do people who seem to brush off the virus have that are missing in people who gets severely ill? And it turns out that one of those genes that you can see over here is exactly this Oass three. So it turns out that if you have this Neanderthal gene, your ancestors survived some pandemic in the last 50,000 years and that's why you are here today. But the fact that you are physically here today in this whole listening to me may also be because that same gene has helped you survive the pandemic that we've all been through in the last four or five years. Quite a, a salient reminder. I think that evolution is not all about dead stuff, it's also about what happens today. And understanding it is really, really important. So that all feels and is ancient history. We're talking about things that happened 50,000 years ago and albeit they may have an impact today, um, but it's still quite difficult to get your head around, you know, Neanderthal matings 50,000 years ago. But the question is, and I'd like to turn to you now, is really can we see anything that's even more recent than that? And I said at the beginning that evolution works on very slow timescales, usually millions of years. So asking whether we can see anything evolutionarily over thousands of years is a bit of a tall order. But nonetheless, um, with the power in particular of very, very advanced genetics that we have received over recent years, we are now in a position to start to see things that have evolved humanity over not just a blink of an eye, but an absolute nanosecond of kind of evolutionary time just in the last few thousand years. And one of the points that I think is particularly notable is that we think of evolutionary events as being kind of standalone, right? We think of, I dunno, for example, humans migrated outta Africa. That was lovely, got the rest of the world end of season. But actually of course that's not how it works. When something changes, it has a knock on impact. So, uh, you know, if we start to evolve tool use for example, that had a direct impact on humans 'cause we could benefit from that tool use, but it also had a direct impact on other species. For example, trees that were now cut down that would not previously have been able to be cut down. So there are follow on impacts. In other words, evolution can spawn more evolution. If you think about the evolution of flight in birds before birds could fly, there was no need for trees to have fruit that could be kind of spread in the canopy as soon as they had a flying birds that could spread it around, it made sense to evolve fruit that might be attractive to those birds high up in the canopy and so on and so forth. So humans have evolved too. So the question is, have we evolved in a way that has then shaped our own evolution? And the answer to that is definitively yes. Um, and the bit of human evolution I want to talk about is in is this one is the transition from, if you like, hunter gatherer, nomadic, individual humans to the kind of humans we recognize today. People who are urbanized, people who live with agriculture, people who do all these kind of things that society today depends on. Um, and we know actually quite a bit about how this happens. So what we know is that around about 10 or 11,000 years ago, uh, up until a point most humans had been hunter gatherers, nomadic spreading over large areas, no particular pattern. Around 10 or 11,000 years ago, we start to see evidence of people returning to the same place again and again. Um, maybe that's because they realized that was a good place to be, it was a safe place to be, it had good food, whatever, but they came back to the same place. What we think probably happened was that in their hunting and gathering, they would of course have brought food home. Um, they would've spilt food, particularly nuts and seeds and grains. Um, and they would've, some of those would've germinated. And then of course, if you're a savvy hunter gatherer 11,000 years ago, you realize that actually if your corn is growing here, you don't have to go out to hunt and gather it and run the risk of being eaten. Um, you can stay here. And so bit by bit what we now recognize as agriculture evolved. So instead of gathering stuff from the wild, you could sew stuff and you could keep it in one place. Subsequently, uh, people then realized you could do similar things to animals. We started to keep livestock, so on and so forth. And that agricultural revolution has been incredibly important for human society, but also incredibly important for human evolution. Um, and we can start to see using modern genetic tools, just how important that has been. So the evolution of agriculture has been most intensely studied in an area called the Fertile Crescent. Um, in a unfortunately is now a very troubled part of the world. So ranging from Egypt through to Iraq in a, in a long suave here, um, it's important to note that we actually know that agriculture was being evolved in parallel in other places. Asia, for example, the domestication of Rice South America. But actually, uh, because most of the work and science, if you like, has been in this area, this is the area we know the most about in terms of the evolution of agriculture. And what we know is that about 10,000 years ago, people started to domesticate certain key crops and we can see that in those crops