CARTA 10th Anniversary Symposium: Schoeninger, Stone, Tishkoff

(electronic beeps) (upbeat instrumental music) – [Man] We are the paradoxical ape, bipedal, naked, large-brained, long the master of fire,
tools, and language but still trying to understand ourselves. Aware that death is inevitable
yet filled with optimism. We grow up slowly. We hand down knowledge. We empathize and deceive. We shape the future from our shared understanding of the past. CARTA brings together experts
from diverse disciplines to exchange insights on who
we are and how we got here. An exploration made possible by the generosity of humans like you. (techno music) (upbeat electronic music) – So, I was given the title of Nutrition and Paleodiet and like Jim I have battled
with what, how to handle this and you’re gonna just
get what I did. (laughs) I made a decision and I’ve done it. So let’s start with the
reasons for focusing on diet. This is where I start my class on the evolution of human diet. Why do we bother to study diet. And I’ve just given you a series of them. Subsistence strategies result from various pressures including
intra-species competition for mates and food. In other words, so you can
begin to learn something about behavior based on what
the subsistence strategy is. Interspecies competition
for food and space, predator avoidance,
and all of those things that are never considered when we tried to reconstruct the behavior
of some fossil species. And I’m not going to
attempt to do that today although I do think about
these things in my mind but what I am going to try to
do today is to raise a couple of questions that we
might want to think about when we talk about
nutrition and Paleodiet. So although Jim says
that this is something that we shouldn’t just focus on, I am going to be talking
about differential survival, and fertility, diet,
and fitness not so much because I think they’re the
only way to look at something but because food is, the incredible thing, you have to survive in order
to reach sexual maturity and after that you have
to have enough food especially the female to feed herself and whatever fetus she’s bearing or if it’s a mammal than
nursing that child afterwards. So food is incredibly necessary both for individual survival and
for survival of the species. The other thing is that
having been at UCSD and looking to see what kind of work Shirley Strum’s
been doing for 30 years, I can tell you it’s absolutely incredible. So let me focus on a
couple of things here. Food and reproduction, getting
it right makes a difference. So differential fertility. What you have here is rainfall
in the preceding months. So between 150 and 550. This is what’s important
for what I’m talking about. Age at the onset of sexual swelling. So that’s the age of
which the female can be or male or female can begin to bear young. And what we’re looking at is a difference of almost two years between
a low rainfall period and a high rainfall period. It’s not the water per se,
it’s a matter of the biomass that’s produced because of the rainfall. Adding on to this is a
follow-up study that she did in which she’s looking at
and introduced opuntia. That’s the opuntia from outside our area where you get those beautiful fruits and you sell them at markets here. And these baboons of
Shirley’s have learned how to roll the fruit in the soil, take the spines off of it, and eat it. Now this is the rainfall
but as rainfall increases, you increase the opuntia production. The thing actually produces
bright fruits year-round. It’s low in acid. 65% is simple sugar. Well you add weight, you
decrease birth spacing which is exactly what
happened with these animals. Increased rain, increase output, increase or decrease the period of time at which you actually
come to sexual maturity and decrease birth spacing and you’ve got a larger
population than the guys next door who don’t have any of these things. So it really does make a
difference in terms of reproduction just in terms of the data that my own colleague was producing. Now differential survival, this is what we’re hearing
about all the time. And I think I’ve heard it from several people
talking about Paleodiet. This actually started with a
graduate student at Harvard and I just checked with Jim and in fact he was a
graduate student at the time that Jim was there and
this is Mel Konnor who then went to Emory and combined with his other colleague Boyd Eaton, they put together a summary of what they found of people in the ethnographic
record of what they ate. And this they called
Paleolithic nutrition. They called it that and it was the title of the article that was published in the New England Journal
of Medicine in 1985. But you go and reread that which all my students had to do, you go back and look at that article and they’re really talking about things like sodium potassium ratio. They’re looking at whether you
can eating unsaturated fats or not and what we’ve managed to do now of course is go on to The Paleodiet, The Paleo Challenge, the
7-day Paleo For Beginners. So you’ve got all of these things. Now the thing about the
Paleodiet by Loren Cordain who was one of S. Boyd Eaton’s students, it’s getting a little inbred here. Loren Cordain pointed out
that these are the things we were designed to eat, designed to eat. And that these were the things that we were really selected to eat. And so that’s where it’s
gone with this Paleodiet. Almost beyond what,
definitely beyond what, Boyd Eaton did originally. You got Love Paleo,
health and weight loss. I even saw diet for children,
