Gresham College Lectures

How Genetic Adaptation Helped Humans Colonise the Globe

June 07, 2022 Gresham College
Gresham College Lectures
How Genetic Adaptation Helped Humans Colonise the Globe
Show Notes Transcript

Modern humans evolved in Africa and successfully colonised the globe only in the last 100,000 years or so, a feat made possible by cultural and genetic adaptation. Human habitats differ dramatically in climate, available foods or pathogens, and genetic adaptation was mediated both by mutation and by interbreeding with archaic humans such as Neanderthals and Denisovans. 

Besides representing a mark of our past, these adaptations contribute to diversity in living people in traits such as skin colour and immune function.

A lecture by Dr Aida Andrés

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- Hello, my name is Aida Andres, and I'm an associate professor at the UCL Genetics Institute at University College London, and my work aims to help us understand how populations adapt to their environment. This is populations that adapt to a particular environment, and how species evolve to adapt to where they live. And we're also very interested in understanding how these past evolutionary events influence individuals living today, because those adaptations, of course, remain in our genomes. I'm going to talk about humans today, and just try to understand how did humans appear and colonize the world. And this is an interesting question for a number of reasons. Human evolution is interesting because, well it's interesting for us, we care about humans, it's always nice to know something about our origins and our evolution, but also, humans are a very interesting species within the animal kingdom, we are pretty unique, we have traits that no other species have, like, for starters, we have cognitive abilities that allow us to present some work or listen to presentations, and that is really unique. So it is very interesting to understand how did these characteristics come to live what were the evolutionary events that allowed us to just have all of these amazing capabilities. Also, humans are pretty unique in that we have colonized basically the whole world. Most species live in particular regions, and there are very species that are cosmopolitan, meaning that they live everywhere in the world, like we do. Even within the primates, this is unique, we are the only primates that live everywhere, and even other human forms that lived before modern humans, before us, they also lived in particular areas, so we are the only primates, actually, that live everywhere. And what is interesting to me is to think that, somehow, our evolution probably allowed us to have traits that allowed us, or even compelled us to migrate, and migrate, and migrate, and explore, find new territories, and colonize them. And at the same time, the fact that we have moved around and live in all of these different places has meant that we had to adapt to those environments, and that, in turn, has influenced our own evolution. So the characteristic of living everywhere is not only a consequence of our evolution, but also causes evolutionary events. And I would argue that besides being interesting, understanding our own evolution is important because, of course, those past adaptations live today in our genomes, and because our genomes encode everything that we are, almost, our physical traits, then those adaptations live today in the genomes of people, they make us how we are, they define how we live in this environment, how we metabolize food, how we fight pathogens, how we respond to cold weather, and also, they influence our disease risk, so anything that has to do with the evolution of our traits is potentially linked to the present risk susceptibility differences that there are between individuals and between populations, or between individuals that live in different populations. So let's start with the very beginning of the origin of humans. I think if I ask you what is the most closely living species to humans, I think most people would correctly identify chimpanzees as our closest living relatives. And this is true, but it is a little more complicated, there are two species that we are very closely related to, that is the chimpanzees and the bonobos. The bonobos are less known, at least for the general public, they have a small population size, and they're really interesting mostly because of their behavior. So the bonobos, even though they are very, very similar to chimpanzees, they live in female-dominated societies with very low levels of violence, and with a peaceful relationship between individuals largely, not completely, but largely. And that's in sharp contrast with the chimpanzees, maybe with humans, depending on how you think about it. So humans share a common ancestor with the bonobos and the chimpanzees only 4 to 6 million years ago, that is a really short amount of time in evolutionary terms. We share most of our biology, most of our physiology, and actually, 99% of our genomes. So if you sequence the genome of a human and the genome of a chimpanzee, and you compare the bases, the letters, 99% of them are identical. In many branches of life, two subspecies from the same species are more different than we are to chimpanzees and bonobos, but of course, we're not considered the same species. Beyond chimpanzees and bonobos, the other great apes, which is our family, are the gorillas and the orangutans. And one interesting aspect of the relationships that matters for my talk today is that while humans live everywhere, cosmopolitan, all of the other great apes live in really restricted areas, and that is partly, now, because humans are just reducing their habitat, but it has always been the case, we believe, they live in relatively limited areas. All the subspecies of all of the species of the great apes, except for humans, are endangered, so we are really bringing them to extinction, actually. And actually, there are other great apes