themselves.'cause you can see hallmarks of very rapid evolution as people started to select for crops that were for example, bigger or more edible or more durable. Um, around 10,000 years ago. Um, so at about 10,000 years ago in this area, certainly of the fertile present and elsewhere in the world, humans were starting to develop agriculture. And that had a really important impact on lots of things about being human. Um, and the first, uh, one and one that's often overlooked is that it allowed us to stay put. Okay? Up until then, for the rest of human history, we'd had to migrate around because if you need to hunt and gather, you need to be where the stuff to be gathered is. It's no good staying put and hoping that you are kind of banana's gonna come to you. You've gotta go and find the banana. When you start to do agriculture, you can stay in one place and you can start to put down roots. In other words, you can start to do what we now recognize as urbanization and build villages and then towns and then ultimately, uh, cities. And this, for example, is one of the earliest examples of, uh, of a town, um, in what is now Turkey. So agriculture, the development agriculture had multiple impacts. The first one obviously is it changed what we ate, probably not into this rather delicious looking meal here. Um, but it nonetheless changed quite radical what we ate. And a common misconception is that it must have made things better. Actually all the evidence suggests it made things worse. Um, if you look at the early nutritional profile of people at this cusp of agriculture, uh, their nutritional profile is actually worse than the hunter-gatherers that preceded them. And the reason for that is that the diversity of their diet collapsed. They went from eating loads and loads of different species, um, to eating a very, very small subset. So they had a much more reliable food source 'cause they were growing it themselves, but a much more diminished one in terms of diversity. And that had quite an important impact in terms of nutrients as we'll see in a second. The second impact is that it allowed humans to start to achieve densities, population sizes that we'd never seen previously. Prior to this point in human history, we were very small groups of nomadic hunter gatherers that traveled around and you couldn't get very big 'cause you couldn't stay in one place. You couldn't sustain a big population. Now you're staying in one place, you're growing your own food, you can expand agriculture, you can get to high densities. And high densities are very important for society. Um, they're also quite important for some bad things, most notably infectious diseases. And thirdly, um, we started to live much more closely with other species, not quite like this, but with other species. Um, by domesticating livestock, we started to share our homes, literally share our homes, uh, with all sorts of species, goats, dogs, sheep, cows, so on and so forth. And a whole bunch of species that we didn't intend, but they came anyway, rats, mice, et cetera, et cetera. And that mixing pot has had a really profound impact on the subsequent evolution of humans over the last 10,000 years. And let me show you a few examples of that. So here's the first one. Um, this obviously is wheat. This is a, a crop that we eat. I said just now that one of the things that happened when we moved to agriculture is we diminished the diversity of our diet. Um, we had plenty more calories, that's a good start, but we missed out on things that were nutrients that were not necessarily present in all our plants. So for example, you know, if you eat 50 different species, you're gonna pick up nutrients from lots of different species. If you eat three species, you may well be missing something that is only produced in that four species that you are no longer eating. Um, and that is true. Uh, so we know for example there is an amino acid called ine and ine. It's actually still a bit unclear why we need it, but we do, we do need it. We don't make that ourselves. And in fact, many, many species do not make ine including most of the major crop species. So we have to get it from things, uh, like fungi for example. So when we switch, and that was not a problem when you were out hunter gathering and finding your own mushrooms and everything else, when you switch to eating largely grain crops, you suddenly missed out on this ine. Um, and that has, that impact is now clear in modern human genomes because the gene you need to harvest ine from your food encodes a protein OCTN one like this, which picks up fin in your diet and puts it into your bloodstream. Um, and this gene we can see in modern human populations comes in different flavors. Um, some people present in the audience probably don't produce very much of this, but many of us have a version that is much more active. In fact, it's 50% more effective at getting hanin outta your food than the other type of the gene. And if you look at where that highly effective gene is found, what you see is a rather wonderful map like this. Those of us in Western Europe are very, very likely to have this what's called a high affinity gene. People who have a a, a longstanding African ancestry, much less so. And the explanation for this is that that's because the evolutionary history in Africa was much was hunter gatherer for much, much