(click)
(inspirational piano music)
- 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.
(upbeat music)
- Good afternoon.
I think I have the longest title talk of today.
So that's something.
(audience laughs)
Thank you very much to the organizers for inviting me
to come and speak.
Hope you feel better soon, Sarah.
So, we've heard throughout the afternoon that modern humans
overlapped in time and space with multiple hominin lineages.
In one topic that has been of enduring interest is,
was there any admixture that happened between modern humans
and these other groups of humans?
And for a long time, the answer was
well maybe yes and maybe no,
and people debated it pretty vociferously.
And that was largely because the data
to answer that question didn't exist.
And it wasn't until more recently that Svante Paabo's group
in Leipzig on developed and pioneered tools for studying
ancient DNA, and they produced the first
Neanderthal Genome Sequence.
And we finally had the tools to be able to say definitively
whether admixture occurred or not.
And indeed, as Sriram talked about earlier,
all non Africans derive about 2% of their ancestry
from Neanderthals.
And what was even more interesting is a few years later,
this same group published another paper
where they sequenced ancient DNA isolated from a small
fragment of a pinky bone, thinking that it was perhaps
Neanderthal or maybe modern human,
and it turned out to be this entire new branch of humanity
that we now call the Denisovans.
And this is in fact, the first species
to be entirely described by DNA.
And so ancient DNA has transformed our understanding
of human history over the past decade.
And we've learned many things,
like what the distribution of Neanderthal ancestry is
in populations across the world.
And again, we saw this this morning,
but we can see that on average,
individuals outside of Africa
can trace about 2% of their genomes
back to Neanderthal ancestors.
And strikingly, we find a very different picture
for Denisovan ancestry.
So here, we really only find Denisovan ancestry
in parts of the world down here.
Oops, that's not working.
So I'll just talk.
In populations of Melanesian
and Australian Aboriginal origin.
So we have a very different geographic pattern
of surviving ancestry.
And that's great,
we can describe global ancestry proportions.
But studying ancient DNA is still hard.
So my interest in this area
can be traced back to a few years ago,
where we had this idea that,
well, if modern individuals interbred
with Neanderthals and Denisovans,
then maybe we don't have to excavate
ancient DNA directly from fossils,
but we could indirectly isolate Neanderthal
and Denisovan sequences from the genomes of modern humans.
And so we call this molecular excavations.
And I borrowed this slide from a CARTA meeting
a few years ago,
which I think is a really beautiful representation
of this idea of molecular excavations.
And so, literally what we're trying to do,
is develop computational or statistical models
and walk along somebody's genome
and pull out the bits that were inherited
from the Neanderthals or Denisovans.
And molecular excavations are really powerful
because they enable us to identify
the specific DNA sequences that were inherited
from Neanderthal or Denisovan ancestors.
So it's one thing to say something about a proportion,
but when you can actually identify the sequences,
you can do a lot of interesting things with it.
So you can test evolutionary hypotheses.
And you can even start thinking about,
well, what's the influence of Neanderthal
and Denisovan sequences on traits and diseases
in present day populations?
And I'll try to touch on all of this in my talk.
So we've discovered methods to identify
Neanderthals and Denisovan sequences,
and we've applied them to
geographically diverse populations.
We've largely looked at around 2,500 genomes
that are part of a publicly available project
called the Thousand Genomes Project.
But we've also worked with colleagues in some cases,
to sample populations from particular regions of the world.
For instance, Melanesia, where we expect
Denisovan ancestry to be the highest.
And so how much of the Neanderthal
and Denisovan genome persists
in modern individuals?
So if we just represent the Neanderthal genome
as this circle,
when we look across all 2500 people,
we actually recover about 41%
of the Neanderthal genome.
And that's pretty striking, right?
That we're not actually sequencing a Neanderthal,
but we're stringing together these bits and pieces
that survive in modern individuals.
And by doing that, we can find
almost half of the Neanderthal genome.
And that might seem surprising,
especially in light that each of us only carries
a little bit of Neanderthal ancestry.
