- Welcome everyone,
to the 43rd annual Darwin festival committee
with tonight's speaker being Dr. Sarah Tishkoff.
I will hand the microphone over to my colleague,
Dr. Jason Brown, to make the introduction.
- Welcome to Salem State, students,
faculty, staff, and alumni.
And to our visitors and our speaker, Dr. Tishkoff.
Sarah Tishkoff has a Bachelor of Science
in Anthropology and Genetics
from the University of California, Berkeley
and a Masters in Human Genetics,
and a PhD in Genetics from Yale University.
She's the David and Lyn Silfen University Professor
in genetics and biology at the University of Pennsylvania,
and is director of
the Penn Center for Global Genomics & Health Equity.
She's a co-author of over 130 publications
with a primary focus on African genetic diversity
and human health.
Dr. Tishkoff is a member
of the National Academy of Sciences,
where she's on the board of global health,
and she received
a National Institutes of Health Pioneer Award
along with multiple other prestigious awards.
And she's on the editorial board of several top journals.
So my students and I are particularly excited
that Dr. Tishkoff was able to join us this semester
during the inaugural run
of our new genetics of human disease course.
So with no further delay Dr. Tishkoff.
- Well, thank you so much for that excellent introduction.
Lemme just get my slides up.
Let me put it on presenter mode.
I have to say that it is a particular honor to be giving
this talk today in honor of Charles Darwin,
whose birthday is just a couple days away.
And I thought I would start by talking about what I think
are some of the key challenges in human genomics research.
And that includes that we need to do much better job
characterizing genomic and phenotypic variation,
ethnically diverse humans.
What do I mean by phenotypic variation?
Just that could be normal, trade variation or disease risk.
We wanna understand the evolutionary processes
that generate and maintain that variation,
and to understand gene-gene, gene-protein,
and gene-environment interactions and how they contribute
both to normal variation and disease risk.
The focus of our research is on Africa,
and there are number of reasons for that.
One of which is the fact
that all modern humans originated in Africa.
These red dots represent the locations
of fossils of anatomically modern humans.
The oldest of which is dated to about 300,000 years ago.
We also have some archeological evidence
for early modern humans from early modern humans.
So for example, this is from a cave in South Africa,
and it was one of the earliest examples
where you could see that they,
somebody has etched into this stone.
And that was around 70,000 years ago.
And then this was pretty neat.
They found what they call
an artist toolkit in the same cave,
but it was actually dated to a bit earlier
around 100,000 years ago,
and they found some pigments in there,
which indicated that they were using the shell to mix up
pigments either for cave painting,
or for painting their own bodies.
So after this origin in Africa,
somewhere around 50 to 80,000 years ago,
relatively small numbers of people migrated out of Africa
and across the globe.
And when they left Africa,
they ran into archaic populations
like Neanderthals and Denisovans,
And we now know that they interbred to some small extent,
such that somewhere between about two to 4% of the genomes
of people outside of Africa are actually derived
from those archaic populations.
So how much do we differ at the level of our genomes?
So identical twins should have no differences in theory.
If we compared the genome, all the genetic material
in the nuclear part of your cell in the nucleus,
then we would differed about one out of 1000 sites,
approximately, nucleotide sites.
If we compared our genome, switch it,
we differed about one out of 100 sites.
And if we compare it to a mouse, it's about one out of 30.
And if we compare it to broccoli,
it's about two out of three.
So given that there are about 3,000,000,000 DNA bases
in the genome, that's about 3,000,000 differences
between genomes, between different individuals.
Now, I like to use this slide.
It's sort of funny.
I say it's a representation of ethnic diversity
amongst beautiful people, but even amongst the rest of us,
there's less than 0.1 divergence or differences
at the genome's wide level.
And that's reflecting this very recent
common ancestry in Africa.
Now there are other types of variation in the genome.
We can call them structural variants.
So there could be chunks of the chromosome
that are inserted, or deleted, or moved around.
Those are not super well characterized.
They actually could be contributing
to a lot of variation between individuals,
but we still have a long way to ago to characterize those.
But every study for the past 50 years has shown consistently
that the majority of genetic variation in humans
is within populations, 85%,
relative to between populations around 15%.
Again, reflecting this recent African origin.
So why should we study African genetic diversity?
Well, one is to reconstruct human demographic
and evolutionary history,
to study the African diaspora and African American ancestry,
to study the genetic basis of susceptibility
to both communicable and non-communicable diseases.
For example, malaria and TB are very common in Africa,
but increasingly diseases like type two diabetes
and hypertension are also on the rise,
particularly in urban areas.
And to understand things like differences in drug response
that could contribute to precision medicine.
And yet there's a major bias towards Europeans
in genetics dataset.
So this is actually from a dataset
where they look for genetic associations with disease.
And from that dataset,
we could see that about 80% of the individuals included
are of European ancestry.
About 10% are of Asian ancestry.
2% are of African ancestry,
about 1% Hispanic ancestry and less than 1% everybody else.
And that's really a problem both in terms of learning about
our human evolutionary history,
but also in terms of more equitable healthcare,
I would say, and health benefits.
So I wanna tell you a bit about Africa.
There are over 2000 ethnic groups in Africa,
speaking languages that have been classified
into four major language families.