longer. Those of us in Europe have been through this agricultural bottleneck. We are the survivors of people who farmed in the Middle East essentially. Um, and so in order to survive farming in the Middle East, you needed this version of the gene to help you get nutrients outta your food otherwise you died. And so those of us who have survived that process have that high affinity gene'cause it's able to scavenge, ine from your food. A very nice example I think of where agriculture has shaped modern genomes in a way that we had not previously predicted. And in fact, we can go one step further than this 'cause we can say, so this is testing an individual gene, but we can turn it around. We can say what is it in modern humans That apparently has evolved very, very fast and a very neat way to do that was done by David Reich's group who looks at, um, relatively recently dead human beings. And when I say relatively recently, I mean the last 6,000 years more or less. Um, and they sequenced DNA from corpses from about six and a half thousand years ago to about 300 years ago. So this is quite a big s swat of human evolution. And by doing that you can look at genes that have essentially not changed over that period of time versus those that are apparently changing very, very fast. And the theory is that a gene that is important for something that is changing will itself change. So if you think about, for example, dealing with an infection, your genes are changing fast as the infectious profile changes, whereas, uh, you know, the way that you pattern an embryo has not changed over the last 6,000 years. So those genes are not evolving very fast. So what you see in front of you is a graph of the whole human genome from chromosome one right down here to chromosome 22. Every gene, each 20,000 ish genes of the human genome has been looked at. And the question is, how fast are those genes changing? What you see is the vast majority of genes are not changing very much at all. And that makes sense, right? Because most of what it means to be human has not changed over the last 6,000 years. But you have these occasional genes that are the tall ones here that are evolving very, very fast. Indeed, these are genes that do something that has changed a lot over the last six and a half thousand years. And one of the very nice things about this analysis is that one of these genes is that one I just talked about, the ine uh, transporter. So you can see that gene here has a terrible name, but nonetheless you can see that gene is one of these that is significantly evolving faster than chance. But there are some other neat ones here. Um, and this one, it clearly is the one that is evolving the fastest. Um, and this one is the one that affects all of us today. So if you're sitting here listening to this, um, scoffing your late night cereal with a bowl of milk, um, then you can thank this gene for that. Uh, if you're sitting here listening to this saying, I wish I could have that bowl of milk, but it would make me sick, you can blame this gene for that because this is the lactase persistence gene. And this is a very nice example of evolution shaping evolution, because as you will know, um, those of you in particular who've got domestic pets, cats, dogs, et cetera, the basic rule for all mammals is that baby mammals drink milk and big mammals don't. Right? If you have a puppy, a puppy drinks milk when you wean the puppy and have an adult dog, if you give your adult dog a bowl of milk, it will vomit, it will back up again, okay? And that is true for most mammals. It is also historically true for humans. Historically, evolutionarily humans could also not consume milk. As adults, we would drink milk as babies, we would wean, and then we would become what's called lactose intolerant.'cause you would miss the enzymes digested. That was not a problem until we started dairying, we started keeping cattle and sheep and other things for their milk. And then it became quite useful to be able to digest that milk even as an adult. There is a mutation that is presumably quite rare in nature that keeps that gene on into adulthood. And for the last million years or so, that's been totally irrelevant. But suddenly, when we started to have a ready source of milk as adults, having that verse of the gene was very beneficial. And the time it was particularly beneficial was when times got really tough. So for example, uh, when in winter when there's no food around, um, you were essentially on the brink of starvation. If you had a cow and you could drink that milk and not to vomit it back up again, you had a significant chance of survival if you drank it and threw it back up again and got no calories from it, that was not helpful. And so what we see here is the very, very strong selective pressure to have this version of the gene that allows us to metabolize milk. And for those of you who are listening to this thing, yeah, but I'm lactose intolerant. I'm sorry. You're one of these people down here, um, who have got the older version of the gene that is not, uh, conferring that ability to drink, um, uh, to drink milk as an adult. So this is an example where we have done something, we have evolved dairying and it has shaped our own genetic evolution quite dramatically. And the other example you can see here is a whole cluster of genes down here, uh, which all the