that have gone extinct before, some of them very close to us, actually. Neanderthals are a very close relative to modern humans, so it's another form of humans, that lived for many thousands of years in Eurasia. We know a lot about them because they left a lot of remains, so we have a very good sense about where they lived, and we know that they coexisted with humans. There are other forms of humans that are less well known, and my favorites are the Denisovans. The Denisovans, we didn't know that they existed until some geneticist sequenced a pinky bone that they found, and then they identified a completely new family of humans that we didn't know existed. And actually, there are not very many known remains of Denisovans, but we know they existed because, genetically, we can see that it's a population that is close to Neanderthals, but different. And actually, even though they are both extinct, they coexisted with humans temporarily, so they lived at the same time in some of the same areas, we know they met, and we know that they liked each other enough to mate and actually have babies, so there has been interbreeding between them too, so many, many, many modern humans now have segments of the genome of Neanderthal or Denisovan origin, so some part of your genome that, one day, was either in a Neanderthal or in a Denisovan. This is really fascinating, but I won't go into the details of this, but they've also disappeared, so right now, the only human form existing is modern humans. So focusing on them, let's think a little bit about our evolution. We know that humans evolved in Africa. This map suggests in South Africa, but it's not clear, very likely to be East Africa, but we know that humans, from that common ancestor with chimps and bonobos, we evolved in Africa, with a lot of movement within Africa, and only in the last 50,000 to 100,000 years, humans successfully colonized non-African environments. So they started moving, probably small groups of humans moving, and then migrating a bit, and then migrating a bit more, and over thousands of years, they ended up colonizing the whole world. This is actually a very quick process even though it's thousands of years, but this is a really quick process. So this African origin, and out-of-Africa migration, that's the name of this migration process, it's really important because it has a lot of effects on our population in genetic differentiation between populations. The first is that the origins of all humans is Africa, we all have ancestors that lived in Africa. The second one is that genetic and phenotypic variation in Africa is larger than outside of Africa, and the reason for this is because you have a whole bunch of individuals in Africa, they have some variation, then you have small pockets of those moving outside of Africa, and they are taking the genetic variation with them, but a lot of the variation that doesn't move stays in Africa. So for example, it is not unlikely that there's more genetic difference between two villages in Africa than between two people, or two populations in different continents out of Africa, and that's because a lot of the variation is in Africa. And the third effect, maybe, or an important effect is that humans are highly homogeneous, because this is a very recent event of just colonizing the world, and it is of relatively recent origin, as a species, compared to many other species, and even compared to many other great apes, we're highly homogeneous. So we are genetically and phenotypically similar, this means both in our genes and in our traits, we are very similar, even though we do see differences, and we will leave that there, very important, but quantitatively, they are really not, and this is both within and across populations. So if you take, for example, the genome of two people and compare it, on average, only 1 of every 1,000 bases, so the letters of the genome, differ between any pair of individuals. So at the genetic level, we're extremely similar, and of course, the phenotype is no more than an expression of that. Another interesting statistic is that, of those differences that we see between populations, 90% vary within populations, and only 10% between them. So if we compare people within the same population or in two populations, the vast majority of the diversity that we have, you have it between people that live in the same population, and there's only a few differences that are different between them. So if we were to represent this, this would be the level of diversity that we see within populations, and there's a little bit, there are differences between populations, obviously, but they're a minority. And just a tiny, little point to say that even these 10% do not represent biological differences among what people would consider races. Races are a social construct, we're not going to discuss them, but they are not biological entities, and even this 10% doesn't correspond at all with what people would consider a race. So the final point that I want to say that is a strong effect of our demographic history is that because, as a species, we evolved in Africa, we're very well adapted to living there. So we have evolved for millions of years in Africa, adapted very well to that environment, and then, very quickly, we moved outside of Africa. What that means is that all of these new environments, they differ drastically, so they have different temperatures, different pathogens, they have different diets, you have to do things differently in order to get food, and humans had a very strong pressure to adapt to those different environments. We know that culture has been important, because of course we are unique, we have culture, and culture has allowed us to adapt to those environments, but we also know that there has been strong pressure to adapt biologically, and we know that humans have adapted biologically, and this is just, actually, what I wanted to discuss today. So how do humans adapt to the local environment, how