the Paleodiet for children, So I didn’t put that up here. Now in terms of what we
were designed to eat, I think there might be
another way of looking at that and that is what is around. So, when we’re looking at a tropical band, what is available? So, in a typical West
African forest, on average, this is by Hladik and Chivers, who did some amazing work back in the ’90s I also have to have my students go back and look at (laughs) the favors that are not necessarily online. So if you look at that, what you see is that the vast majority of
available food is leaves. So you’ve got 12,000
kilograms of leaves compared to 23 kilograms of invertebrates, and 500 kilograms of fruits. But if you look at primates, and I’ll go into a little
bit of why in a little bit, but when you look at primates what are the foods that primates go for? Fruit, because it’s high in energy. Insects, because they’re high in protein. And leaves because they’re
also high in protein. But if you look across
all living primates. there are definite patterns
and that is a relationship between food and body size. So if you look at the insect eaters, they’re all small, very small. This is something you hold in your hand. Microcebus is one of the tiniest primates and it’s almost fully insectivorous. The large animals can survive on leaves. So mountain gorillas about the only one that survives totally,
excuse me, totally on leaves. But most of them combine them with fruit in order to get the energy because you can’t get
enough from these others. So you’ve got frugivore/insectivore which are sort of on the smallest side. You have frugivore/folivores
which are on the larger side. Humans, we fall into
the frugivore/folivore but not many of us are folivores. If you look at it another way, this was John Fleagle’s description. What he did is he showed
insectivores and folivores. There’s some fairly pure folivores. We won’t talk about those. Those are colobine monkeys. Frugivores, total frugivores but most of them are going to be mixed. Fruit and insects or fruit and leaves. Where are humans? This is where we are. We’re almost up by the gorillas which can eat just leaves and we don’t. So do you think I’m
gonna give you an answer? No. The question is why,
why are we so different? So, where we have to go is
back into the fossil record as Bill said and I’m really,
I’m not a paleontologist but we definitely need more information from the fossil record. And I’m going to give
you a couple of examples. One is an archaic primate
called Carpolestes. The next one is the Aegyptopithecus and it is at the base of the division between monkeys and apes. So you’ve got the combination there. You’ve got Proconsul which is at the base of the apes, it’s gonna be. Then you have Ardipithecus. And depending on where
you put that position, there is a very different interpretation. And mine will be different from Bill’s because I put the time period in a different place than he did. So let’s move on. Carpolestes, this is
a mouse-sized primate. Lived 58 million years ago and it was an almost complete skeleton. I mean, it’s incredible. Been reconstructed and now
reconstructed arboreal. As someone else was pointing
out, these are all arboreal. We are also arboreal primates. But the thing that’s so incredible about this primate is its hand because what that is doing is it has hands on both the forefeet and the
hindfeet, as was pointed out. And what that thing can do is grab and pull something toward it. So it doesn’t have to jump in the trees which was the other idea
they jumped after insects. It actually can pull toward it. It does not have complete
three-dimensional vision but it’s enough of an overlap
that when it pulls toward it, it knows exactly where
that thing is in space. So that’s a baseline primate is to be able to pull something towards
you and feed on it which is usually a fruit,
which is the energy. Let’s jump to 30 million years ago. And believe me I did select
these on purpose, (laughs) ’cause to me these are really critical divisions,
what happens here. They are prior to the division between the apes and the old world monkeys but the thing that’s of
most interest is that it does not look like an early monkey. It has a body like a monkey, it moves around on the trees,
it’s arboreal, it grabs, but it has a head like an ape. So this is not like anything alive today. This is something completely different. And if we’re going to look
at the evolution of diet, we have to think about these animals, not just the ones that are alive today. Today this is what the area looks like. Back then, this is what it looked like. It was a forest. They had crocodiles there,
snakes, various things like that. Thank you. So here we go. We got Aegyptopithecus in the trees as a fairly large primate. We move another millions of years to Proconsul, baseline ape. Again, it is a monkey-like body and it’s got an ape-like head. So the teeth look like apes,
the head looks like an ape, the body is moving around just
like a monkey without a tail. And what we know from
the biochemistry of it, what we know from the microwear of it, everything, we know it’s tree living and it’s fleshy fruits and leaves. Now depending on where you put that line, Ardipithecus is at the base
of chimpanzees and humans or where Bill put it was up where humans and not with chimpanzees. That gives you the interpretation that the last common ancestor
was a knuckle-walker. Keep in mind, that the two knuckle-walkers in Africa do not do it the same way. So gorillas do not knuckle-walk
the same way chimpanzees do. And the way in which Tim