In blue, I'm showing the distribution of languages
that have been classified as Afro-Asiatic.
These are mainly in Northern and Eastern Africa.
In red is the distribution of populations
that speak Nilo-Saharan languages,
mainly in Central and Eastern Africa.
These groups tend to be pastoralists,
so they raise cattle and they drink milk.
An example you might have heard of are the Maasai.
The most widespread language family is Niger-Kordofanian,
or Niger-Congo that originated in Western Africa,
and the largest sub-family, sub-language family,
I guess you could say,
are the Bantu languages that are thought
to have originated around along the border
of Cameroon in Nigeria.
So these populations had developed iron tool technology,
and something called slash and burn agriculture.
So they were very successful at cutting down the forest,
growing crops, sustaining large population sizes.
And somewhere in the past 4,000 years or so,
they migrated to the east and then to the south,
and to the west and to the south.
Then they interbred with local populations,
and have really shaped the genomic landscape in Africa.
And then in green, we see populations
that have been labeled as Khoisan.
These are groups that speak with the click.
They would include the San population from Southern Africa,
who until recently have been living
a traditionally hunting and gathering lifestyle.
And then in Tanzania, there are two groups,
the Hadza and the Sandawe who speak with clicks
and also practice a hunting and gathering lifestyle,
at least until recently.
So all of this research has been done in partnership
with a number of faculty in different countries in Africa.
And I'm gonna show you a little bit
of what the field work is like that we've done.
So we are mainly studying genetic diversity from groups
that are minority populations in Africa.
So they tend to live in more rural areas.
It can be challenging to get to these groups,
requires bringing a four wheel drive vehicle,
we have to bring all of our supplies with us.
Here you can see,
this is sort of how we're doing
the biometric measurements that we look at.
This individual in the upper right and the lower left,
these are members of the Hadza tribe who speak with a click
and this woman in the upper left,
she speaks Nilo-Saharan language and practices pastoralism.
This is from Botswana.
You can just see some of the ethnic diversity.
And this is a more recent expedition to Cameroon.
Some of our colleagues from
the University of Yaoundé Medical School
and people in my lab who have contributed to this research.
So this can be very challenging.
This is just one example of challenge we face,
getting up these roads
when they're just completely muddy.
I remember this bridge in Cameroon and it would terrify me.
I just was like so scared
that we were gonna go crash into the river.
And then the other thing in Cameroon
is that they have these giant logging trucks,
and when they're in front of you,
they're going like 5 mph and you wanna pass them,
but on the dirt roads, they're kicking up all this dirt
and you can't see.
And then when they're behind you,
they're going like 100 mph and it's really scary.
When we do this research, we are particularly careful
to do this in an ethical manner.
So that means that we go through ethical review
and we get IRB approval at our university in the US,
but we also have to go through many rounds of ethical review
in each country until we get a research permit.
We also spend a lot of time having community discussions,
we explain the project in layman's terms,
we translate into the local language,
we talk about the risks and the benefits if any,
it's only after getting community consent
and ultimately individual consent
that we proceed with the research.
We also think that it's really important
to return results to participants,
and this is a way of benefit sharing.
Training and capacity building is also really important
and I've had the honor
of training a number of grad students
and post-docs from Africa.
So in these populations, we're mainly obtaining blood,
and from blood you can get DNA and RNA and plasma.
We also look at fecal samples,
so look at the gut microbiome,
we get detailed ethnographic information,
information about diet,
any health information that they may have.
And then we have to process
these samples without electricity.
And so what we typically do now is just bring a generator,
as shown in the lower left, out to the bush,
and we can just set up our lab anywhere.
So we also are measuring phenotypic variation
in whatever we can do in a noninvasive manner,
in a very rural setting.
So this includes very detailed anthropometric phenotypes
like height and weight and limb length,
and we have looked at cardiovascular, lung
and blood phenotypes, like blood pressure for example.
We look at metabolic function, lactose tolerance,
glucose tolerance and infectious disease status when we can.
And then we are using different types
of Omex technologies in my lab.
We integrate these together and also look at the impact
of diet and other environmental factors
and how those are influencing
both normal variable traits and disease risk.
So I wanna tell you first about a paper we published
a number of years ago that looked at highly variable,
they're called Microsatellites short tandem repeats.
There are little repeats of two to six nucleotides,
an example would be CA, CA, CA, CA,
repeated multiple times, and they're highly variable.
These are what are used, for example, in forensics,
because they're so variable,
they're really good genetic marker.
And we looked at this in over 2,500 African
from 121 ethnic groups shown here,
and in '98, African Americans from four regions in the US,
and then a large comparative data set
from non-African individuals.
So I first wanna show you this slide is representing
a measure of genetic diversity,
and it's color coded by geographic regions,
so we could see that the most genetic diversity
is in Africa.
We see decreasing diversity as we go west to east,
across Eurasia, into East Asia, Oceania and the Americas.
And that's reflecting that migration I told you about.
So when people, when ancestor...
When people left to Africa and there was a bottleneck,
you see a loss of diversity,
and then as they go into different areas
like into Oceania or into the Americas,
again you see a series of founding events.
This is a phylogenetic tree.
You can't see any details.
I'm just gonna point out the general trends.