different functions, but they are all to do with the immune system. And I said right at the beginning of this lecture that one of the strongest forces in immunity is infectious disease because it kills people. And in particular it kills young people before they have reproduced. And so we should expect genes that confer resistance to disease to be evolving fast. And they are. So, there are genes here that are evolving very, very fast. Um, and one of the reasons they have evolved particularly fast over the last few thousand years is because we ourselves have dramatically increased the risk of infection. And we've done that by living very close to each other. We're all here in a fairly crowded hall for starters, um, able to spread diseases quite well, but also 'cause we have brought into our lives things that spread diseases to us either deliberately or inadvertently, like this rather cute fluffy thing here. For example, um, rats, mice, the fleas they bring, the parasites they bring are often damaging to humans. And so that onset of urbanization and agriculture exposed us, uh, to new diseases. And in particular, uh, one of the diseases of course that it brought that these animals brought with them that has been enormously influential in human evolution, um, is this one here. This is the bacteria that causes the bubonic plague. Okay? And this, as you will probably know, is carried by the bacteria is carried by fleas. The fleas live on rodents. Um, and so getting exposed to those, uh, fleas on your, your, either your pets or your more likely your rodents that live in your house is the root by which you pick up bubonic plague. It is very likely that bubonic plague has been around for a long time. But it was a very minor evolutionary pressure when we were hunter gatherers because A, you didn't often come into contact with these things carrying it, and b, even if you did, you are only living in a band of a few people. You know, even if it wiped out your tribe, it was not a major impact in terms of evolution. When you start to live in a town or a village or a city of thousands of people, now you have the opportunity to have proper pandemic plague and a very significant evolutionary impact because as we know, only too well over the last few years, disease spreads fast in crowded conditions. And we know from very good historical data that the magnitude of the impact of these bubonic PLAs has been quite astronomical. Um, so for example, this is a, a picture of the plague ash dod, which we don't actually know if that happened, but nonetheless. Um, but uh, we do know from good contemporary historical, uh, data, for example, that the plague of Justinian, uh, towards the end of the Roman Empire swept around the coastline of the Mediterranean. Um, and multiple historians from that time tell us that it killed about one in four people. Um, and bearing in mind this is the, you know, this is the Roman empire, this is the sort of center of the, the, the global universe at that point. So 25% of the people in the Mediterranean was a big chunk of the world's population who died within just a couple of years, and they're much closer to home. We are here in London, those of us in the hall at least. Uh, and we will all be very familiar with the impact of the black death in Europe. Um, the same disease, different names, same disease, same bacteria, uh, in particular the Black death, uh, which peaked around 1350 in, at least in this part of the world, is estimated to have wiped out between 30 and 60% of the population of Europe. So this is a enormous mortality, right? A really, really strong selective force. And so it stands to reason that the slightest advantage would actually be a really, really big advantage in evolutionary terms, even if your chance of survival was 1% better than the guy next door over that kind of level of scale that's going to be visible, um, in our evolution. And it turns out, uh, that that is indeed true. Um, and so there is an absolutely fantastic study done by Elio ero, uh, which I really love, which uses an amazing historical resource just down the road, uh, from here. So down at East Smithfield, um, just by sort of Tower London here, uh, in 1348, um, Edward iii, who was king at the time, um, was hiding well away from the plague, very sensible. Um, but watching London be decimated by plague, um, he was very astute bit of biology. Um, and Edward III thought, this is not very good to have dead plague victims everywhere. What I'll do is I'll buy a big lump of land, I will dig a big hole and I will tell, uh, my soldiers to throw anyone who dies of the plague into that pit, which is at East Smithfield. Uh, and then by about 1350 the plague is over in London. They cover over these dead bodies. Uh, and you know, very astute bit of government there. Well let's not waste this resource. It's a little bit like, you know, HS two in this country. Let's not waste this resource. Uh, let's think what else we can do. Um, we've got a big pit. I know we'll put other people in it now when they die on top. So what you have in East Smithfield is a layer, a layer of people who died of the plague and then above it a layer of people who survived the plague and died of something else a couple of years later. And that is an amazing genetic tool because you can look at the DNA of those different layers and say, what are the genes