does this process work, and how do we learn about those adaptations? Adaptation happens by natural selection, which is a very old concept from Darwin that is based on the idea of fitness, and the idea is that individuals that are better fit for their environment, meaning, typically, that they are better able to survive in that environment, or better able to reproduce, or both, those that are better fit are going to have more offspring. If the trait that is beneficial is heritable, so for example, if it's genetic, then that offspring, it's going to have that trait, they're going to also be better fit, they have more offspring, and so on, so over time, you're increasing the frequency of beneficial traits. And the other way around, if there are traits that are deleterious, that reduce the fitness of individuals, slowly, they're going to reduce in frequency in a population, and that is how populations adapt. There are different types of natural selection, but this very classical type is called positive selection, because it's a positive effect, where you're increasing the frequency of a beneficial allele. So let's very quickly go over what you expect to see if you have a trait where you have two forms. We have an orange form here and a green one, and let's say this is neutral, neutral means it doesn't affect the fitness of the individuals, so it won't be under natural selection because it has no effect on fitness. It can have noticeable effects, but it doesn't affect fitness. So what's going to happen from one generation to the next? These individuals are going to reproduce, and then they reproduce, and so on, and there's some variation, it's not that, always, everybody has the same number of offspring, so in some generation, maybe there are two greens, and because we're keeping the population size stable, there are going to be only three oranges, but then in the next generation, this might change, and so on. So over time, there is change in frequency, but it's not very much, or very quick.

Now you have positive selection:

imagine that the green trait is beneficial, it increases the fitness, well it's going to have more offspring, so in the next generation, there are going to be more green individuals, and in the next one, more green individuals, and so on, up until a point where either almost all of the individuals in the population, or actually, often, all of the individuals of the population, are green. And now we've gone from a situation where, under neutral evolution, you are in a situation that's very similar to the old one, under positive selection, almost everybody is green. If this trait is encoded in our genes, this is exactly the same thing if we think about the variance in the genome. So if you have a variant that determines whether you are orange or green, under neutrality it's not going to change very much in frequency over time, but under positive selection, the variant that encodes for the beneficial allele is going to increase in frequency very, very much, so you're going to see this difference over time. So how do we look at this in genomes? Well now, because of technical advancements, we can sequence thousands and thousands of genomes very easily, and actually quite cheap. So you can go and have a sample of genomes from whatever population you decide, you extract the DNA, you do some sequencing with them, and you read the genome, so you're going to read every single of the bases of the genome, A, G, C, and T, for every individual. Now you have these thousands of sequences, one next to the other, and you can start identifying the genetic variants. So here, what we have is this individual has T in his two chromosomes here, and the other individuals have a C. We're going to encode that as a T chromosome. So this is a variant, it's a position in the genome where, if you compare individuals, some people have one letter and some people have another one, and those are the two alleles, this is how we call the variant, so the two alleles are allele C and allele T. And we can count how many times we observe this in our sample, we observe it 2 out of 10, so the frequency of the T allele is 20%. And because we are now able to sequence lots and lots of genomes, and full genomes, actually, we can do this across the genome and say, we have the genetic variant, that has this frequency, and for every single position in the genome that is variable across humans, we can establish what is the frequency in the population. And we could do this for this population, and we could do this for a number of populations. So this is really helpful in understanding evolutionary history, and almost necessary to understand adaptations. And as I said, we have now thousands of genomes from people across the world, and actually, it's so easy that if I have a good internet connection, I can just download thousands of genomes into my computer, they're freely available, and once you know how to deal with them, it's really easy. We also have hundreds of genomes from old human remains, these are remains from dead people from a few hundred to many thousand years old that we can also sequence from the bones, and we can also analyze, and we have also genomes from archaic humans, so the Neanderthals and the Denisovans I told you, well people got that pinky, as I said, and you have the genome, and you can analyze it. So we use all of this information in order to infer evolutionary history. So let's just look at the toy example of our green and orange, let's imagine that we are looking at a population in Africa, it doesn't matter where it is, this is just a toy example, where we have this green allele that is neutral, and then it has a certain frequency in the population. Humans migrate around the world, if this is neutral, it's not going to change in frequency very much across populations, but there's going to be some difference. And now let's imagine that the green allele is highly beneficial in the British and Irish islands, so it has increased in