[ Music ]
>> G6PD also in Mediterranean
climates gives resistance
to malaria-- the
Duffy blood group.
The blood group molecule
on the surface
of the red cell is the
molecule used for vivax malaria
to infect the red cell.
And so Duffy null is essentially
fixed in Equatorial Africa.
Not in Southern Africa.
The Kwazan do not have it.
They don't have a
malarial environment.
And it's extremely rare
out of Africa basically
until more recent migration,
the gene didn't leave Africa.
I just mentioned lactase.
Alcohol dehydrogenase that I've
worked on also shows evidence
of the selection and I'll
come to that in a bit.
So many others are candidates.
So here are samples that we
study in our lab at Yale.
It's taken over 25 years
to accumulate where it's
about 2800 individuals from 57
populations around the world,
all are transformed
lymphoblast cell lines,
which in itself is
a major effort
and so we have infinite
amounts of DNA on these.
We can just thaw another
ampule of cells out, grow it up
and isolate more
DNA if we run off.
Purified DNA is not finite.
It's a very, very
stable molecule
but it doesn't survive a
student dropping the tube
on the floor [laughs].
So, notice we're reasonably
decent in this part of Africa
and some in Eastern Africa,
nothing here, nothing here,
nothing here, we're sort
of okay in the Middle East.
We've got a fair number of
European samples only one Indian
and look at the huge part of the
world where we have no samples.
Right along the coast of Asia,
we've got lot of samples.
When you talk about Asians,
most people are talking only
about a few of these populations
but all of this is Asia.
We've got some Melanesian
and Micronesian,
a few North American and South
American natives obviously
because this is all
funded by NIH.
We have European-Americans
and African-Americans
but for anthropological studies
they're not of much value.
So just remember, when
you see things like this,
it represents a subset
of human variation
that is not randomly selected
from around the world.
But, notice one--
the bootstrap values
for every red dot are
a hundred percent.
The bootstrap means, if
we scramble resample,
draw another tree, 100 percent
of the time the populations
on one side of that segment
of the tree are separated
from the populations
on the other side.
It doesn't say they're always
in the same order up here
but 100 percent of the time
the tree can be divided
at that point signifying highly
significant genetic difference.
So lots of those red dots
among the African populations
and the length of the
segment is proportional
to theoretically evolutionary
time divided by population size.
So related to genetic
drift modified
by migration between
populations.
So even though there are very
small differences up here
between the Yoruba
and Igbo from Nigeria
who are two Bantu-speaking
groups and the Hausa
from Nigeria which is
not Bantu-speaking,
it is still a highly significant
genetic difference albeit small.
And it's based you can see
on a lot of DNA markers,
a lot of time collecting
the data.
The Middle East, Ashkenazi Jews
fall in there as due the Druzes
and the Yemenites
and the Samaritans.
Everybody know who
the Samaritans are?
The Christian, New Testament,
there was the Good Samaritan.
It's come to mean good,
there are medical outfits,
hospitals called Samaritan
without the good on it.
But it-- he was just a good
man from the Samaritan tribe.
That tribes still exists,
reproductively isolated
at least since biblical times.
A hundred years ago, there
were only a 100 left.
The population is
currently around 5 or 600.
Reproductively isolated
lots-- a small population,
lots of genetic drift hence
a long branch in this tree
but clearly anchored
in the Middle East.
Then we come to this group.
If you've seen one European,
you've seen them all.
There is virtually, well here,
there is no highly significant
variation among these Europeans.
At some low side there is
very highly significant
but overall, there isn't.
Then a lot of difference as we
think about human expansion,
what are we doing here?
We're going from the
Ethiopians out of Africa,
huge loss of genetic variation
into the Middle East branching
in one direction into Europe,
branching in the other way
across Asia up into Western
Siberia out of Central Asia
into the Americas and into
Eastern Siberia into the Pacific
into the Far East of Asia.
So this fits basically
what we can infer
from many other aspects of
anthropology and archaeology
of how humans spread
around the world.
We can look at the
same individuals
in a principal component
analysis trying to plot them.