that made you susceptible to the plague? And you're in the bottom layer or helps you resist the plague and you're in the top layer. And when you do that, you find them, it's fantastic. So here we have a plot, just like the one I showed you of all the genes and the ones up the top are the genes that are significantly overrepresented in the survivors. So if you had that version of the gene, you were much more likely to make it through the plague. You might have got run over by a horse the following year and died, but you didn't get the plague and die. So they were advantageous in helping you to survive. For example, CTLA four or the EAP genes there. And unsurprisingly, these genes are all to do with immunity. Um, so for example, the EAP genes are used to reveal to the immune system the presence of a pathogen. Having those helped, presumably these medieval Londoners to say, oh my goodness, immune system is a bubonic plague happening again to deal with it fast and help me survive. So that version of the gene helped me survive, um, against the plague all those years ago. And we can see that evolution today. But the last twist to this tale and perhaps a slightly miserable point to end on is that this gene having these genes is why we are all here today. Especially those of you who have long distant, um, London ancestors. The reason you're alive today is 'cause you are great. Go, go, go. Great, great, great, great grandparents had this version of the gene and survived the plague. Unfortunately, you've now got this version of gene and that's probably also the reason if you're sitting there rubbing your knuckles, uh, that you have rheumatoid arthritis.'cause it turns out that this gene is really good at triggering the immune system against plague. Unfortunately, it's also a bit good at triggering it when you don't need to and inducing autoimmune diseases like lupus and rheumatoid arthritis. And so what you end up with is a gene that was massively advantageous a long time ago. Now, unfortunately, having a bit of a negative consequence. And of course the really bad news is, as I said at the beginning, evolution works on reproduction. So it's really important to be resistant to sub, to plague and have your babies grow up. Uh, by the time you get rheumatoid arthritis. Most of us have done our reproduction, it doesn't impact at all on our ability to reproduce. And so evolution doesn't see this. And so you are gonna be stuck with this gene probably forever now 'cause there's no evolutionary pressure to remove it again for the population. Bad luck. But that's evolution for you. Thank you very much. I'm very happy to Questions. Oh, okay. So for those listen online, who can hear that? How has modern medicine changed evolution? Well, um, I'm gonna be really mean and say stick around because the next lecture we're gonna talk a bit about that. But I'll give you a, I'll give you a quick, you know, spoiler alert. Um, so the short answer is we, it is probably too soon to see anything particularly dramatic, but there are some very nice examples of where, uh, we will very soon I think see evolutionary impacts. Um, and probably the biggest one is around reproduction. Uh, because things like IVF of course have just changed this beautiful model I've shown you about. It's all about how successful you are at reproducing because now you can reproduce if you actually couldn't reproduce previously. Or indeed you can choose not to reproduce even though you're biologically capable, which is something that has not happened for millions of years and is undoubtedly gonna reshape evolution in some really interesting ways. And that's all I'm gonna say. I'll have to tune in for the next lecture to find out some more <laugh>. I'm gonna go to question online, then I come to the audience with a whole series of questions which I, I think are kind of points of clarification about genetics. Yes. And people are asking questions about how lactose intolerance genes change their expression over the life course and whether how they're inherited, whether if you are lactose intolerant, it means that one of your parents is lactose intolerant. So they're just some people who want some clarification on those points. Yeah, very good point. So, um, and, and I I just slightly brush over that. So how does the lactose gene work? So essentially you have a gene lactose, which helps you digest milk, sugars, lactose. If you can't digest the sugar, it makes you sick and you, you vomit it back up again. So having that enzyme express produced is critical to be able to digest milk genes work. You have the thing that you're making, so that enzyme and what's called a promoter sequence beside it, which tells the body when to ex when to put that protein into production, when to turn it off. So for instance, there are some proteins that are produced at different times of the menstrual cycle. If you're female or when you go into adolescence or so on and so forth. You don't want, you know, the gene for beards being turned on when you're six months old. Uh, you only want it when you're at, when you're in puberty. Um, and so, so those promoters are, if you like the timer lactase, this enzyme has a timer which says, turn me off forever. As soon as you finish, you know, uh, wean as soon as you weaned, essentially you finished drinking milk from your mother. Um, and that works