frequency very much in this population because it encodes for some trait that is beneficial there, but it's not beneficial anywhere else, so it only increases in frequency there. So what we would say is that this population is genetically adapted to its local environment, so this is what we mean by local adaptation. Not all humans carry that trait, all these populations have it at very low frequencies, but it's really common in this population, and that's because that trait is adaptive. We usually use pie charts because it's easier to see, and you can see that there's a very strong difference between these two. So what is happening here is, if I came to you, and I told you, I'm studying this genetic variant, we have been sequencing genomes, and we have been getting genomes from existing databases, and we just calculated the allele frequencies, and this is what we observe, after I just told you that humans are so homogeneous, and that allele frequencies don't change very much, you would probably tell me, Aida, there's something interesting here, and you would be right. So what we're doing is using the fact that these genetic variants show striking differences in allele frequency between populations in order to say this is a hint that this site has been mediating adaptation to the environment, that's what we call a signature. So this is a pattern in the data that you don't expect under neutral evolution, and you expect under selection. So if you see one of these, well you may believe that maybe you're into something. If you see several patterns that you expect under positive selection only, under local adaptation only, then you would become more and more convinced that, really, this particular variant has been mediating adaptation to this environment, and that is actually what we do every day, we use the signatures of local adaptation. And the reason we have to do this is because we cannot observe the past, we don't know what happened. We're starting to have ancient DNA, but we really cannot observe the processes, we cannot experiment in humans, we cannot see who has higher fitness or lower fitness in which environment, so we have to rely on these signatures of positive selection, this footprint that selection leaves, in the same way that if you go to the beach, and you see some footprints on it, you can make inferences about whether somebody has been walking here, in which direction they were going, how long ago, maybe, they have been here, how big their foot is, which maybe tells us something about their size. In the same way, we use all of these signatures of selection in order to make inferences about what has happened in the past, and then try to understand why, what are the environmental factors that are responsible for that, what are the consequences today of those adaptations. And again, there's a number of different signatures, I'm focusing only on allele frequency today just for simplicity, but we use many more sophisticated signatures. And actually, these signatures not only allow us to identify the variants of genes that have evolved under positive selection, but also learn something about the evolutionary forces. So for example, if I give you this map, and there's not a lot of information here, but if we have some more money, and then we spend some more time studying this variant, and we see a pattern like this, really, this pattern is very, very different here, then we know, most likely, these populations have adapted to a very local selective force, an environmental force that is very unique to these populations. If we do the same, and we observe a pattern where, at high latitudes, all of the populations have a similar pattern, that means that they are probably sharing that environmental factor. For example here, you could say maybe it's something to do with cold, where these populations share that particular environmental factor. And it's important, because if this variant also has an influence, for example, on disease, so the predisposition to disease in this case would be, these populations are different from the rest of the world, but here, we would expect them to share some disease predisposition. So now that we hopefully understand how these processes happen, and how we can learn about them, even though we cannot study them as they happen, I would like to discuss how did genetic adaptation help humans colonize the world. The first thing that I want to say, I won't go into the details, but we do know that genetic adaptation did help humans colonize the world. If you look at the genome scale, at the whole genome, you do see this pattern of local adaptation, we know it has been important. As I said, culture is important, but biological adaptation also exists. So I want to give you a hint of which ones are the adaptations that we think are more important, or interesting, or we know better about, and their consequences today. Perhaps the most famous adaptation that we know of is not a local adaptation, but it's a very important adaptation, which is to diet, and there are several known examples of adaptations to diet. Diet is obviously very important, you need to be very well nourished in order to just survive and have offspring, but adaptation to consuming milk into adulthood is one of the most famous ones. In most species of mammals, adults are unable to digest milk, and that is because once you can eat food, then why would you eat milk? You can get your nutrition from food, your mom can have another baby, you never drink milk again. And that happens once you become older, then you stop producing the enzymes that you need in order to digest milk. Many adults in many human societies are actually able to digest milk due to the continued expression of lactase. Lactase is an enzyme that allows us to metabolize the sugars in the milk, and many of us continue to express this, and to have lactase well into adulthood, and we can drink milk. And not everybody can, many of us cannot drink milk. But this is unique