And it's constructed by estimating the genetic distances
between pairs of populations.
So at the ends of each of these branches is a population,
the branches are color coded according
to the language spoken in Africa.
These are the African populations,
and a pair of the non-African populations.
And we could see that at the root of this tree,
the most basal lineages
are those from the San hunter-gatherers,
from Southern Africa,
followed by so-called Pygmies,
Central African hunter-gatherers,
and then we see that people largely are clustering
by geographic region.
Western and central Africa, and then here Eastern Africa.
And they generally cluster based on language,
but with some exceptions.
And then we could see that outside of Africa here is India.
This is actually blocked in my screen.
I think it's Central Asia, Europe, East Asia, Americas,
Oceania, and then we have North Africa.
Again, that's consistent with that out of Africa,
model of human origins.
We then used a computational approach
to infer genetic ancestry,
which is represented by the different colors.
So the way to look at this is that,
you could see that this is made up of a bunch of lines
and each line represents a person.
And for each person we've inferred their genetic ancestry.
Think about if anybody's tried 23 in me,
it's similar to the kind of results you get from that.
And what we could see is here, are non Africans,
people who self-identify as European
or middle Eastern are shown in blue.
People from India shown here in the sort of fissure color,
and then we have people from Pakistan, central Asia,
East Asia, Oceania, and the Americas.
When we look at Africa,
you see a lot of colors relative to the rest of the world.
And what that's telling you
is there's a lot of genetic diversity
and a lot of what we call population substructure
or genetic differentiation amongst the populations in Africa
compared to the rest of the world.
Now, if we repeat this analysis just for Africans
and we pool individuals by geographic region or language,
again, you could see all the diversity in Africa
and that populations in Western and Central and Eastern,
Southern and Northern Africa,
are very divergent from each other,
and that even within a region,
there's so much diversity, so much admixture.
You can also look at these faces
and see that there's a lot of phenotypic variation.
And we think that this is reflecting
the demographic history of Africans,
and also their adaptation to different environments.
So, in terms of the African American ancestry,
not surprisingly,
we see predominantly West African ancestry.
We see some European ancestry on average, it's around 20%.
We see small amounts of ancestry from other groups
and a little bit from this Nilo-Saharan ancestry,
which I think is actually representing
a group called the Fulani,
who are very common throughout
sort of the Sahel region in Africa.
Again, this is simply reflecting
the history of the slave trade.
Now, one of the biggest sources
of the slave trade in fact was Angola.
And I'll just point out that we currently know very little
about variation in that region.
It's been a place that,
it's been dangerous, frankly, to do research there.
So there's a lot we still have to learn about,
in terms of both African history,
and African American ancestry.
So I now wanna tell you about a study
that was done by a former post-doc Shauhua Fan,
in collaboration with
the Simons Genome Diversity Project and David Reich,
and we sequenced 94 individuals from 44 African populations
at the whole genome levels.
So sequencing the entire genome,
and from that, we could construct again,
one of these phylogenetic trees
and it's consistent with what I showed you before,
the San have the most ancestral lineages,
followed by the Pygmies,
and then we see clustering mainly by geographic region,
non-African would be up here.
We can also use computational approaches to make inferences
about changes in the effect of population size,
going backwards in time.
And what's interesting.
You can just ignore all the stuff that's really recent
because this method doesn't do very well for that.
But we could see that we start seeing divergence
around 250,000 years ago,
close to the fossil evidence
for the origin of modern humans.
And that in the past,
the San in the Pygmies have maintained
the largest effect of population size,
even though today, they have a relative small census size.
We can also estimate
when populations diverge from each other.
And we see that the earliest divergence is the San
from all other groups,
could have been as early as 160,000 years ago.
We see divergence between the San
and some of these other hunter-gatherer groups
like the Hadza, the Sandawe and the Pygmies,
around 70 to 85,000 years ago.
We see divergence between Niger-Kordofanian speakers,
Afro-Asiatic, Nilo-Saharan speakers,
around 16,000 to roughly 35,000 years ago.
But even amongst some of these San populations
that speak slightly divergent languages,
they are estimated to have diverged
as much as 30,000 years ago.
So again, it's consistent with this history
of sub-structure populations, having been separated
for a long period of time,
but with a lot of migration and admixture between groups.
I wanna tell you just a little bit
about phenotypic variation
for some of the traits that we've studied.
And this is work that was done by Matt Hansen in my lab.
And we are looking at groups that have very different diets.
So hunter-gatherers have a diet that's heavy,
in nuts and tubers and fruits to a lesser extent, meat,
pastoralists have a diet heavy in milk and blood,
and to a lesser extent meat
and the agriculturalists have a diet
heavy in grain and maize, fruits, and tubers.
So here we have,
these are different populations
we're actually just looking at the data from women here,
and they've been color coded according
to the subsistence pattern.
And we could see if we look at height, for example,
at the very, the short end
are these so-called pygmy populations,
and at the very high end are some of the pastoralist groups
and some of the food producing agriculturalists.
At the low end for BMI,
are some of the East African pastoralists.
They tend to have very tall and thin body types.
And at the high end are some of the agriculturalists.