Again, here we have Africa
with the pygmies coming
through here are
African-Americans,
the Ethiopian Jews.
Here we have Middle
East to these squares,
Europe then we're branching
sort of into Siberia,
here's East Asia, the Pacific,
here are North Americans
and South Americans.
Notice, Native Americans
didn't come from Far East Asia.
>> They are not closely
related to Far East Asia.
It's a very independent set of
migrations and differentiations.
Now, along the lines of
their being no races,
genetic variation is distributed
in a very quasi continuous way.
Here are genetic distances
from the two populations
furthest away in that tree
that I showed two slides
ago, the Mbuti pygmies
and the Karitiana
from South America.
And here is how each one relate
to every other population.
So here is the Mbuti, identical,
here are the other pygmy
and then the other Africans are
similar, we get to Ethiopia,
we get out of Africa, Europeans
and then here we're into some
of the Pacific then East Asia
and here are two
Pacific Islanders
and then North America
and South America.
And here coming the other
way, from the Karitiana
to the other Native Americans
very similar then jumping
into the Pacific, these are
a tile from the Eastern side
of Taiwan-- the aboriginals
on Taiwan.
Then East Asians like
Melanesians, Micronesians,
Europeans, Middle East and
then the Africans again,
sort of in the reverse
order from closest
to the Middle East
into the pygmies.
So yes, there's some
discontinuity or large jumps
but we don't have many
populations intermediate
in those regions which
might make things smoothly.
So here is just the
rainbow example
of why I think the U.S.
is so absurdly focused
on race and classifications.
Our country was founded
by Native Americans
but I've only got
three dots here.
But if-- even if we
ignored Native Americans,
we have founding populations
from Western Europe initially,
not Eastern et cetera, from
West Africa not East Africa,
and from Far East Asia
coming from California,
there are huge Chinese
and Japanese communities
that started with the gold rush
days and building the railroads.
Those look very distinct
if you just look
at those far distant
populations.
But there's a genetic
gradient between them.
So it's this disparity of
sampling that I think gives
so many people the idea plus
the confusion of culture
with biology that there
are distinct races.
Of course there are differences.
As I mentioned early,
the expectation,
allele frequencies
will be different
in different populations.
Primarily we think random
genetic drift that accumulated
as small groups of people
advanced as we spread
around the world to occupy
it or our ancestors did.
Some genes in some parts of the
world have changed more recently
and I'm sure, we're
still evolving.
But most of this variation
is normal even genes
that give different
enzyme activities.
I've studied
Catechol-O-methyltransferase.
It's thought be associated
with risk
of various psychiatric
disorders.
Maybe associate with risk
but there are probably all
three genotypes for the rapid
versus slow alleles at
this locus in this room.
Because while it may
be an increased risk,
it's still only a
small difference
between having the susceptible
form and not having it
in neither case is
the risk very high.
So that's part of what
gives us differences.
I mentioned here hypertension,
that's also a difference.
There's only one reason and I
don't have the example here.
A finding of one particular
gene that seems to be the cause
of the African American high
risk of kidney failure compared
to any other population.
And it's a gene that
occurs at a 20--
20 percent frequency in
Africa and a high frequency
in African-Americans and is
almost entirely the explanation
because of the very high risk
of kidney failure if you have
that particular allele.
Now, here are three
examples of high FST markers
that are very good ancestry
informative markers.
So we have DARC.
That's the official locus name
for the Duffy blood group locus
and the allele that
gives resistance
for vivax malaria
essentially fixed in Africa
and virtually absent every place
else where we do see it in,
here, c'mon-- here we see
it in one Maya individual
and I'm not sure
who those two are.
But we know Native Americans--
current Native American
populations have
in many cases a small amount of
African admixture because that's
where escaped slaves went.
The orange is one of
the skin color alleles.
And presence of this allele
is strongly associated
with lighter skin color.