in the animal kingdom, at least as far as I know. The lactase gene has some of the strongest signatures of local adaptation in the whole human genome, and actually, I say one of the strongest, and it's the one that we always use a classical example because it's so clear. In Europe, it appeared very recently, maybe 2,000 years ago, we don't know exactly, but really recently, it increased in frequency very quickly, to the point that the majority of individuals in many European populations can digest milk. What is interesting is that the alleles that maintain expression of lactase, that allow us to consume milk into adulthood, have appeared in European and in African pastoralists, and those are actually different. So mutations appear in these two locations that continue lactase persisting, and they were under positive selection in both, which means we have different societies right now that can consume milk into adulthood, and this was beneficial completely independently. And of course, many other societies don't share this. What we don't know for sure is why is milk so important. Of course it's a good source of nutrition, and once you've learned to domesticate cows, or other mammals, then it is a good source of nutrition, but milk is also a source of clean water for those who don't have clean water. So we're not 100% sure of what is the reason why consuming milk into adulthood is so strongly selected, but it is very clear that it was beneficial. And actually, there are other adaptations to diet that I won't talk about, but diet is clearly a very important selective force. Another classical one, just because it's so visible, is adaptation to solar exposure. Solar exposure, it differs dramatically around the world, with higher levels of exposure around the equator, and then lower exposure as you get further away. And actually, this is a really important selective factor also because the Sun is fantastic, and we need it, but it's also quite dangerous. If you live in regions of the world where there's high solar exposure, then you need protection, because otherwise you get skin cancer very quickly, we don't have fur, we're completely exposed, so in those cases, it is beneficial to have dark skin. It is the melanin, so how well your skin can protect from the Sun, that's the level of protection. If you live in places like the UK, where there's really not a lot of sun, then what happens is that you need exposure to sun to generate vitamin D, because we do need the Sun in order to generate it, so now you're in a situation where, even though you need some protection, the need for vitamin D is more important, and in those situation, then it's better to have lighter skin. And what we know has happened is that there has been some evolution so that populations that live at higher latitudes, for example, places where there's lower solar exposure, they have evolved to have lighter pigmentation. And actually, this has resulted in an amazing diversity of skin pigmentation around the world in a really beautiful way, people, depending where you live, there's some balance in between how much protection you need versus how vitamin D generation you need. Of course, this is very visible, one would argue maybe it's not very important for many things, but it's very clear that these populations have adapted to where they live. And actually, there are very, very strong signatures of positive selection for multiple genes that are responsible for this. Of course, the consequences today are a bit different, we live in a world where we spend a lot of time indoors, and so on, so the selective pressures have changed. We also maybe go on holidays to other places, and then we have more sun, so of course, all of this has changed over time, but this is a very clear example of very strong selection for individuals to adapt to their local environment. So besides these very classical examples, I just wanted to say adaptation to pathogens is really important, and there's very strong selection, of course, because pathogens will kill you if you are sensitive to them. And there are other characteristics, for example height, so there are populations that we know have had very strong pressure to reduce the height, and we believe that maybe in other populations, there's selection to increase height, and there's a whole bunch of different phenotypes that have been under selection. And again, what I would like to say is, this is interesting, but also, it's important in the sense that many of these variants have consequences in health today, so as much as understand our evolution, we will understand the reason why they exist, and if they're different between populations, that can help us understand population differences in risk. I'm going to spend a bit of time talking about adaptation to ambient temperature, and that is because I really like this example, it's very close to home, we've been working on this for a number of years, but also, I think it's a very nice example that really tells a story about how important these adaptations are. I would argue that ambient temperature is one of the strongest environmental factors that anybody has to deal with, because if pathogens can kill you in a few days, well if you cannot adapt to, for example, very cold environments, if there's a sudden change in temperature, and you don't realize, or you don't change your metabolism or your behavior, then that kills you in hours, so I think it's a really very strong selective force. But also, it varies dramatically in the world. So just an example, in Nigeria, the average temperature across the year is 28 degrees. If you go to Finland, it's six degrees. This is a huge difference, and this is the average across the year, I'm not talking about the winter. So individuals living without our modern culture in those two places, they really have very, very different environments, and there's a whole gradient, of course, in between them, so I think it's interesting to ask have humans adapted to