If we look at waist circumference,
we could see at the very low end
are actually the San populations
and at the higher end are some of the food producing groups,
and percent body fat, we see a similar trend at the high end
or the food producing groups in the Herero.
So this is a Herero woman.
This ethnic group lives in Southern Africa.
They speak a language related
to these neighboring agriculturalist groups, and in fact,
they came from that Bantu migration that I mentioned.
But they consider it culturally desirable
for women to be very heavy.
They see it as a sign of fecundity.
So I wasn't an entirely surprised to see this result.
So now for the last part of my talk,
I wanna talk about our studies
of the genetics of adaptation.
And I love this quote from Charles Darwin's classic book,
"On the Origin of Species",
and he says, "This preservation of favorable variations
"and the rejection of injurious variations,
"I call natural selection."
So what I'm showing here
are different examples of how people have adapted
to different environments
and different diets across the globe.
You might have heard for example, of Sickle Cell Disease,
being common in people from Africa,
where there's a lot of malaria
because people who have one copy of a sickle mutation,
and one of the normal copies,
are actually protected from malaria.
So this variant remains in the population.
But the example I'm gonna tell you about right now
is the genetics of lactose tolerance.
The ability to drink milk as adults.
So the ability to drink milk is due to the expression
of a gene that codes for lactase,
actually Lactase-phlorizin hydrolase,
and this enzyme breaks down the sugar lactose
into glucose and galactose,
and those are rapidly taken up into the bloodstream
in people who can digest milk.
But in people who can't digest milk shortly after weaning,
we can see that they are not able,
they're not expressing this,
they're no longer expressing lactase after weaning,
and so they're not able to break down that sugar.
It's gonna go to the lower guts,
it's gonna cause severe intestinal distress.
And interestingly, I mean,
anthropologists have noted for quite some time,
that the ancestral state is actually lactoses intolerance
and lactoses tolerance, the ability to drink milk
as an adult is a drive state.
It's an adaptation.
And we see that it's most common
in Northern European population.
It's a little bit less common in Southern Europeans.
It's very uncommon in East Asian populations.
And it's uncommon in most African populations,
except for those who practice during who are pastoralists.
So we wanted to understand the genetic basis of this trait.
And so starting in, I think it was 2002,
we gave what is called a lactose tolerance test.
So giving the sugar lactose,
and then every 20 minutes measuring the blood glucose
using like a diabetes monitoring kit.
And as I said,
this is every 20 minutes over a period
of a little over an hour,
and then we look at the maximum rise in the blood sugar.
And according to the medical literature,
if you have a rise that's greater than 1.7 millimolar,
then you're lactose tolerant,
if it's less than 1.1, you're lactose intolerant,
and some people are something in-between.
Now around that time,
there was a beautiful study done by a group in Finland
that had identified a mutation
associated with lactose tolerance in European populations.
And it was in an intron and non-coding region
of this neighboring gene and a regulatory region.
So we sequenced that region in the Africans
and we didn't see it.
We didn't see the same mutation that's found in Europe,
but we saw three other variants that were associated
with lactose tolerance, and as I said,
they arose independently from the European mutation
and they have an interesting geographic distribution.
The common variant in East Africa
is at position minus 14010.
This variant in the Middle East
is at position 13915,
and we think it was introduced into Africa by migration.
And then this variant at position 13907,
is common in the Horn of Africa.
We also wanted to see if there was a genomic signature
of natural selection.
So we use something called
an extended haplotype homozygosity test.
What is that?
Well, basically, this shows you what the process looks like
or what you might expect
under a very strong recent selection.
So here are some, this is,
let's say it's around the lactase gene
or the regulatory region,
and there's some variation in that region,
and a mutation arises, and in this case,
it's the variant that's associated with lactose tolerance.
And if it increases the fitness of the individuals,
so they have more children,
and their children have more children,
it's going to rapidly rise to high frequency
in the population, as shown here.
And when that happens, it's dragging with it,
the neighboring variation,
and that actually can go on for millions of nucleotides.
And so this is what we see,
is that in red I'm showing individuals who are homozygous.
They have two copies of the C variant
that is associated with lactose tolerance.
And we could see that there are homozygous going out,
almost 3,000,000 nucleotides.
If we compare that to people
who have the ancestral gene variant,
we could see that they don't have this kind of
extended homozygosity that it only extends on average,
about 1800 base pairs.
Now, one of the ways you can estimate the age of this
is to look at the breakdown of this,
basically how these red lines are breaking down
due to a combination, every generation.
And using computational approaches,
we can estimate the age of this East African variant
to be around 3,000 to 7,000 years old.
And that's interesting because it corresponds
with the origin of cattle domestication
based on the archeological record,
it's about to have originated in either Sudan,
or the Middle East at around nine to 10,000 years ago,
which by the way we estimated
was the age of the European mutation,
but cattle domestication was not introduced
south of the Saharan Desert till roughly 5,000 years ago.
And so it corresponds really well
with the age estimates that we obtained.
And it's a great example of gene culture co-evolution.
So lastly, I wanna tell you about our study
of the genetics of skin pigmentation.
So it's thought that skin color is an adaptive trait,
in the upper left, these blue dots
are representing the levels of melanin,
that's the dark pigment in skin.
And you could see that it is correlated with UV levels.