brilliantly well in all animals, including ourselves. What we have done at some point in, in, in evolutionary time is there has been a mutation that has broken that switch and it stays on forever. No use at all. In fact, in fact possibly slightly disadvantageous 'cause you're making a protein of no relevance, um, up until the point when you start being exposed to milk as an adult, then massively, massively important. So, so that's how it works. And the question about inheritance, so there are two sorts actually of lactose intolerance. I should have made that clear. The clean genetic type is that, so if you don't have the enzyme, you can't digest the sugar, you are lactose intolerant. There were secondary issues, for example, allergies to milk, which are nothing to do with that enzyme. Um, and, and are to do with whether you've been stimulated by a particular antigen, so on and so forth. So I guess the, the cautionary tale here is don't be listening to this at home and thinking, oh, actually my milk allergy is all nonsense. I don't have that gene. I'm gonna go and drink milk. If you've been told you're milk allergic, don't drink milk. Okay? Regardless of whether you have this gene or not. So there are different systems. Um, but yes, if you are genetically lactose intolerant, then whether your children are or not depends on the gene of your partner too. Because if you, if your partner is lactose tolerant and they're lucky, they'll get that gene and not yours. So then on the lactose, my cat loves a nice drop of milk or yogurt or cheese or whatever. And, and the story I've always heard is that they became domesticated when we took up dairying and they killed the mice and the rats in the dairy. So is there something about cats that enable them to drink milk as adults? Adults? So, so the question is about cats and cats that drink milk in particular and how they got domesticated. And, and this, this sort of reminds me of that thing about, you know, you should never work in television with children or pets, right? You should never answer questions about cats. Um, cats. So, so, so the, the domestication of the cat is actually a bit enigmatic. I mean, we know it's quite early on. Um, and as anyone who owns a cat knows, it's a bit unclear whether we domesticated them or they domesticated us. Uh, either way. Um, they're, they're, they are now living with us. So, um, some cats, so some cats are better at drinking milk than others. There's some variation there. And I have to, I don't know, be interested now if anyone online listening to this can post in the chat, um, whether they know whether that's because of the same sort of mutation or not. Um, cheese you mentioned about eating cheese. So when you process milk into something particularly hard cheeses, actually the lactose is largely, uh, destroyed because the fermentation process gets rid of that, which is why people who are lactose intolerant usually can eat cheese, um, but not drink raw milk. So it depends a bit on the, the amount of lactose too. Okay, there's a question again, I'm going to oscillate it again. I'm trying to put together some questions here. There are lots of people thinking about what future evolutionary pressures are likely to be. They're talking about changes in diet, changes in obesity. Somebody's mentioned that in Southeast Asia around Polynesia. People have, uh, also said, well, if you have all these pressures, modern day pressures, how does that play out now that there are fewer generations per century because we are reproducing older? And so whereas we would have three or four generations a century ago, now we only have two. That's, so there's, so that's very interesting. The second part, first. So the question is about whether evolution is running at a gallon different clock speed, I guess if we reproduce more slowly, which we do now. Uh, and the short answer is, so yes, generally that's true. So evolution is measured on generational time. Uh, so if you have, I dunno, uh, 20 generations of a thousand years or 15, that makes a difference. The clock rate. So, so to a first approximation, evolution is running more slowly. The slight caveat to that is that it's also about the mutation rate in your DNA and as you get older, if you reproduce at older ages, you carry more mutations, sorry to say, but it's true. Um, so, so, so there is a higher chance, I guess, of variability in your offspring that is not enough to compensate for the change. It's not that it will stay static. We are still essentially evolving slightly more slowly. Um, but it's not a linear change in that, in that kind of rate. Um, and in terms of the question about what's gonna happen in the future, again, we have a trailer over the next one. I think there are lots of interesting things. Um, you know, my, my, uh, teenage kids would, would tell me that, you know, a key skill for reproducing these days is be able to use TikTok. Um, so maybe, you know, there'll be, we'll see some sort of genetic selection for good use of TikTok. Um, uh, I dunno. Uh, but there are lots of slightly true, there are lots of things I think that will change. Um, for example, you know, through most of human history, being able to kind of, yeah, wield a weapon and and kill your opponents was quite a big selective force. Happily for most of us today, that's not a big selective force. So even weedy people