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- [Kay] So I would like to start with acknowledgments. So the work I'm going to
present is actually the work of many, many people who are involved in sequencing
these two genomes I'm going to talk about and helped analyzing them. I will give
some more credit during the talk. So let me start by just introducing the samples
that were used to generate these sequences. So, both of these samples were
found in the Denisova Cave in the Altai Mountains in Russia. And one was actually
a small finger bone that you see here on top, yeah. And another one was a small toe
bone that you see on the bottom. And the reason that we are actually having two
genomes from the same place has to do with the fact that the Denisova Cave actually
preserves the DNA in these bones particularly well. It's one of those
exceptional place where most of the DNA that we get out of these very old bones
really comes from the individual that died and are not from bacterial or microbial
contamination. So what this allows us also to do is to not just sequence these
genomes to a low coverage, meaning just a couple of sequences from the nuclear
genome, but we can actually sequence them many times over. And how this looks like,
then, is that you have small sequences stacking up like this that are distributed
randomly over the entire genome, and you always have several of those for each
position. And so taken together, you have 34 coverage meaning on an average position
in a genome, you will have 30 different fragments for the finger bone, and for the
toe bone you have 50 fragments. So using these genomes, then, to actually
understand how they're related, you see that one of those two genomes that we
produced from this cave falls together with other Neandertals that we have
sequenced before to lower coverage. And we call this the Altai Neandertal. And the
second individual, the nuclear genome is from a sister group of Neandertals that we
call the Denisovan because they fall outside of the variation that we observe
of Neandertals. So they are more closely related to Neandertals but they are not
looking close enough related to deserve to be just called a Neandertal and we rather
call them Denisovan. So one of the questions that you might ask yourself is,
"Why are we actually bothering with sequencing these genome so deeply? Why do
we sequence them 30 or even 50 times over?" And the reason for this is the fact
that we are diploid organism. So we are actually having each chromosome twice. One
complete set is inherited from the mother, and another complete set of chromosomes is
inherited from the father. And so, one of the things that you can do when you have
so many fragments and so many sequences is you can call confidently the differences
between these two copies that you have from the mother and the father. And this
is really the reason why we are sequencing it so deeply so that we can call the
differences between these chromosomes. And one of the most easy analysis that you can
actually do once we have sequenced so deeply and called these differences
between the chromosomes is to just asks how different are they on average. So this
is called heterozygosity. And you can actually put this into perspective by also
showing, as in this plot, the level of heterozygosity, so the level of
differences between the chromosomes in modern humans, in present-day modern
humans. And we have some individuals from Africa here and some individuals from
outside of Africa and what you can see is that Africans have about 1 in 1,000
differences between the chromosomes that they inherited from the mother and the
father, while non-Africans have between the 6 and 8 in 10,000. And the archaics
are much reduced compared to both of these present-day human populations, or
present-day human regions. And they are at a level of 2 to 3 in 10,000. And there's
even a quite significant difference between the two archaics and that the
Denisovan is higher than the Neandertals. So the Neandertal is further reduced. So
one can actually look into this in more detail by looking over the chromosomes. So
just going in a small window over the chromosomes and just counting the
differences that you observed. And we have done this here for a French individual,
the Denisovan and the Altai Neandertal. And what you can see is that the level of
heterozygosity, so the differences between the chromosomes, varies over the genome.
But there's one thing that is very special and that is that the Altai Neandertal has
this very long stretch, here for instance on chromosome 21, there are other
stretches like this on the other chromosomes, where there is hardly any
difference between the two parental copies. And so now, what one can do is one
can actually take the size of these stretches and how much of the genome is
actually residing in those stretches to calculate back how closely related the
parents would have to be to generate stretches like this. And this is an
analysis that Flora Fief [SP] in Monty Slatkin's lab in Berkeley was carrying out
for the analysis of the Altai Neandertal genome. And what she found is that there
are several different relationships between the parents possible that would
actually generate exactly the patterns that we see. And so I guess one easy way
to say this is that the parents of this individual would have to be at least
related on the level of whole siblings to generate these patterns. So they were
closely related. And then you can take a step further and you just take your
prediction of how much you would actually expect in terms of long stretches that are
looking like this, almost identical, and you just ask if I would subtract now,
based on what I understood the family relationship of the parents would be, if I
subtract this away, is there actually anything left? And this is in fact the
case, so for the Altai Neandertal you still see an excess over the stretches
that you see in the Denisovan and in modern humans. And this actually means
that this is not just a singular event that just once happened, that just by
chance the parents were closely related, but also further back in the past there
were probably closely related ancestors. So another topic that I would like to talk
about is Archaic Admixture. And so we already heard about archaic admixture from
Neandertals and Denisovans into modern humans. What I would like to talk about is
really archaic admixture between both archaics. But before I get to this, I
