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Eric Green: Thank you very much. It's certainly a pleasure
to be here. I want to welcome everybody here this evening on behalf of the National Human
Genome Research Institute, one of the 27 institutes and centers that make up the National Institutes
of Health. As you heard, this is one part of a series of programs that are associated
with this wonderful exhibition in Hall 23 of this great museum, Genome Unlocking Life's
Code, which really reflects this great new partnership between the NIH and the Smithsonian
Institution. And it's a real pleasure to be a part of this program tonight, but also this
entire series. And it has proven to be remarkably enjoyable and productive to be working so
closely with the Smithsonian Institution and also the Smithsonian Associates Program for
putting together programs such as this, which really have brought in some spectacular guests
and speakers to help round out what you can learn from visiting the exhibition itself.
So my role here was simply to welcome you and tell you it's really a pleasure for our
institute and for NIH to be involved in programs such as this, and also to introduce Dr. Rick
Potts, who's going to in turn give a more detailed introduction of tonight's special
guest. Just by way of background, as you heard, Rick Potts directs the Human Origins Program
here at the Smithsonian's National Museum on Natural History, where he holds the Peter
Buck chair in human origins. His research investigates Earth's environmental dynamics
and how human adaptations have evolved over the past six million years. Bridging many
research disciplines, Rick leads field projects in the East African Ridge Valley and in Southern
and Northern China. He's also a curator and a visionary for the Smithsonian's Hall of
Human Origins and is the author of the companion book, "What Does it Mean to Be Human?" So
with that as background, please welcome Dr. Rick Potts.
[applause]
Dr. Rick Potts: Thank you very much, Eric. And I don't know
what it is but as I was stepped out into the lobby and came back in here there was such
a feeling of excitement about tonight. Maybe it's snow, but I have a feeling it's Neanderthals
or something like that.
[laughter]
Anyway, I wish to offer my gratitude to Dr. Eric Green and the extraordinary partnership
that's already been alluded to, the partnership that developed surrounding the human genome
exhibition, a partnership between the Smithsonian's National Museum of Natural History, and the
National Human Genome Research Institute, which Eric leads and directs at the NIH. Great
thanks also to the Smithsonian Associates for organizing tonight's event, which is absolutely
thrilling to me, as it would be to anyone who was involved in the study of human origins.
Dr. Svante Pääbo has led the effort to create a new field of discovery directly relevant
to the subject of human evolution. The study of ancient genomes has offered a novel means
of delving into the actual genetics of early human lineages, beginning with the Neanderthal
Genome Project. Dr. Pääbo's research team wowed his fellow scientists and the public
by mapping the molecular foundation of what it means to be a Neanderthal. And with that,
with those findings, those findings have shed great light on the genomes of many people
alive today, as well as the complexity of the later phases of human evolution. And for
his work and for his earlier research in genetics, Dr. Svante Pääbo has received numerous recognitions
and awards. In 2007, "Time Magazine" named him one of the most 100 influential people
in the world for that particular year. And I think that continues because that was three
years before his team produced the first draft of the Neanderthal genome. More recently he
received the Theodor Bucher Medal from the Federation of European Biochemical Societies.
And last year Svante received the Gruber prize in genetics for his pioneering research and
leadership in the field of evolutionary genetics.
In addition to the Neanderthal genome project, the further discovery of the denisovan genome
is equally amazing. Svante is here to tell you about it all himself. One of the great
adventure stories in modern science told at the molecular level and guaranteed to inform
our evolutionary history and the distinctiveness of being human. It is my considerable honor
to ask you to welcome Dr. Svante Pääbo.
[applause]
Dr. Svante Pääbo: Thanks. Well, first of all, let me thank you
very much, Rick, for that very kind introduction and for the invitation to come here and also
see this amazing exhibition that I actually heard a lot about all the way to Europe. And
what I wanted to do today is use my time so that I first talk a little bit about our efforts
in general to retrieve DNA from old fossils in particular from Neanderthals, then discuss
Neanderthal [unintelligible] in detail and what has that taught us, and also the genomes
of this relative of Neanderthals from Siberia. And in the last third of my time or so I'd
like to discuss where we're going from here, how we will exploit the knowledge we now have
to go further. And please tell me if it's not loud enough and you don't hear me. I can't
gauge how loud I am.