like me can successfully reproduce 'cause I haven't been attacked by someone with a sword happily, thus fast. Dutch wood. Um, I was just wondering, could you maybe argue that the most healthy diet is a paleo diet, but then with a bit of milk and carbs? Um, and then the other thing was in reference to his, uh, the question, um, of the man behind me about healthcare. Could you maybe argue that with the, uh, the onset of the industrial revolution, the um, infant mortality rate decreased from like 50% to 1%, less than 1%, and that's caused maybe quite a lot of mutation and therefore we've maybe become more unhealthy as a population. So there's a lot, there's a lot in those questions. So, so uh, going in reverse order. So, so the unfortunately infant mortality rate globally today is still at about five or 6%. So, so we, and I mean that is good in the sense that it has fallen from highs of, you know, if you look historically it was not unusual to lose half your children before the age of five, for example. So we've done quite well. I would argue there's still an awfully long way to go. 5% still a very big number. Um, so, uh, so, so there is something about that in terms of, in industrial revolution, I think that depends very much. So seeing an evolutionary fingerprint of that would be difficult I think, because it was not even right. So there were indeed people who lived in, so for example, smog resistance, uh, might have been quite important. Having good lungs, it were important if you were in the middle of, you know, smoggy Manchester or London or something. But actually a large part of the population was not exposed to that even during the industrial revolution. And so many of us will not have been through that selective pressure. So I think that'd be quite hard to see in terms of the, the, the best, I make it a point to principle never to advise people on the best possible diet. Um, but uh, if I was to say, so I think it's very tricky to say, you know, the paleo diet is sort of attractive 'cause I said hunter gatherers had this better nutritional profile that is of course at a time when the switch was to subsistence agriculture in a very different way than it is now. Most of us, even people who grow your own, you know, we are actually fortunately at very low risk of starving to death.'cause you can still always get down the road to the supermarket if you need to. Um, and so I think the idea that you just kind of roll back the clock and go back to kind of stone age paleo diet and everything will be well is a bit, is a bit simplistic. Um, that notwithstanding, there are certainly things about that diet that would be useful advice for people like having fresh fruit and nuts and, you know, fiber, um, we know is infinitely sensible. Uh, and so that's kind of worth considering. But I would just, I would caution against someone thinking, let me live as a, as a stone age man and everything will be perfectly<laugh>. Um, how could mRNA vaccines affect and present in our genome and long term term health and what negative side effects could there be that we don't commonly speak about? Oh, that's an interesting question. So mRNA vaccines, uh, which we're all familiar with. So the good, so the, the clever thing about mRNA vaccines is they don't integrate into your genomes. They produce a protein, but they don't get inherited. So if like me, and hopefully like all of you, you've been, you've been vaccinated quite possibly with an mr A vaccine, you're not gonna pass that on to your kids. It's not inherited in any way. Um, it is a transient, if you like, uh, process. I think there's a sort of second part to the question there, which is theoretically you could do something that is stably inherited, uh, that might be useful. So for example, you could tweak people's immune system. So one thing you could do right, is you could go back to those genes that we know have protected against bubonic plague and you could say, well, maybe we should kind of change those in the genome of people who don't have that version to make them more resistant. There are very plausible reasons that you might want to do that for kind of infectious disease purposes. I think the rheumatoid arthritis example is a, is a good caution against that.'cause of course you might do something for all the best intentions to change in one way. Um, but you need to be very, very cautious about the unintended consequences about unleashing some secondary effect there. Um, but yeah, in terms of the question itself, mRNA vaccines definitely don't affect your genome. Um, in terms of any inherited way, um, and actually I, I'm a huge fan. I think they're a massively exciting technology that, uh, you know, has been hugely beneficial for a Covid to 19 and hopefully will be for lots of other things in the future. And we'll talk a little bit about that, um, in next year's series. So if you're really keen to come back, see you in 2025 and we'll talk about those. Um, the map you showed at the beginning with the hybridization events showed one in Australia. Does that mean that, um, the earlier forms of human reach Australia? And if so, which ones? Oh, Australia is like, it's like cats a very contentious topic. Okay. So in terms, so in terms of interbreeding, what we know definitively is that homo sapiens inter bed with Neanderthals in Europe and with Denis Sas in essentially