would actually like to go a little bit deeper into how we actually know what
signal we have to look for to understand that there's really admixture. And so, as
a very simple way of depicting this, just imagine that you have a certain individual
and of course, as I already explained, every chromosome has two copies so this
individual has these two copies of a certain chromosome, an arbitrary one. Of
course, you can go back to its parents and one of those copies will come from the
father and the other one will come from the mother. So I can paint them now blue
and red. But I can also go a step further and actually paint them according to
whether they come from the grandparents or from which grandparent they come. And what
you see in this picture now is that there is actually a process called recombination
that is actually mixing up these different chromosomes in the parents of the
individual. So now you have kind of these random stretches from all the grandparents
that are painting these chromosomes. And of course, you can take another step,
another step, another step. And so essentially what this means is that you're
breaking up the ancestry...when you go through the ancestors, you kind of jump
between different ancestries when you go over the chromosome. So you change which
ancestors' genome you look at. And so when you repeat this process for a very long
time and let's say you have ancestry from one population for most of the genome, but
you have a couple of ancestors from a different human group hiding among your
ancestors, then what's the most common outcome will be is that you will have
these short stretches where one of the chromosomes actually shows this ancestry
of this other human group while the other chromosome is actually looking like the
chromosome of the majority of the groups, because these stretches will be randomly
replaced on your two chromosomes. And now we can actually use the Altai Neandertal
and the Denisovan to find out whether there is any Neandertal ancestry in the
Denisovan, or whether there is any Denisovan ancestry in the Neandertal
individual that we sequenced. And so in one direction, just showing so if
Neandertals would contribute to the Denisovan what we would expect is that
there are some stretches where the Denisovan looks very much like a
Neandertal but on the other chromosome, we would expect that it actually looks like a
normal Denisovan. That means that the two chromosomes are actually very different.
And so the prediction that this makes is that if you go to regions where, that's
shown here on the left-hand side, so the X-scale is giving you how closely related
you can make any particular window that you look through, how closely related you
can actually make that to the other archaic. So when you have windows where
the Altai Neandertal is very closely related to the Denisovan, shown here in
blue, you actually see no effect but if you look in the same for the Denisovans
when the Denisovan can be made very closely related, or it looks actually very
closely related to the Altai Neandertal, you see that the two chromosomes are very
different, and this is shown here in red at this position. So this is a hallmarks
sign that there is actually among the ancestors of the Denisovan some Neandertal
ancestry. The last signal I want to talk about is actually the one of unknown
archaic material that we found in the Denisovan. And so the first signal that we
saw for that is really just when you look for divergence to Africa, so that's
nothing else than just looking for how many differences we observe. We actually
see when we take larger windows and we just compare to an African that the
Denisovan is always a little bit more different than the Altai Neandertal. So
these two distributions that you see here, the one of the Denisovan in blue is
slightly shifted to the right. And you can look even deeper into this by actually
looking at different allele frequencies and divide up your comparison by how many
Africans actually carry a certain derived variant, meaning a new variant that
occurred sometime after the split from chimpanzee. And when all Africans are the
same, you actually see that the signal is the strongest. So you see the most
differences. And in an analysis that also Monty Slatkin's lab carried out in
Berkeley with Fernando Racimo, what they did was essentially taking the signals
that I just described and they tried three different models to actually compare how
this could come about. And so the first model assumes that there was gene flow
from Neandertals into the common ancestor of all modern humans. The second model is
assuming that all modern humans actually gave some material to the Neandertals. And
so these first two models are essentially trying to explain how you could make the
Neandertals and the modern humans more closely related. And the last model is one
where you have some lineage that we haven't observed, so we don't know what it
is, that contributed to the Denisovans and that would make the Denisovan more
distantly related to modern humans. And so in most...comparison model three was
actually the best explanation that we could find for the data. And so we believe
that there is this super archaic admixture of some very deeply divergent lineage into
the Denisovan. So, what I would like to say in the end is...or what I would like
to show in the end is really just a general overview of the different gene
flows that we have now observed. And this picture is not quite complete yet. So what
you can see is that we have the ancestry, this deeply divergent ancestor that
contributed to Denisovans. We have the Neandertal admixture into the modern
humans. We have contributions from Denisovan to modern humans. And the
Neandertal admixture into the Denisovans that I just talked about. And it seems
that there is, by now, there are also other publications that say that there are
contributions to Africans and so on and so on. And so, I think what this all means
when you sum it up is that these different types of admixtures are actually something
that is quite common. So it actually happens quite a lot in the past and it is
something that is really a transition in our thinking because originally, I think
we were all very skeptical that there was actually any admixture between these
archaic groups. And with this I would like to end and say thank you for your
attention.
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