But the reason this works is that the 2%
of Neanderthal sequence that I have might be
a little bit different than the 2% that you have,
and when we look collectively
across large numbers of individuals,
we can recover a substantial amount
of the Neanderthal genome.
And on an individual basis,
non-African individuals have about
55 million base pairs of Neanderthal sequence
per individual.
And this is pretty similar across populations.
So East Asians, South Asians, Europeans
and American individuals,
there's a little variation, but it's fairly consistent.
And incidentally, if you get your 23andMe report,
and they tell you, you either have the most Neanderthal
ancestry or the least Neanderthal ancestry,
what it's really saying is that
if you have the least amount,
you have about 40 megabases of sequence,
and if you have the most,
you have 60 megabases of sequence
and whether that's interesting or not,
that's entirely up to you.
(audience laughs)
So we can do the same thing for Denisovan sequences,
again, represent the Denisovan genome
as this circle.
And here, we don't do quite as well,
so, but we still recover 10% of the genome,
which is a substantial amount.
And the reason we don't recover quite as much
is that Denisovan ancestry is largely confined
to Melanesian populations.
So in fact, Melanesians have about 40 megabases
of Denisovan sequence per individual,
and you find very little Denisovan sequence
in other populations.
And in fact, this 10% number
is actually pretty good
because we only have a sample size
of 35 individuals,
compared to the 2,500 individuals
that we're looking for Neanderthal sequence in.
So in fact, there's a lot more
of the Denisovan genome to be found.
So that's interesting, we can identify introgress sequence,
but really what we're interested in
is understanding whether admixture was just
an interesting side note to human history,
or was it something more significant.
And in particular, did the sequences
that we inherited from Neanderthals and Denisovans,
did they have negative fitness consequences?
That means were some of these sequences deleterious,
were some of the sequences advantageous
and confer an advantage to our ancestors.
And then ultimately, we'd like to know,
what are the phenotypic consequences of hybridization?
I'm going to focus mainly
on these two issues today.
So this is an overwhelming slide
showing the distribution of Neanderthal sequence
that we can find in modern individuals.
In European individuals in blue
and East Asian individuals in red.
And each place we find Neanderthal sequence
in one of these populations,
we put a tick mark on the chromosome.
The gray regions are just parts of the genome
that are too structurally complex to analyze,
so we just ignore them,
and the black circles are centromeres.
And one thing that you might be able to see
if you stare at this long enough,
and we stare at it for long times,
is that there's a non-uniform distribution
of surviving Neanderthal lineages.
For example, this region,
also highlighted by Sriram this morning,
is about a 10 megabase region
on chromosome seven that's significantly depleted
of Neanderthal sequence.
It's also significantly depleted
of Denisovan sequence.
And what this suggests is that
there once probably was Neanderthal
and Denisovan sequence in this region,
but it was deleterious in modern humans
and eliminated by natural selection.
And as Sriram pointed out,
right in the middle of this region
is the gene FOXP2,
that's been implicated in speech and language.
So if we're interested in the genetic substrates
of uniquely modern human's phenotypes,
these deserts of archaic sequence, I think,
are a really, a good starting point.
But not all sequences that we inherited
from Neanderthals or Denisovans
were deleterious.
Some, in fact, were advantageous.
And we know that there's
somewhere on the order of 50 to 100 places in the genome,
where there's examples of adaptive introgression.
That is, Neanderthal and Denisovan sequences
were beneficial and rose to high frequency
in the population.
We can find examples of this
in all of the populations that we look at.
And this is pretty fascinating,
because as modern humans are dispersing
into these new environments,
they're admixing and picking up
beneficial copies of genes
from species or group of populations
that have been there for hundreds of thousands
of years before them.
And so this is a pretty efficient way
to adapt to new environmental conditions.
And you can sort of generally say that the phenotypes
that we're likely influenced by adaptive introgression
tend to fall into a couple categories.
So things that influence our ability to adapt
to new environments like high altitude, for example.
Vast majority of adaptive introgression genes
are involved in pathogen defense.
We know that pathogens are of the strongest selective
pressures in humans.