White interpreted this is that the last common
ancestor could just as easily been a biped as a knuckle-walker. If you think about it that way, that gives you a slightly different way of thinking about diets. So whether or not that’s
what turns out to be correct, we ought to at least think
about that as an option. Pan was a knuckle-walker. Ardipithecus was a
facultative upright walker. Highly accomplished a climber, Pan. It was competent, Ardipithecus. Enlarged incisors for eating fruit? Yes, fruit eating, that’s
what all primates do. And the Ardipithecus, woodland to forest omnivore and fruit eater. If we just go through these,
we get very fleshy fruits, nut-like oil seeds in the early ones. And this comes from bone chemistry. It also comes from morphology. If you look at the very
robust australopithecines, what you find is that
they’re probably adding in things like these sedges which no self-respecting
primate eats like that. In fact, I’m ready to take them out of the primate order based on diet. If you then look at these others, the australopithecines, the later ones, you’re looking at things
well, there’s some grass in it but mostly again fleshy fruits and leaves. You move into the more recent ones and what you’re getting are berries, grasses, roots, nuts, a
whole mixture of things. And if we look at the very early Homo, what we’re finding is a modern body size, we think they’re eating meat. And what I want to leave
you with here is why? We still don’t know why. It’s not because meat’s
that easily digested. Yes, it’s good for us. There’s not much fat on it in a desert. So going forward before
we can answer anything, I’ll just go through
these extremely quickly. More fossils. I would put it at the late Miocene, the mid to late Miocene. We definitely need to know that. Between 4.4 and now, we
don’t have that many fossils. We need to have more
studies on gut microbiota and how it varies across primates. How, and this is one of the things that Alyssa will be
talking a little bit later but she and a colleague Schnorr actually have been starting to look at this in the Hadza. Genetic physiological,
morphological adaptations of primates at different
substance of systems strategies. And finally, I’ll give a shout-out
for Richard Wrangham, we need to know more
about when controlled use of fire occurred and when
cooking began to occur because we are the only animal that cooks. Thank you. (audience applauds) – It’s a great pleasure to be here today and I would like to congratulate
the directors of CARTA for (clears throat) an
amazing organization and I’ve really enjoyed
coming to the seminars over the past 10 years. It’s been a real pleasure. So today I’ve been tasked with the job of providing an overview
on ancient DNA research. And so I will attempt to do that. And really ancient DNA is a toolbox. It’s a way that we can try
to pull genetic information from the past and make inferences about evolutionary history. And it’s a field that’s
about 35 years old. And is really standing on the shoulders of technological advances
particularly, initially, with PCR and it was very much
stimulated by that work. The first ancient, archaic human DNA was published in 1997 and in that paper, we reported the results
of mitochondrial DNA. We very laborious PCR’d small fragments, put them together, and compared
it to modern human variation and at the time, we concluded
that it was very unlikely that humans interbred with Neanderthals. Now if you’ve been following the news, I’m sure you know that we
were not right. (laughs) And that’s actually what’s so exciting. There have been so many
technological advances that have enabled us to
look at complete genomes and put together a more complete story. And so the Neanderthal genome
project really pushed a lot of these technological advances
and in the last 10 years, in addition to next-generation
sequencing, methods of really pulling out tiny fragments of DNA. So as opposed to long reads
like Evan was talking to about, we were looking at really short reads. And a lot of the methods we were using, we’re actually pulling, we’re actually losing a lot
of the shortest fragments that we now can recover
and we can take that DNA and when we extract DNA from a sample, we’re extracting all the DNA. And what we do is we make a library. And this library has various indices and tags on it that
let us then amplify it, almost immortalize it. And we can then use our
library and sort of go fishing. And we go fishing using probes that capture the DNA we’re interested in. That might be a whole genome. It might be a pathogen. And then to those little baits,
we can attach magnetic beads and then through the beauty of magnetism, pull that DNA to the side of the tube and wash the DNA that we’re
not so interested in away. So this enrichment really has fostered our
ability to address questions about human population
history over the last 500,000 years now. After enrichment, we have sequencing. And I should also say that advancements in bioinformatics have
been equally important. So we’re now using methods
of machine learning to try to make inferences
about population history. So what do we know for certain. Because of the Neanderthal genome project and subsequent discoveries,
we know that in Eurasia archaic humans had pretty small
effective population sizes and more inbreeding than we see in modern humans or in humans today. Interbreeding was more
common than we thought. So we were incorrect from
the mitochondrial perspective because once we look at
the full genome sequence, we can actually see