And it's thought that
when our ancestors migrated out of Africa,
that there would've been selection for lighter skin,
possibly to promote synthesis of vitamin D,
it's synthesized in the skin in response to UV,
and in places where people are close to the equator
and where there's a lot of UV,
there'd be selection for darker skin to prevent skin cancer
and possibly break down a folic acid,
which is very important for development of the fetus.
So most studies have been done in Europeans,
the study of this trait in Africans,
we use a spectrophotometer,
we shine the light under the arm,
that's an area that's not getting a lot of sunlight,
and we measure the wavelength of the reflection.
And from that we can infer the melanin levels.
And what we see is a big range of variation in Africa.
The most lightly pigmented population are the San.
And remember I told you
that they have the oldest genetic lineages,
and then we see a lot of variation
with the most darkly pigmented people
being the Nilo-Saharan speaking pastoralists
who originated in South Sudan.
Then we did something that is called
a Genome-Wide Association Study.
So what we do is we look at single nucleotide variants,
variable parts of the genome.
We look at millions of them,
in this case, 4,000,000 sites of the genome,
and we look for an association with skin color.
And if there's an association,
then it means that that variable site that you're looking at
is near a causal mutation that is impacting pigmentation.
So we found eight new sites at four regions of the genome
shown here, and I'm gonna just quickly step through.
And this is work that was done by Nick Crawford
and Matt Hansen in my lab.
So the strongest association was at a gene called SLC24A5,
(coughs) excuse me,
there's an amino acid substitution in this gene
that actually, this was already known to play a role
in light-skin color in Europeans.
It was actually the very first gene identified
to play a role in skin color in humans.
It was first identified, I believe, in a zebra fish.
And then they looked at the distribution
in human populations,
and we could see that the variant
associated with light skin, shown in blue,
is at almost 100% frequency in Europe.
It's also really common in Pakistan, in some parts of India.
And you could see it's really common in East Africa.
So we wanted to know,
did that mutation arise independently in Africa,
or was it introduced by migration?
So one of the ways we can do this
is to construct something called a haplotype network.
So what's a haplotype?
A haplotype is just how the different variants are arranged
along some stretch of the chromosome.
In this case, we're looking over 70,000 nucleotides.
Each circle represents a haplotype.
The size of the circle indicates the number of people
who have it, and the colors represent
the relative proportion in different populations.
This is also kinda like a phylogenetic tree in that
these haplotypes are very different genetically
from these haplotypes.
And what we see is that this variant
associated with light skin color
is really common in Europeans,
and it's on this long haplotype background,
which is consistent with recent positive selection.
The East Africans have that variant
on the identical chromosomal background.
So what that tells us is that this was likely introduced
by back migration into Africa.
We think within the past 5,000 or so years.
Now, the second strongest association was at a gene
that had no name at the time that we studied this.
We're the first people to characterize this gene.
It's called MFSD12.
And we found two different associations,
one in a regulatory region,
it's regulating the expression of this gene.
And the other is in the coding region here.
We don't know exactly what it's doing.
It could be altering splicing of this gene
or something else that we still don't know.
So if this variant upstream,
we could see that the variant associated
with light skin color is common in Europe, in East Asia
and in India, in East Africa, and look at the San,
how common it is in the lightly pigmented San.
So we did a number of functional studies
to characterize this and we worked with our collaborator,
William Pavan at NIH,
and he knocked this gene out using
CRISPR-Cas9 gene editing technology,
and it had a pretty dramatic impact
on the color of this mouse.
This isn't a goodie mouse.
It has a sort of brownish-yellowish sort of color
that's actually produced by pheomelanin.
That's the pigment that gives sort of a yellow, brown color.
And when it's knocked out,
you see that this underlying gray color.
So this gene has now been characterized by others.
It's been shown to play a role in the color of, I believe,
ponies and dogs and different human populations,
and has been shown to play a role
in risk for melanoma skin cancer.
Then the third association where two different sites near
a gene called DDB1, and what does that gene do?
Well, that gene plays a really important role
in repairing DNA when it's damaged by UV exposure.
So that's kind of interesting,
'cause there's like this UV connection,
but what does that have to do,
and I was gonna say that,
people who have a mutation in that gene
or in genes that code for proteins
that interact with that gene,
have a disease called Xeroderma Pigmentosum.
They're not able to be exposed to sunlight
because they can't repair the damage to their DNA.
But again, what does this
have to do with skin color in humans?
Well, we don't know,
but the interesting thing is,
when I was looking this gene up,
it turns out that it is the gene
that causes the color of tomatoes.
So it is playing a role in pigmentation.
We just don't know exactly what it is yet in humans.
It also showed a very strong signature of a selective sweep.
So when this variant, the light variant,
was introduced out of Africa,
it rapidly rose to high frequency and those haplotypes,
it drags with it all the neighboring variation.
And so what you see is actually a decrease in variation.
This is an indication of how variable a site is.
And you see a decrease of variation in Asians and Europeans
across a very large region, it's about 500,000 nucleotides.
We don't really see these in Africans so much.
And when you look at the haplotype network,
we see this long, common haplotype.
This is about 200,000 nucleotides,
and very common only in non-African populations.
So here would be the African populations.
We can then construct what's called a gene geneology.