It's associated biologically
with transport
of melanin granules so there's
a clear biological relevance
and the ADH1B, this gray is
a rapid metabolizing form
of alcohol dehydrogenase
and at least in East Asia,
it is strongly associated
with the flushing reaction
and I'm sure all of you have an
Asian friend who with three sips
of wine starts turning
bright red.
Here is another way of
representing variation,
each little triangle is where
a population has been studied
and these are data in the--
from the ALFRED Database.
Does it make much difference
whether you have wet
or dry earwax?
But there is a genetic
variant that determines that.
>> A quick go through
because I've studied alcohol
dehydrogenase a lot.
Here are three variants
in the same gene.
They tend to occur on different
chromosomes except the two green
ones almost always occur
on the same chromosome,
the two variants.
So you see the--
at least in Europe,
the two greens are super imposed
but then they become
different in East Asia.
They're not on the
same chromosomes.
The orange is a variant
that's African specific.
Another gene in the
complex here,
the two pink variants are all
around the world essentially
on the same chromosome,
both amino acid substitution
and you can see,
they're up to 50 percent
in many parts of the world.
They have differences in how
rapidly you metabolize ethanol
and yet they're perfectly
normal but they vary
around the world
in their frequency.
Two other of the metabolic genes
where again you can see there
is significant variation
around the world for that
promoter variant, the light blue
and the other two shows some
variation around the world
with one of them essentially
fixed showing no variation
in East Asia.
And so, here is another one
of these frequency plots
of this rapid metabolizing
form I showed you earlier
in cross section.
But here, it's been
studied in maybe a dozen--
no, a hundred different papers,
we've accumulated the data.
So every little red
triangle is a data point
and you can see there is a
very high frequency greater
than 40 percent along Far
East Asia and another section
of high frequency
in Southwest Asia.
And the second enzyme in the
alcohol metabolism pathway,
aldehyde dehydrogenase-2
has a null allele
that is very locally defined
only in Far East Asia primarily
in South-Eastern Far East Asia.
And that's the one that
really is the primary cause
of the flushing reaction
because it slows down
and in the homozygote
blocks degradation
of the intermediate
product which is alde--
acid aldehyde atoxic
and the accumulation
of the toxin gives rise to
the physiological reaction
of flushing and nausea
and headaches.
All of the students in
my lab who have worked
on this project have been
of East Asian origin.
They've understood the
phenotype very well.
So that's a bit about variation
and geographic variation.
What about what a
person looks like?
So there are four primary skin
color and eye color genes,
there are many more but
four have been studied most.
The golden, the MATP
ocular albinism 2
and melanocortin 1 receptor,
they're all expressed in skin,
affect the processing of
melanin, melanin granules
and in some cases they're
homologous to genes
and mutations in the
other individuals.
And here are how the four are
distributed around the world.
Do you notice a Eurocentric
aspect of this?
Well, where most of the skin
color studies have been done
and so this is something
in population genetics,
we have to be very conscious
of that there is a
strong ascertainment bias
for European ethnicity
because that's where most
of the research has been done.
Even in the US,
European-Americans are
by far the most commonly
studied population.
So all of these are polymorphic
in all of these populations even
in Europe but they have
different distributions
and consequences.
Let me skip that.
Just before we break,
let me just mention one
of the resources on the
web, are you familiar--
have any of you come
up with the University
of California Santa
Cruz, Genome Browser?
It is great.
It's free.
It's online.
It's fast.
It can do hundreds of things
that I don't know how to do
but it's very good if you go in
and I just typed in to search
for ADH1B and here is
a schematic of the gene
with the introns and
exons and the three prime
and translated region and
sequences that are available
from other organisms across
the comparable region.
One can zoom in on
a small segment
of DNA here near the
three prime translated--
no this is one of the introns
and get the actual sequence
in all the other individuals,
find out about polymorphisms,
tremendous amount
of information.
So if somebody talks
about a gene
and you want a little
information, that's probably one
of the first places to go.
So let me take a little break
and see if there are questions.
[ Pause ]
>> I should have said you can
stop me at anytime if you want.
If I haven't explained anything
and that will apply
going forward.
[ Pause ]
>> Can I ask a couple questions?