evidence for interbreeding among different populations. We also see that there
were some adaptive alleles that are the result of gene
flow from archaic humans. So in 2010, with low coverage
genome from a Neanderthal we were able to see that inbreeding did in fact happen and make estimates of
population divergence and also look at, get some idea of what genes perhaps distinguish the lineages. Now one thing that has
been really amazing is that from Denisova Cave, we have both Neanderthal and Denisovans. Who are they? Who are really providing
fascinating information about past human evolutionary history and essentially surprising us about it almost daily, I think. But so here you can see that this particular cave has really amazing preservation
and what’s great about it, it’s allowed us to get high coverage genomes. Now, 1X coverage, there’s a lot of problems about making inferences that you’re statistically confident in
but once you have a 52X, a 30X depth of coverage so you the number of sequencing reads on average out of sight is very high and so your confidence
statistically is higher. And so this enables you to really make much more sophisticated analyses
about population history. So for example, Denisova Cave,
you can see here comparisons of genetic diversity along chromosomes. And what you’ll notice is the French, there’s a lot of, as you’re
sort of average European here, there’s a lot of diversity as you compare along the chromosome. Denisovan, there’s still some but less but you’ll notice the Neanderthal in particular has quite a few stretches that where there’s very
little to no diversity and this is telling us that inbreeding, our population sizes were much smaller. So these are some of the
many fascinating things that have come out of the
genome projects related to Neanderthals and Denisovans. We’ve also learned a lot
about population history in the last 10,000 years and the place we probably know
the most about is Europe. There have been a huge number of studies. We now have I think hundreds of genomes from ancient Europeans. And what this has shown us is that there’s been a lot more gene flow and replacement than we expected. So early populations in Europe
represented on this map, the hunter-gatherer populations which would have been
represented by the blue color and they actually don’t show individuals just from that group but once the farmers come in, you’ll notice that you get almost a replacement in some areas. However, this this ancient
hunter-gatherer ancestry sort of makes a resurgence after a bit. Probably gets pushed to the edges but then through interbreeding gets mixed into the European gene flow, gene pool. Then you see the Yamnaya, these Eurasian steppe populations
coming in the Bronze Age with a very strong signature
that persists today. And I think that was very
surprising to many people. We also learn a lot about
patterns of adaptation over time. And I think, people often ask oh, so humans have stopped evolving right? And this is one of the major
problems, well there’s many, with the Paleolithic diet.
(people laugh) It assumes that we haven’t changed since the Paleolithic and
in fact we have. (laughs) So, one of the examples
would be lactase persistence, the ability to digest milk. And so this is a cheese strainer from 5000 years ago in Poland. And what you see over time is that this sort of red color, this is the lactase persistence allele, it’s very low early on but
then increases quite rapidly. We also see what looks like shifts in patterns of pigmentation. There’s some estimates that
perhaps early Europeans actually had darker skinned and blue eyes. And that the skin color
lightened through time. There’s some debates about
this because the inference of past alleles is often very difficult, what the phenotype would be. And so, that’s one of the challenges of course is to try to infer
function and then phenotype. We also see, of course, strong selection at genomic loci involved
in the immune system. That’s a constant pressure. And the new methods in
ancient DNA analyses are also allowing us to look at human pathogen interactions. This is a very vague statement (laughs) and that’s kind of for a reason and that’s because we often
find what we don’t expect. So, this slide could be
called The Black Death and The White Plague because people assumed that the
plague didn’t really appear until the the first great pandemic, the Justinian Plague. But in fact we’ve learned that
it’s much older and we can actually see the different
changes in the pathogen. We also surprisingly learned
that while plague is older than we thought TB is
younger than we thought. And it was actually brought
to the Americas via seals. (audience murmurs) This was not expected. So what are we not sure about? A lot. (laughs) Was there hybrid and compatibility? How much gene flow was there? And what about populations and places where we don’t have good
ancient DNA evidence? So, we also know that there
have been major shifts perhaps in other parts of the
world since the Neolithic. And how much is this
true outside of Europe? And also how do the patterns of pathogen, how do pathogens change
pre and post agriculture? As I said, just a brief example, people are applying
different methods to try to make inferences about the
number of gene flow events. Kuhlwilm et al. found estimated six. Mondal et al. recently
have used machine learning to estimate additional
events of interbreeding. And these ghost populations
also become quite intriguing. What else do we need to