So think of this, if we unwounded,
it's like that phylogeny that I showed you,
and at the end of each of these branches
is actually an individual sequence at that region.
And if the individual, if at that region,
they have the variant associated with light skin,
they have this open circle,
and they have the variant dark skin,
they're shown over here,
and in this particular case,
we could see evidence that there was a rapid coalescence
around 60,000 years ago,
which is around the time of migration out of Africa.
So this is very consistent with the rapid selective sweep
occurring when modern humans left Africa,
we still don't know the reason for that.
And then the last region
was near two genes called OCA2 and HERC2.
Now these were already known to play a role
in skin pigmentation.
And actually there had been mutations found in this,
HERC2 gene that are enhancers or regulatory regions
that influence the expression of OCA2.
And in non-Africans,
they play a role in light skin color and eye color.
But the mutations that we found
arose independently from those,
but we did show that they are influencing
the expression of OCA2.
Now, then we found this other variant
that is what's called a synonymous variant.
It's not causing an amino acid change in Exon 10
in the coding region of this OCA2 gene.
Now it happened to be in a region that had previously
been shown to cause certain mutations
in that region, cause albinism,
but it wasn't associated with gene expression.
What it was associated with was alternative splicing.
So people who have the variant associated with lighter skin
have a shorter transcript that's missing Exon 10,
and it's in frame.
It still codes for a protein,
but it's missing this very important transmembrane domain.
That's gonna really alter the function of that protein.
Now, when we look at this gene geneology,
we could see that it has a very old time
to most recent common ancestor, over 2,000,000 years.
And that's actually a kind of classic signature of what we
call balancing selection.
So balancing selection,
think of it as sort of the opposite
of recent positive directional selection.
It's maintaining different variation
for a long period of time.
So different variants at this region have been maintained
for a very long time, millions of years.
So in summary, what was also interesting is that
for half of these genes, the ancestral variant,
is the variant associated with the light skin.
And when we estimate the age of the derived mutation,
it typically predates the origin of modern humans.
So that means that both light and dark associated alleles
have been segregating in Africa for a very long time.
Now, what does that tell us
about the evolution of skin color?
Well, this poor chimp lost all its body hair.
We could see that it's relatively lightly pigmented.
Now I've been told by anthropologists that some chimps
do have darkly pigmented skin,
but anthropologists have also speculated that
this might have been the ancestral status,
having lighter skin.
And then when are ancestors left the forest
and went into the Savannah there would've been selection
to lose body hair, partly for thermoregulation.
And when they lost that body hair,
there'd be selection from more darkly pigmented skin.
Now, whenever you see these drawings,
they always have like really darkly pigmented people.
But I wonder,
could there actually had been variation for skin color,
even in Africa over the past few million years?
And then another really interesting finding was that
the only other place
where we saw the dark associated alleles,
were in South Asia and Australo-Melanesia.
And those are places where we see darkly pigmented people.
Anthropologists had speculated that this might be
due to convergent evolution,
adaptation to being in a high UV environment.
But we showed that actually these were introduced,
they're on the same haplotype background as in Africa.
So they were introduced during the out of Africa migration
and then they were maintained due to natural selection.
So in conclusion, people often ask me,
are and humans still evolving?
And I would say absolutely, yes.
We've seen an example, certainly at lactose tolerance
where there has been very rapid recent evolution.
And with that, I would just think that many people
who've contributed to these projects
and my funding organizations.
And with that, I'm happy to answer any questions
that you may have.
And I'll leave the slides up for a bit
just in case I need to refer to anything.
- Good evening. This is Dr. Ethegwood,
from biology department.
I'm going to ask the first question.
Wonderful talk, Dr. Tishkoff.
I'm curious to know if you are conducting any studies
on how mitochondrial haplotype affects phenotypic variation,
as seen on low haploble variations.
- Well, that's a really good question.
So we have some mitochondrial genome variations,
so that's the genome inherited
in the mitochondria organelle.
It's circular, small, it's only 16,000 or so nucleotides.
We can actually sequence the whole genome,
but it's only passed on through the maternal lineage.
And so it can be an interesting marker for tracing ancestry.
And so we have done that.
We've used it to look at some of the migrations
and population history in Africa.
But we haven't yet looked at the impact on phenotype.
I think that would be really interesting.
There's actually a guy named Doug Wallace,
professor at children's hospital, which neighbors us.
And he's been doing re search on that for very long time.
And I actually think it would be really interesting
to take a look at that.
- Thank you.
- Dr.Trishkoff, wonderful talk.
I have another question from the audience for you,
and it reads as follows,
since more and more people are tending to have
and develop lactose intolerance, would it be possible
that eventually all of the human population could have it?
- Wait, did you say evolving lactose tolerance?
- Yep, that's what the question is.
- It's certainly possible.
I mean, one thing is that this variant can be introduced
through interbreeding, right, we call it admixture.
And so since we're becoming more and more of an urban,
there are so many urban places
that urbanization is occurring around the world.
And with that comes a lot of admixture.
So you could imagine it gets introduced that way,
but it takes a bit of time for natural selection to occur.
So typically it would only become common if that person is,
if the population is drinking a lot of milk.
So it also tends to co-evolve with culture,
but there are some culture of modifications
that people have made,
so that they don't need this.