>> Yes.
>> I noticed that you
have samples that you used
that you were talking
in the sort of may --
interested in, do
you mind if I ask you
about your standards
in particular?
>> No.
>> The Mexican sample
that you used is made
of up of 21 individuals.
How diverse is that from across
Mexico do you know off hand?
>> We have two samples
from Mexico.
We have a sample of
Mexican Pima where--
>> For individuals or something?
>> Yeah. We actually have some
children but they're related,
those are the unrelated.
We have a sample of Maya from
the Yucatan and they come
from one village
in Campeche State.
They-- our understanding
is that that area when one
of the revolts of
Native Americans
against the Spanish
government occurred
that area was a refuge
area for a lot of Maya
from across the Mayan region.
So how well it represents
the region more broadly,
we do not know.
But it was only one relatively
isolated village in the middle
where most of their people
had been raised nearby
and their parents and
grandparents were from nearby.
>> How well do those two
populations represent variation
of Native Americans in Mexico?
Not well at all.
But it's all we've got.
Would I like to see more?
Yes. Most Mexicans are fairly
significantly admixed these days
so we've tried to get
relatively unmixed populations
and our tree structure
argues we've been
relatively successful.
But on the other hand we know,
in our Mayan sample we have seen
alleles we've only otherwise
seen in Africans.
Or only otherwise
seen in the European,
the same with our Quechua
sample, they're not African
but European and yet, in those
few instances we've seen these
its been in different
individuals
and they don't know their--
probably don't know
they have this
in their ancestry 'cause it was,
you know, how much do you know
about your five generations
ago ancestors.
Yeah?
>> I may have missed this part
but you said the Native American
did not come from the Strait-- ?
>> No. I said they didn't
come from Far East Asia.
>> Far East Asia.
>> Of course they came out of
Central Asia or a root more
in Central Asia went north
clearly they crossed Meridia.
And there is clearly a cline
of variation from North
to South even within the Native
Americans as they spread.
>> I'm just curoius
because the --
is it the allele,
not the allele.
But the gene that
has the -- alcohol?
>> Yeah.
>> Was that for the
Native American population?
>> No. No.
>> Oh. Is it the
alcohol tolernace?
>> No. No.
>> Okay, I must be getting that
confused with something else.
Because I thought
that was also common
in Native people --
Native Americans.
>> Not those alcohol
dehydrogenase variants.
>> Okay.
>> I-- We identified
other variant
that is only in Native
Americans.
We don't know what its
functional consequences are.
>> Okay.
>> It hasn't been
studied in that sense.
>> Just two questions
on migration then.
What about the possibility
of by some
of those ancestrial markers --
what about some sort
of Micronesia
or some Pacific Islanders
getting
from this normal whatever now
went over to the Americas and --
I assume that decline that
you mentioned progresses
from Europe, I'm sorry from
the Egypt, from the North
with just Africans not
across and then from.
>> Correct.
>> Okay. And the other is
for how long do you think the
African continent was basically
sitting there and brewing before
it finally burst out through
with that -- what, an ice age
ending and then they migrate
after how many hundreds
of thousands of years?
>> Around 100,000 years ago
the sea level was lower.
It was one of the
more glacial maxima.
And so it's not clear
whether it would have been
up through the Sinai
or across the bottom
of the Red Sea or both.
We just don't have fine
enough distinction genetically
to be able to do that
because too many things have
happened subsequently.
It's not at all clear
that the transition
to Homo sapiens resulted
in a major bottleneck
in genetic variation.
We've look at one locus
where the coalescent,
meaning the point at which
current alleles would have had a
single common ancestor is
approximately 800,000 years ago.
So that means that even 200,000
years ago there was probably
residual polymorphism
at that locus
in the Homo sapiens population.
And the genetic variation
is very high in Africa and--
but it's high within
every population not just
among populations.
And so in a sense, there's
an element of homogeneity,
the same variance occur all the
continent slightly different
frequencies which is why
things are so similar and
yet across many loci,
it highly significant.
[ Music ]