this? Let me very shortly tell you about how we sense temperature, this is a really important process, and actually, the Nobel Prize for Physiology or Medicine last year was awarded on the discovery of temperature and touch sensors, because it's how we interact with the environment. So we sense temperature by some neurons that innervate the skin, so they come from the brain, and they arrive to the skin, the mouth, and so on, and if they activate, they tell your brain, for example, it's cold, and this is how this works. There's a number of proteins, and they are in the membranes of cells, and these are what we call ion channels. So these are proteins that allow ions to go in or out of the cells, and by allowing ions going in or out, they activate the cells that they belong to. And this family has a number of different channels, and each of them activates at different temperatures. So if it's really, really hot, then you're going to have TRPA1 activate, it's going to allow exchange of ions, it's going to activate the cell where it is, and this cell is going to tell your brain it's really very hot, and this is the thermo-sensation, and then your brain is going to make you change your metabolism, and maybe your behavior, depending which species you are, and depending how you deal with this. If it's cold, TRPM8 is going to do the same, it's going to tell your brain that it's cold, and this is how, by the combination of these in the different neurons, we can know how cold it is, which, as I said, I think it's really critical for survival. One thing that is very funny, or fun at least, about these receptors is that they're also activated by components. So mint, for example, activates TRPM8, so when you have mint-based gum or toothpaste, and you have this feeling of freshness, that is TRPM8 activating because of mint, and telling your brain it's cold, and then you believe it's cold, but it's not cold, it's just the mint activating. And actually, all of these, or many of these, are activated by other compounds, for example this one is activate by chili pepper, so a lot this feeling that we have of temperature is by the same receptors that tell us about temperature. So I'm going to talk about TRPM8 because it's the only one where we know for sure that there are signatures of selection, and that's the one that we studied in my group. TRPM8 is interesting because it's the best established cold receptor, the one that we know has a very important role in cold reception in living organisms, and actually, is has mediated adaptation to cold, we believe, in some other animals. This is not my group, but people have compared four animals living in habitats at different temperatures, what is the activation level of TRPM8, this protein, and they studied, from penguins, that live in very cold environments, to elephants, that live in very high environments. And what we see is that the level of activation of TRPM8 increases with temperature. Or the other way to think about it, the species that live in very cold environments, they have a not very active cold receptor, and this perhaps is because, if you live in a very, very cold environment, and you're metabolically very well adapted to that, you don't need to constantly be feeling that it's cold, because that is where you live, and you want to be able to just do your life without this constant pressure of your brain telling you it's cold. And actually, something similar happens in rodents, where non-hibernating rodents, or rodents that just keep going through the winter, they have a normally active cold receptor, while hibernators, they have a very inactive receptor, very similar to the ones that live in very cold environments. And we also believe that this is just to adjust to temperature. So it is clear to me that this particular cold receptor has helped species adapt to the environment, and now the question is, okay, humans that have evolved for millions of years in very warm Africa, did they also use TRPM8 in order to adapt to living in Finland, for example? I'm going to show the allele frequencies of a genetic variant that we believe has function, although I won't talk about that, and we have here a number of populations from around the world, this dataset, it's called the 1,000 Genomes, and what you can see is that this allele has very low frequency in Africa, it has intermediate frequency in several populations in Asia, and it has very high frequency in Europe, and this is really unusual. By now I think you will agree with me that there are very large allele frequency differences across populations, and this is unusual. And actually, it's unusual to the level that only 0.02% of all of the SNPs in the genome have larger allele frequently between Yoruba and Finnish, and this is just an example, but I will give you similar numbers between other populations, so this is really a very unusual SNP. And actually, when we try to identify these additional signatures of local adaptation, we do find there's a bunch of them, we're very, very sure that this allele has increased in frequency because of positive selection at higher latitudes. And actually, there's a significant correlation of the frequency with latitude. So if we plot latitude, north, and we plot the frequency of the allele, we see that as populations live in more norther environments, they have higher frequency of the allele. This is slightly complicated, and I won't go into details, but you can do analyses that allow you to take into account the fact that populations are not independent from each other, but this correlates with latitude much more than you expect under neutrality, and very, very few variants in the genome have a correlation like this, this is not what you expect. So what we believe has happened is that this variant in this co-receptor has slightly contributed to adaptation to increasingly cold environments as humans migrated to higher and higher latitudes, so that selection was stronger and stronger in higher latitudes, so