know and how do we proceed? Well, who were the Denisovans? What’s their range? Were there additional archaic hominins that contribute ancestry
and how do we detect this? Katerina Douka and others
are applying zoological, zooarchaeology by mass
spectroscopy to try to identify what species little fragments
are at archaeological sites. And then use the DNA to
gain further information particularly in places
where ancient DNA is harder to come by but also full size
remains are hard to come by. Other questions relate
to the adaptive legacy and in particular related
to complex traits. So a lot of the low-hanging fruit of simple traits has been looked at but of course more complex traits like cognition are of great interest and even epigenetic analyses. And we can make inferences
about epigenetics based on the damage patterns in the DNA. This is work by David Gohkman
and Liran Carmel’s lab. And this has intriguingly in
a paper that’s been submitted, highlighted the vocal tract and face as having major differences between modern humans and archaic humans. Finally where and what
extent are we expected to find pathogens in
archaeological material? Pathogens hang out in
different parts of the body. So there’s a lot of pathogens
we’re never gonna learn about from ancient DNA
because they just don’t hang out in the bones or the teeth. What are the population
dynamics through time? How do we understand the
microbiome and its changes. And that’s, I think, a very
intriguing area of research. And we’re learning that
there are major differences perhaps based on diet but we know, for example, that rural populations and first world populations have quite different gut microbiomes and meanwhile here are the apes. And so why are these ecologies different? What’s the functional importance there? So for example, the red complex
in humans has been related to periodontal disease but it’s also quite common in other apes. This is my postdoc, who’s
been working on this. And so what does this mean in terms of do we see the same type of evidence in other human populations as
well as our closest relatives? And how do we look at this both over time and across different populations. So work in science, of course,
is done with big teams. And so I have to thank my laboratory and funders and you, for your attention. Thank you. (audience applauds) – So I’m really excited to be here today to celebrate the 10th
anniversary of CARTA. And I’ve been charged with talking about human population genetics. But I’m gonna focus on evolution
and adaptation in Africa. So let me start with what I think are some of the key challenges in human evolutionary genomics research. The first is that we simply need to do a better job characterizing genomic and phenotypic variation in
ethnically diverse populations from around the world. We need to understand the
evolutionary processes that generate and maintain that variation. We need to better understand where did modern humans
originated in Africa? What was their demographic history? And how did modern humans adapt to changes in environment and diet
during human evolution ? So, lemme start with something
that we absolutely know which is that modern humans
originated in Africa. These red dots represent
the sites of fossils of anatomically modern humans. The oldest of which was
dated to 300,000 years ago. What we need to know is still
we need a better idea of when and where did modern
humans originated in Africa because there’s a major bias that we’re not finding fossils in tropical areas, for example. So this is still an outstanding question. We also think that after modern
humans originated in Africa that relatively small numbers
migrated out of Africa within the past 100,000, giving rise to populations across the globe. But what we need to know were things like how many migrations were there. So for example could there have been a southern migration route into South Asia, in Australo-Melanesia in addition to a northern route? And what were the source
populations in Africa? Now as you just heard from Anne, we think we know now, it’s
pretty certain I would say, that after modern humans left Africa, they intermixed or interbred
with archaic populations like Neanderthals and Denisovans but a big outstanding question
is was there admixture with archaic popular in Africa? My own research and that of
some other teams suggests that there was but because we, again, we don’t have those fossils
that are preserved well, we don’t have ancient DNA so
it’s a very tricky question to address at this point. This is from a paper
perspective, we just published. I think came out about
two days ago in Cell. And it’s pointing out that there’s a major European bias
in human genomic studies. So the figure on the right
here is showing the number of individuals by ethnicity included in genome-wide association
studies that look for an association with
variable traits or disease, it’s in your glossary if you want to look, and almost 80% are Europeans. The numbers for Hispanics is 1%, Africans 2%, bit more Asian
representatives about 10%, and then everybody else less than 1%, So this is problematic
for a number of reasons. One is in terms of biomedical knowledge that it could exasperate
health disparities but secondly in terms of what we can learn about human evolutionary history. So to help alleviate
those disparities, myself and my African collaborators
have been doing fieldwork in Africa for the past 18 or so years. We’re collecting biological samples from blood DNA and RNA in plasma and we’re getting detailed
ethnographic information, information about diet. And then we have the challenge of processing these in areas