Siberia, everything else is, is not known in terms of, uh, InterG aggression. There is a little bit of evidence about some interbreeding with a mysterious species that we don't know yet. Uh, that's still far from determined. The arrival of ancient humans in Australia is a massively contested date. So, um, which is widely variable. Um, and as far as I know, I'm again happy to be corrected by those listening online or those in the room. There's no evidence for specific interbreeding in that region. And actually the entire question of um, who arrived in Australia when is, is kind of strongly contested. One of of the most interesting things come out just in the last few weeks actually, is the whole genome data on, uh, native Australian populations. And there is very interesting, very high levels of diversity in those aboriginal populations, um, which is, which is very interesting in terms of their kind of dynamics. So for example, it looks like different groups did not mix that radically early on in the history of Australia. Um, and there's, I think it's a sort of untapped, interesting science question there about the human evolution within Australia. That doesn't answer your question about m meeting with other groups outside of it though. I think we have time for two questions. I'm gonna take one question here and then I've come to you for the last question 'cause you've had your hand up. Some people are really interested in language when you've showed the Fox P two and how language conferred potentially, uh, as sort of an advantage reproductively, but they've kind of extended it forward in their questions to ask how culture and human culture and art and potentially even religion may have imprinted on our genome and had selection pressures. Another brilliant question. And again, I feel like some kind of, you know, I keep saying, you know, follow me for the next exciting one.'cause in a future lecture we will talk a little bit about that kind of cultural evolution. But, um, but let me talk a bit about that now. So, so language, absolutely. I think language is kind of one of those interesting places where it's not quite as obvious as survival advantages, like fighting off infection or, or, you know, growing good and true or whatever. But it's probably, it's less culturally there's something more intrinsic, right? If you can't speak, if you can't communicate, it is quite difficult to reproduce. Um, and so, so that's in that hybrid place, I'd absolutely think that culture itself will also select and we know anecdotally right, about certain things. So historically, if you were the wrong religion, your chance of successful reproduction was a, is a lot lower because you might have been burned to the stake or whatever. Um, but usually those periods are relatively brief. Evolutionary speaking, I'd be kind of surprised if you could see enough genetics, for example, um, around, you know, religious belief or cultural belief because they're, they're so short and they're so localized. But I'm always happy to be proven wrong. And who knows in the future we might discover, you know, some strong genetic factor for, I don't know, religious conform, uh, conformity or something. Okay, final question. I think Very interesting, uh, lecture. I really appreciate it. I'm not, uh, medical qualified, I'm not a physicist, but the impression I get is that modern medical science is causing us to defy evolution, evolutionary pressures. Um, I do think we're in the long term able to keep up with evolution of viruses and bacteria so that we'll always have a solution to whatever befalls. That's, that's a high pressure question to end on, isn't it? Will we survive forever? Um, uh, so I rather than defy evolution, I would say we are, we are certainly changing it. So think happily, right? So many of the things that killed babies 300 years ago are not a big worry to us, at least here in, in Western Europe. Um, and that's a great thing. It it clearly changes the evolutionary impact. I think the idea that we've somehow stepped off the, the evolutionary out of there is a mistake. There are other pressures. Now there are lots of other things that influence whether we reproduce and whether our kids reproduce, for example, cultural things and they will play a, a role too. I'm pretty optimistic generally about the opportunity for medicine to deal with big disasters. And we've seen happily, you know, a, a, a very strong response to COVID-19. Am I optimistic that we'll be able to do that forever? Not so much. Uh, you know, I, I think historically most species come to an end at some point. The only question is, is it gonna be in a hundred years or a million years? I'm voting, well, I guess a hundred, I'm still gonna be gone. It doesn't really matter. But, you know, let's, let's aim towards a million at least. That'd be good. And on that positive note, <laugh>, I'd just like to thank Professor May again. Your next lecture is, is when, and that's going to pick Up it's ai. That's a good question. It's about four or five weeks time I think. And we're going to be answering some of the questions that you asked tonight actually about, uh, the impact of society, human impact, uh, things like antibiotics, disease resistance, and where we might all go from here. So come back again, find out more, have more of your questions answered. Thank you again. Thank you.