the allele has reached higher and higher frequencies in higher latitudes, and this has generated this gradient that we observe today. We continue working on this example, but we're pretty convinced that this is true. What is interesting in humans is that, actually, the derived allele, so the allele that has high frequency at high latitudes, increases cold sensitivity, so this is the opposite of what you see in other animals. My personal opinion is that what probably has happened is that humans are, metabolically, not adapted to living at very cold environments, so it is possible that if you live in a place where it gets cold quickly, you need to be very sensitive to this because you need to metabolically adapt, or maybe behaviorally adapt, maybe the penguins don't have to do this, but we do. So even though I don't have proof of that, I think it's very likely that what happens is that you need to be more sensitive to cold, and knowing that it's coming, if you live in places where it's going to become very cold. An interesting association of this gene is that the allele that has high frequency in Europeans is associated with increased risk of migraine, which means individuals that have this allele have higher risk of migraine. Migraine is a very complex disease, it is multifactorial, and there are a lot of environmental factors, but it is true that this SNP contributes to your risk. And actually, populations that have a higher frequency of this allele have a higher prevalence of migraine. Again, it's a very complex disease, but probably, this has an effect. So what we believe might have happened is that we have this adaptation that has increased cold sensitivity, and as a side effect, nobody wanted this to happen, but as a side effect, has increased the frequency of migraine in some human groups, just because on top of helping you feel the cold, maybe this increases your risk of migraine. So very quickly, I want to touch on cold habitats, because, of course, I mean I told you about Finland, but there are places that are much colder than that, in Greenland, for example, that's the average temperature, and there are actually people that live there year-wide, so you could ask how does TRPM8 look like there. Well it doesn't look particularly striking, and actually, some of our colleagues have studied genetic adaptations in the Inuit, I think believing that one would find adaptations to cold, but actually, if you study them, what they find is the strongest signatures of adaptation are in FADS genes. FADS genes are fatty acid denaturases, and we believe that this is an adaptation to a diet that is very, very rich in fish and other mammals, that has a lot of that type of fatty acids, and it has very little fresh produce, fruits and vegetables. So there's an excess of some types of fatty acids and a deficit of other ones, and what my colleagues believe is that there has been an adaptation to the diet. And actually, these mutations that they identify are associated with a number of traits that they believe protect from cardio-metabolic disease when you have this type of diet, diet that people that are not adapted to eat would have real cardiovascular issues with, so maybe they're protected from that. But I still find it interesting that the strongest selective forces that one sees in the Inuit is not on the temperature, but it's on the diet. And actually, when people have gone and tried to identify adaptations to very extreme environments, so extremely high altitudes, for example, in Tibet, or living where you are fishing, and you have to spend a lot of time underwater to fish, where that's a very important part of the diet of the population, they do see these types of very strong adaptations in these populations. So it's clear that not only colonizing the world, but also colonizing these very special, very difficult to inhabit habitats, or territories, there has been genetic adaptation to those, and those, of course, are part of the genomes of the people living there. So just to finish, to wrap up,

some conclusions here:

so how did genetic adaptation help humans colonize the globe? We know that human populations are highly homogeneous, if you have to take one thing from this, it's that we are very similar to each other, both genetically, in our genes, and phenotypically, in our traits. Still, as humans migrated around the world, local positive selection allowed them to adapt to their novel environments, and this has been really critical in our ability to colonize the world, I believe. And this has resulted in key adaptations to different climates, to diets, pathogens, and so on, and in addition, there are specialized genetic adaptations that have allowed humans to colonize even extreme environments that are very difficult to live in, at least for a mammal that has evolved as a species in Africa. I think it's also important to recognize that these evolutionary events live today as differences among individuals, and among populations, in important traits, including disease. So as I said before, if you have two populations that have differences at the genetic level, in particular genes, and those genes are involved in disease, you're going to differences in disease risk between the two populations. And of course, most of the medical differences between populations are not genetic, are due to environmental factors, but the ones that are genetic are something that we can understand, and perhaps do something about, it's important to understand them. So I believe that the study of genomes using evolutionary population genetics is a critical tool to better understand human evolution, and also has important effects on not only evolutionary history, but also the people living today, so I think it's important that we start linking human evolution with our understanding of disease across populations. And I'll just finish with that, thanking UCL, which is my current institution, and I'll be happy to take any questions if you have any.