where there’s no electricity. So what you can see on
the bottom left here is that we now bring a generator with us. We just set up this bush lab. And we try to measure
phenotypic diversity including very detailed anthropometric
traits like height and weight and limb length and skin pigmentation. We look at cardiovascular
lung and blood phenotypes. We look at metabolic function, lactose tolerance, glucose tolerance, and infectious disease status when we can. So this is from a study
that we published a number of years ago, looking
at genome-wide variation over 3,000 Africans,
from 121 ethnic groups but it remains one of the largest studies of ethnically diverse
populations in Africa. What we know is that you can
see these different colors, these are genetically inferred
ancestral populations, so all the colors are
telling you there is a lot of genetic diversity
between African populations. They also have the highest
levels of genetic diversity within populations compared
to the rest of the world. And that’s just representing
their demographic history and adaptation to different environments. This is a new study coming out soon in Genome Biology consisting
of a whole genome sequencing in 94 individuals from
44 African populations. And from this, we can
make a phylogenetic tree. So we can look at how
populations are related to each other based on
genetic similarities. And what I could say
that we know for certain and all other studies
have shown this actually, that the San populations who traditionally have practiced
hunting and gathering and they speak with clicks and
they live in southern Africa, they have the oldest genetic
lineages in the world, followed by the rain
forest hunter-gatherers in Central Africa, commonly
referred to as Pygmies. We’ve also used computational
approaches to try to estimate when these populations
diverge from each other. And we know that the oldest divergence is between the San and all other populations but we see that populations in Africa have been
subdivided for a long time. So, for example, even two San populations that speak slightly different
languages have been diverged for about 30,000 years. However we need to develop better models that take into account really
complex demographic histories that include things like migration and gene flow and divergence. This is from another review paper that we published a couple of years ago, showing examples of local adaptation. One that you may be familiar, I think there was some mention of it earlier, is on lactose tolerance
which we showed evolved independently in East
African pastoralists, relative to Europeans. And as you heard, Anne say,
actually a real challenge is to understand molecular
mechanisms of human adaptation particularly for complex traits that are caused by multiple genes. So I’m gonna give you an
example, a recent example of our study of the genetics of skin color which is thought to be an adaptive trait and it’s caused by
influenced by multiple genes. So on the left is inferred melanin level. So melanin is the pigment in
skin that makes it darker. And from global populations
and we could see it’s very correlated with UV levels so it’s thought this is an adaptive trait. And it’s thought that when
modern humans left Africa and they migrated to higher latitudes there would have been
selection for lighter skin to facilitate the production of vitamin D which is synthesized in
the skin in response to UV. And in places closer to the equator there would have been
selection for darker skin to prevent cancer, skin cancer, and also folate degradation. Folate’s very important for development. But most studies have been
done in European populations and little is known about the genetics of skin color in African populations. So to alleviate this bias,
we inferred skin color by using a machine a spectrophotometer where we basically shine
light underneath the arm so that’s an area that’s not
exposed so much the sunlight. And we look at the reflection
the wavelengths of a light that’s reflected and from that we can infer the melanin levels. And what we find is the San who had the oldest genetic
lineages are the most lightly pigmented people in Africa. We see a wide range of
skin color with the most darkly pigmented being
the Nilotic pastoralists, who originated from southern Sudan. We then looked at over
4 million variable sites across the genome and we did a
genome-wide association study and we found eight independent
loci or regions, variants, associated with skin color
that are in four major regions at a genome-wide level significance. So, I’m just gonna go
through those quickly. So the top association is
at a gene called SLC24A5 and this was actually the very first gene that was identified to be associated with light skin in Europeans. There’s a non-synonymous
variant in this gene. And in these figures, the circles that are light colored
are showing the frequency of the variants associated
with light skin color or that blue, I should say, or those that are associated
with light skin color. And we can see that this is at almost 100% frequency in Europeans, very common in Pakistan and
India and also in East Africa. So one of the questions we had is well, did this arise independently in Africa? And one of the ways we can address that is to make something called
a haplotype network. So a haplotype is simply how
different variants are arranged along a short region of a chromosome. And these circles represent
different haplotypes. The size of the circle
represents the number and the colors represent