But before starting all this then, I just want to remind you at what I think you all
already know, that our genome, our genetic material is stored in almost all cells in
our body on the chromosomes and it's stored in this famous double helical DNA molecule.
And when a new cell divides, a [unintelligible] of interest is then in our germ line where
new germ cells are formed, so new individuals may appear. There are [unintelligible] that
unwind these two strands and synthesize new strands with the old as templates. So there
appears two molecules which are more or less exact copies of the earlier copies -- version
of our genome. And this is a very exact process, but nothing is of course absolutely perfect
in nature. So now and again an error is made. For example, instead of building in what should
have been a "G" here, an "A" is built in. And if that's not repaired fast enough before
the DNA replicates again, it will appear as a mutation in the next generation. And you
can then discover these mutations as sort of consequences of these mutations when you
compare DNA sequences from two individuals. So if you compare the genomes of two people
in this room we will find a difference every 1,200, 1,300 such letters in nucleotides approximately.
If you add in the [unintelligible] "C" here we will find a lot more differences, one every
100 nucleotides approximately. And we can then use our models for how we think these
mutations occur to reconstruct the history of the whole genome or a part of the DNA sequence.
And we generally depict that in the form of trees like this. In this case it's very simple.
The two human sequences go back to common ancestor quite recently. Much further back
is their common ancestor, [unintelligible].
So our genome, as you also know, is over 3 billion base pairs. So we have something in
the order of 3 million differences between any two people in the audience or between
the two versions of the genome that you inherited from your mother and from your father. So
there's a lot of information there to begin to reconstruct human history. And if you do
that on a world-wide scale, what you will find is that most variation is found in Africa.
So although there are a lot less people living in Africa than outside Africa, the total amount
of variation outside is less than you'll find inside Africa. And not only that, for most
of the variants you find outside Africa, you have closely-related variants of DNA sequences
inside Africa. But there's a component of the variation in Africa that you don't find
outside. And the interpretation of this is that modern humans, humans that are essentially
as us, evolved in Africa and a part of the variation that existed there sort of went
out and colonized the rest of the world.
And by some genetic tricks, for example, looking at how associated variants are with each other
along the chromosome, you can also estimate approximately when this happened. And it's
in the order of 100,000 years ago, so quite recent in terms of human evolution. So this
is the recent African origin of modern humans. But there's a problem, if you like, with this
model and that is that 100,000 years ago there were not only modern humans around. There
were many other forms of humans. And outside Africa most famously Neanderthals in Western
Eurasia and in Eastern Asia other forms that are less well-described. So big question has
always been what happened with these other forms of humans? Did they contribute to people
who live today or did they go extinct without any sort of [inaudible]. And most interest
has been focused on Neanderthals. Here are some reconstructed skeleton of a Neanderthal
compared to a modern human. As you may also know, Neanderthals appear in the fossil record
depending on how you define a Neanderthal, maybe 300, maybe 400,000 years ago, and they
exist until about 30,000 years ago when they become extinct about the same time in different
areas when modern humans appear.
So there have been these two ideas around in paleontology for decades about what happened
when modern humans appear in Africa and come out, one idea is a sort of total replacement
idea where Neanderthals in Europe and other forms in Asia become extinct without any contribution
to present-day people. Another one -- idea is a simulation called here, where modern
humans come, mix with Neanderthals before they become extinct so they contribute to
people in Europe today and the same in Asia. So you can regard these two ideas on a sort
of sliding scale where total replacement would be zero contribution from these earlier forms.
And you could have more and more of contribution until total continuity that I think no one
really believed in until quite a while ago already.
So we got a first chance to sort of test this with molecular means back in the mid-90s when
we got access to this fossil, which is [unintelligible] and in the Neanderthal, it's sort of the Neanderthal
that was found in Neanderthal in 1856 and yet it's named to the [unintelligible] of
humans. So we got a sample from the arm bone here. It was an extracted DNA under really
clean room conditions to avoid contamination from yourself or from dust in the air or from
chemicals into your experiments. And with great effort at that time with a message we
had a [unintelligible] at a particular variable part of the tiny piece of the genome, the
mitochondrial genome, which is inherited from mothers to offspring. So it gives a very one-sided
version of history, if you like, just a female side and it's also a tiny little piece inherited
as a unit so very much influenced by chance. But it has advantage that occurs many copies
of this [unintelligible]. It's a bit easier to retrieve. It's a bit like some fragments
of it have survived.