So for example, if you make yogurt,
if you ferment milk and you make cheese,
then the lactose gets broken down.
So you don't actually need that.
So in the Middle East, for example, they've gotten around,
they don't have to have this genetic mutation.
I find it fascinating.
Why do Europeans, why Africans have those,
not have the cultural adaptations?
- Let me ask another question from the audience.
This one says, does darker skin in the equatorial region
confer protection against sun damage to DNA?
- Absolutely.
I could tell you that one of the regions
where we do research is in Cameroon.
And when I went to Cameroon,
I was just amazed by how many albinos I saw there.
It's actually something I'm really interested in studying.
What is the cause of albinism being so common in Cameroon?
Like every street corner I was seeing albinos.
And like, you're just not used to seeing that.
Now, I've also met with a number of representatives
of some of the albino organizations and asked them
what some of the problems are that they're having,
there's a lot of problems,
so one is there's a lot of stigmatization
and traditionally they're actually killed at birth
if somebody has an albino baby.
Now in Cameroon they're becoming more and more accepted.
There's actually a chief now
of one of the villages who's albino.
In Tanzania people are maimed and killed
because they believe that
body parts of albinos bring good luck.
It's really horrible.
And I actually hope that maybe through education,
if we could explain to people
that there's just one little change in the genome
that causes this and they're just like them
in every other respect.
But the people that I,
they also have a lot of health issues,
and for example, they get skin cancer in their teens.
Because there's not pigment in their eyes,
they get really bad sun damage in eyes.
They lose their vision early,
often they can't even make it
past eighth grade because of that.
So there are some really serious health consequences
if you don't have that kind of protection.
- Dr. Trishkoff, another question for you,
actually from one of my students,
and the question reads,
do you expect your findings
will eventually alter overall healthcare
when it comes to African Americans and Africans?
- We hope so.
I didn't talk quite so much today about some of the studies
that we're doing, looking at, for example,
the genetics of cardiometabolic traits.
Also looking at genetic variation at genes
that play a role in drug metabolism,
which may be very likely or adaptive.
And so you see different frequencies
in different populations.
So people may actually respond differently to drugs.
And so we do think it's a way to promote health equity,
to promote studies of more ethnically diverse populations.
I actually just started a center for global genomics
and health equity at Penn.
And that's actually one of our goals, is to increase studies
of more diverse populations.
Because if we don't,
they're not gonna benefit from the genomics revolution.
We now know that a number of methods that are used
to predict risk for disease, for example,
have been developed in Europeans,
because that's where all the studies are done.
But they do terribly when you try to predict
risk for disease and other ancestries.
That's just horrible.
So we really to promote equity,
I think we need to promote studies
of more diverse populations.
- Thank you.
- I'll ask another question from our audience.
Could you expand more
on linkage disequilibrium with skin colors,
specifically with your own research and findings?
- Okay, that's a tough one. (laughs)
That's a detailed genetic question there.
I'm not sure the context in which I might have said that,
but, so as an example, let's go to this one,
actually, I think DDB1.
So it would be very similar to what we were talking about
with that pitch of the red extended haplotypes, right?
That the non-random association of variants
is referred to as linkage disequilibrium,
and a number of things can cause it,
but one of them is natural selection,
that when you have this new mutation
and it rises to high frequency,
all the variants nearby are linked to it.
So, we actually see a very similar signal.
There's sort of other tests that you can use.
And we see that at this region actually.
So there is evidence of strong,
positive selection in non-Africans
and particularly in Asia,
like really, really strong signature selection.
And we don't know why.
I think that's an interesting question.
I'm not so sure it has to do with skin color.
These genes are pleiotropic
meaning that they can affect many different traits.
- Dr. Tishcoff, two questions that I'll try to combine.
I think the first part is a sort of
clarifying broad-brush question.
Why are genetic populations in Africa,
so broadly, are varied,
and in your,
you did mention the work that you did in the United States.
And so the second part of the question is,
conclusions you may have drawn from genetic variation
in African Africans versus African Americans.
- So first question in terms of
what's causing all that diversity?
So let's go back, let's go to this slide,
that really, I think nicely illustrates all that diversity.
So, what's causing it is the fact that what,
they arose 300,000 years ago.
So there have been modern humans living
on the continent of Africa longer than anywhere else, right?
So you have a long period of time.
Two is that you've got people who migrate
to different regions.
They may be separated from each other
for long periods of time,
could be due to changes in climate.
So things like the Saharan desert is a major barrier,
and the climate really shifts over time.
There could be cultural difference and so on.
And so they remain separate populations
and they're sort of accumulating differences
and frequency of variants,
either due to what we call random genetic drift,
just random fluctuations or due to natural selection.
And then you've got on top of that though,
all this migration.
So like in orange, this is the migration of the Bantu.
This is representing that West African ancestry.
And you could see how they migrated to the east,
into the south and then admix,
and then the question about African Americans.
Truthfully, we're not right now focused
on studying African Americans.
That was a collaboration.
We looked at variation in African Americans,
in collaboration with some other groups.
There are other people
who are doing studies in African Americans.
There's a lot of interest
in trying to infer ancestry from Africa.
That's very complex.
It has not, in my opinion, been done well yet.