And then there's a set of genes that we don't
really fully understand that are involved in skin
and hair biology,
and they too show a very strong signature
of adaptive introgression.
So we'd like to continue to understand how hybridizing
or mating with Neanderthals and Denisovans
influenced the trajectory of human evolution.
But in the last few minutes that I have,
I want to tell you about some work that we published
just a few weeks ago, actually,
in which we developed a new method that reveals
a new twist in our understanding
of human history and mixing with Neanderthals.
And one thing that you might have noticed earlier
in my talk, is that when I talked about patterns
of Neanderthal ancestry,
I exclusively focused on non-African populations.
So, I showed you how much Neanderthal sequence there were,
there was in East Asians, South Asians, Europeans
and American populations, but didn't say anything
about individuals of African ancestry.
And that's because all of the methods up until this point
have assumed that Neanderthal ancestry in Africa
was either very little or non-existent.
And so we recently developed a new method
that didn't make this assumption.
And so we were excited to apply it to individuals
of African ancestry.
And to our surprise, we actually found substantial amounts
of Neanderthal sequence in African individuals.
And these were the five populations that were available
for analysis from the 1000 Genomes Population
or Project.
Purple here represents African admixed individual,
so largely African Americans,
but even in these African populations
from the 1000 Genomes Project,
we find about 17 megabases of Neanderthal sequence
per individual.
And just as a comparison,
when we look at sort of the same individuals
and call Neanderthal sequence using previous methods
that we developed that make this assumption
that there's little Neanderthal ancestry in Africa,
we only call maybe 500 kilobases,
so, like, two orders of magnitude less.
So this was a really strong signal,
and it was very surprising.
So we do see Neanderthal ancestry using this new method.
But what explains the signal?
Well, to make a long story short,
there's really two primary explanations.
So, the first is that there were migrations back to Africa.
So people left Africa
in the the major heart of Africa dispersal,
hybridized, or admixed with Neanderthals,
and some returned back to Africa carrying the Neanderthal
sequence with them.
And our results show that the amount of back migration has
probably been much larger than we've previously thought.
So that's one part of the signal.
The second part actually is really fascinating
and something that we really wasn't on our radar until we,
we got this result.
And that is that part of the signal of Neanderthal ancestry
in Africa is due to an early out of Africa dispersal
and gene flow from humans into Neanderthals.
And so, let me unpack that a little bit for you.
So this is a simple phylogeny, showing the relationship
between Neanderthals and three modern human populations,
so Africans, Europeans and East Asians, and so the bottom
here represents the present and we go into the past as we go
towards the top, and this hatch mark just is to indicate
that the times aren't going to be drawn proportionally.
So we know that Neanderthals and modern humans
split around 600,000 years ago,
and what our data shows is that not only was there
this out of Africa dispersal that happened 80,000 years ago
that resulted in the peopling of the world,
but there was also a much earlier dispersal of humans
out of Africa around 200,000 years ago,
and they encountered Neanderthals and admix with them.
So, in fact, some of the sequence that we call
as Neanderthal,
it's not Neanderthal sequence in modern humans,
it's that Neanderthals have modern human's sequence.
And so this adds a further twist to sort of this
complex pattern of admixture,
and gene flow and arrows pointing in every direction.
So in conclusion, there is substantial amounts
of the Neanderthal and Denisovan genome
that remain in modern individuals.
There were fitness consequences to hybridization,
both good and bad.
Humans, Neanderthals, and Denisovans have mixed
multiple times likely in multiple places,
and that there were multiple dispersals
both in and out of Africa.
And I think this last point is something that
is really important in genetics
is that we often have a simple models
of how humans dispersed around the world,
and that the more data we look at,
the more complex these models become.
And that it's important to take into account
the dispersals both out of Africa and back into Africa
to really understand patterns of Neanderthal ancestry.
So I would like to acknowledge my lab, in particular,
Ben Vernot who did a lot of the early work
on finding Neanderthal sequence, my collaborators,
and my two boys who I'm sure are not watching right now.
Thank you very much.
(chuckling)
(clapping)
(upbeat music)