proportion in different populations And it’s sort of a
phylogenetic reconstruction because these haplotypes
are very different. They have a lot of different mutations, for example from this haplotype. So what we see is that this
non-synonymous variant is on one common long haplotype in Europeans, consistent with recent strong selection. But East Africans have this variant on exactly the same haplotype background. So that means it had
to have been introduced by migration back into Africa. The second strongest association was at a gene called MFSD12 that had never previously been characterized. We found two independent associations. One is in a regulatory region,
upstream of the gene MFSD12, that is influencing
expression of the gene. And the other are variants within the gene that we actually think are playing a role in expression as well. And what we could see
is that for the variant in the regulatory region upstream, the variant associated
with light-skinned is at nearly 100% frequency in Europeans, East Asians, and it’s very
common in East Africans and actually in the San as well. So we collaborated with Bill Pavan at NIH and he used CRISPR-Cas9 technology to knock this gene out in the mouse and it had a pretty dramatic effect. So it caused this sort of brown, yellow agouti mouse to lose the, it’s, became gray. So basically what we find is
that Africans have lower levels of this and darker skin and
then has the opposite effect on pheomelanin which
causes yellow-colored skin. We can then estimate the age
of these different mutations. This is again just like
a phylogeny and lineages that have the light allele
are shown with open circles and those with the dark
allele are shown here. In this case the ancestor
allele is the one associated with light skin color. And the ages of both alleles are very old, on the order of a million years. The next locus where we saw
an association was at DDB1. This plays a critical role in DNA mismatch repair in response to UV. So if people have
mutations and the proteins that this interacts with, they have a disease called
xeroderma pigmentosum. They can’t be exposed to sunlight at all because they’ll get skin cancer. Now what does that have to
do with color in humans. We don’t know but this
happens to be the gene that causes the color of tomatoes. So it has something to
do with pigmentation. Again, we see two independent
associations of this gene. When you look at the haplotype network, we’re also seeing evidence of a very strong, selective,
sweep outside of Africa. This is one really common long haplotype. And in fact, if you look
at the gene genealogy, all of the lineages outside of Africa with the light associated allele, they coalesce at around 60,000 years ago the time of migration of
modern humans out of Africa. So when that light allele was introduced, it swept almost 100% frequency,
for reasons we don’t know. And then the last region is OCA2/HERC2. Variance in HERC2 were
known to be associated with skin color and eye color in Europeans but we found an independent association. And we showed that they
influence the expression of the OCA2 gene. But we also found a variant within OCA2, within exon 10 which is
a synonymous variant. It doesn’t cause an amino acid change. But it was in a region that has been known to have mutations that cause albinism. And it turns out that the
variant that is associated with light skin has alternative splicing. A part of the protein
basically is missing, that plays a very critical role. There’s still a protein but it
has a very altered function. And in this case, we see evidence
for balance and selection. That different lineages
have been maintained for a long time. So what does this tell us about
the origins of skin color? Well, I’m going to point out that at half of the low-side,
the variants that we found, the ancestral allele is the
light-associated allele. Furthermore most of these are older than the origin of modern humans. So and this poor chimp loss its hair due to a skin disorder but has relatively light skin although I did see some images earlier of darkly pigmented chimps so I don’t know, have
to discuss that later. But anthropologists have argued that this would have been the ancestral state. And that when modern humans left the trees and went into the savanna there would have been selection for decrease in body hair and increase in sweat glands for thermoregulation. And then there would have been
selection for darker skin. But we’ve shown that both dark and light alleles variants have been around for a long time. So, we don’t know exactly how
darkly pigmented they were. And the last point I’ll show is another outstanding question has been, what accounts for the dark skin color in South Asians and Australo-Melanesians? At the regions we studied, we found that they had the identical variants that we found in Africans suggesting they were introduced by migration. But it’s still an outstanding question whether they have other
variants that play a role? So how do we proceed in the future? We need to include more
ethnically diverse populations in studies of genomic
and phenotypic variation. We need better computational approaches to infer complex demographic histories. And identify targets of natural selection particularly for complex traits. And we need better
functional genomic approaches to identify causal genetic variants that are influencing these traits. And I will just stop by thanking
everybody who contributed. (audience applauds) (upbeat ,electronic music)

About the author


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