And that's because most of the African American ancestry
is from these groups that are shown in orange.
And they're pretty genetically homogeneous, actually,
if you look at these guys compared to each other,
look at these four populations, right,
and compare them to these.
These guys are,
these populations are pretty homogeneous.
And so it's really hard to know, well,
which population did the ancestry come from?
And the truth is that over time,
because of interbreeding between different people
from different parts of Africa,
you may see that parts of the genome,
one part might be from this region,
another part might be from this region,
another part from this region,
and then as I said, we don't have anything,
very little from Angola.
So we're missing a lot of that,
but also it is really important
there are health implications,
that it's really important to understand both genetic,
but also environmental social risk factors for disease
in ethnically diverse populations to promote health equity.
- Thank you.
- I'll ask another question from the audience.
How do you explain that Mbuti pygmy
speak a Nilo-Saharan language or Central Sudan
and that the Luo of Kenya are genetically Bantu
or West African, yet also speak Nilo-Saharan language?
- What was the part about the Kenyan?
Say it one more time.
- So how do you explain the Mbuti pygmy,
- Yeah, that one with the Nilo-Saharan
and then what was the next part?
- And the next part was, and that the.
- Luo?
- Luo of Kenya,
- Okay, that's what I thought, I just wanted to make sure
- Are Bantu and also speak Nilo-Saharan?
- Okay, so let's look at the Mbuti.
Let's see, here are the Mbuti right here.
And they're a hunting-gathering population
they're from Central Africa.
One of the interesting things about them,
is this looks like shared ancestry with the San.
I find that fascinating.
Now all so-called pygmy populations,
these Central African hunter-gatherers,
now speak the languages of neighboring groups.
And they have been kind of dominated.
It's a really like a cast system.
It's really horrible.
I mean, I have actually spoken
to some of the Bantu speaking populations.
They say they own the Pygmies,
I mean, they really believe this,
it's shocking that this happens today,
but this has actually probably been going on
for a number of thousands of years.
So the Pygmies have adopted the language
of whatever the neighboring groups are.
And my understanding, if you look at where the Mbuti are,
look at this, are really close to where Nilo-Saharans are.
Now, I don't see a huge amount of Nilo-Saharan ancestry.
The Nilo-Saharan ancestry is shown in red.
I've seen a little bit, I'm not seeing a lot,
but it could just be that they adopted the language
of the neighboring people.
Now at the same time,
I will say that some recent research we're doing
showing some very interesting connections with Nilo-Saharans
that there might have been some ancient gene flow.
And we're still trying to figure that out.
Now, the Luo.
All right, let's look at the Luo.
It's kind of cool, Oh God!
I'm never gonna be able to read this.
I know. (laughs)
Here they are.
I actually saw, okay.
Here are the Luo, all right.
So the Luo, that you could see by the red,
they speak Nilo-Saharan language,
but look where they're clustering.
They're right here with all the Bantu speakers.
That is a great example
where there has been so much admixture
that there's been almost a turnover in the genetic variation
it's largely Bantu, but they maintain their language,
their ancestral language.
And that's a really interesting question
from an anthropological perspective.
Why do some populations maintain their language
in the face of all this admixtures and others don't?
So actually that's the tribe that Barrack Obama,
his father was from the Luo tribe.
So anyhow, that's the reason for that.
- Thank you.
- Dr. Trishkoff ,I think we've got time
for two more questions.
So I'll take a flier at one.
Do you have any potential hypothesis
for why there are so many albino individuals in cameroon?
- Oh, I got all kinds of hypothesis.
No proof. (laughs)
I have, honestly, I don't know.
I mean, the theme that I found intriguing is the fact
that there's such obvious selection, negative selection,
against being albino in Africa, right?
You're not, you know, without any intervention,
you're gonna do pretty poorly.
Health wise, you're stigmatized.
They're often killed at birth.
This is about a strong negative selection
as you could possibly have.
So why does this variation maintain?
Some people have argued
that it was what's called a founder event
so that it might have originated in certain Bantu groups
that the founder of those populations had this variant
and sometimes in small populations through random drift,
you can get variance shift in frequency.
So that's one theory,
but the one that I have,
is I think there's some kind of heterozygote advantage.
And that's why when we go back to Cameroon,
we want to study that,
and try to determine what that might be.
- Right.
Dr. Gordon, do you wanna ask the final question?
- I'm gonna ask this one.
Do you think you will ever be able to go
or to plan to travel to Angola in the future
and to study the future into the slave trade
and how that relates to the genetic diversity and evolution?
- Well, it would certainly be great. (chuckles)
I find that there's just so many interesting places to go,
not enough time.
And it partly depends on having partners,
and the safety, and the politics.
I do work in Ethiopia.
I can't go to Ethiopia now because of the politics.
I can't go back to Northwestern Cameroon
because of the politics, so we'll have to see,
but one group that we have studied,
we have done research in Botswana,
and there's a group in the Northwest of Botswana
that came from Angola about 100 years ago,
within the past 100 years as refugees.
So by studying them, we might get a little bit of a clue,
but I think there are other groups, other researchers
who are also interested in that.
- Thank you.
- Well, Dr. Tishkoff
thanks for a wonderfully illuminating talk.
It is.