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- [Announcer] 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.
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- 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 originate in Africa?
What was their demographic history?
And how did modern humans adapt to changes
in environment and diet during human evolution?
So let me 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 originate 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 years,
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 and Australo-Melanesia,
in addition to a northern route,
and what were the source populations in Africa?
Now, as you just heard from Ann,
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 populations 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,
that 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 field work in Africa
for the past 18 or so years.
We're collecting biological samples
from blood, DNA, and RNA and 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 could 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 had 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 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 diverged
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 lactose tolerance, we showed evolved independently
in East African pastoralists, relative to Europeans.
And as you heard Ann 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 levels.
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
to sunlight, and we look at the reflection
and the wavelengths, the light that's reflected,
and from that we can infer the melanin levels.
And what we find is, the San,
who have 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 four 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 of significance.
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 variance associated
with light skin color, or that blue, I should say,
are 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 ranged 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,
and 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 skin
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 its, became gray.
So basically, what we find is that Africans
have lower levels of this, and darker skin,
and then it has the opposite effect on pheomelanin,
which causes more 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 ancestral 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 that association was at DDB1.
This plays a critical role in DNA mismatch repair
and response to UV, so if people have mutations
in the proteins that this interacts with,
they have a disease called xeroderma pigmentosum.
They can't be exposed to the 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,
at 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.
Variants 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 the influence,
the expression of the OCA2 gene.
But we also found a variant within OCA2,
within axon 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 in 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 wanna 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 this poor chimp lost its hair
due to a skin disorder, but has relatively light skin,
although I did seem some images earlier
of darkly-pigmented chimps.
I don't know, we'll 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 thermal regulation,
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
and 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 applauding)
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