So we've [unintelligible] reconstructed piece of this by shorter little pieces. You could
retrieve believing the things we could reproducibly find and reconstruct in such a tree as I showed
before. And if you look at the mitochondrial genomes of present-day people -- now the pointer
has died -- of the modern humans there, they go back to common ancestor between 100 and
200,000 years ago. The Neanderthal mitochondrial genome was found to go back much further in
time, about half a million years or so. And since then we and others have looked at other
mitochondrial genomes from other sites and they all go back to common ancestor outside
a [unintelligible] of modern humans.
So the [unintelligible] there's no battery in this. It doesn't forward either. So in
this scale of thing it's quite clear that no one today runs around with a mitochondrial
genome from a Neanderthal. So it's total replacement. And this mitochondrial genome also gave us
another piece of information. It suggested that the split between Neanderthals and modern
humans -- wow, that is really nice, wonderful, thanks a lot, great -- split about a half
a million years ago or later because that was the time we had between the mitochondrial
genomes there.
So this was what you could see from this tiny little piece of the genome. But it was of
course clear to us and everyone else that the full story would be hidden in the nuclear
genome because then we could really study all parts of the genome and also find things
that would have appeared more recent than humans since we separated from the Neanderthals
here. And I think I'm on the published record something like eight years ago saying we will
never see a nuclear genome of a Neanderthal. It's too degraded. It's too little there.
It's impossible.
[laughter]
And you should, of course, never say things like that because generally you're overtaken
by technology. And in this case it was quite clear it was high through-put DNA sequences
-- sequencing that changed it -- machines and techniques that came around to sequence
millions of DNA molecules really rapidly and inexpensively. So you could then instead of
trying to find a particular little piece of DNA you're interested in, simply extract all
the DNA from the fossil and sequence all the fragments you had there, all the pieces of
DNA, make up a little database and then start looking through that database and see what
parts fit to the human genome. So they might count from the Neanderthals which parts -- which
fragments are from bacteria and so on.
And the first place where this worked was in Croatia, a beautiful site in southern Europe,
and from this little bone, which is 38,000 years old, this part of the bone there. And
the first thing one sees and when one looks at the DNA sequence is that they are indeed
very short. It's tiny little pieces, hardly anything as big as 200 base [unintelligible],
average 50, 60. The other thing you will see is that the vast majority of the DNA in such
a piece of bone is not at all from the Neanderthal. Our very best bones have something like up
to 3, maybe 4 percent of Neanderthal DNA. The rest is all from bacterial and fungi that
colonized the bone when it was deposited in the cave.
So we started a project where over a couple of years worked a lot on improving the efficiency
with which we come from the DNA and the bones to something we can feed into the sequencing
machines. The machines got more efficient in that time in terms of how many molecules
it could sequence. We looked through many, many sites and many bones to find the ones
with the most Neanderthal DNA in them, found three ones from that site in Croatia that
were then used and sequenced a little over a billion DNA sequences from them. The vast
majority of [unintelligible] do not come from the Neanderthal, but from bacterial. But -- so
we sort of matched these fragments to the human genome until we had gotten together
about three billion base [unintelligible] Neanderthal DNA. So that means you had random
fragments here that together would add up to three billion base [unintelligible] the
size of the human genome. But these fragments were of course from random places in the genomes.
So sometimes we had fragments that we saw a piece twice, sometimes even three times,
but were lots of pieces we also just missed by chance. So the genome we had back in 2010
covered around 55 percent of the Neanderthal genome. But it allowed us to have a first
overview and start to ask some questions. And one of the first questions -- we were
interested in [unintelligible] question. Was there interbreeding with modern humans when
they came out of Africa? And we tried to ask that question in many different ways. I'll
just present one here. And that is saying that if modern humans came out of Africa and
would mix with people, Neanderthals in Europe, we would expect people in Europe today to
share more genetic variants with Neanderthals than people in Africa, where there have never
been Neanderthals. So we were then looking for tiny little signals in the genomes. So
we're very worried about errors in our sequences. So we went out and sequenced five people that
live today to compare with so we would know the spectrum of errors would be exactly the
same in them. So one person from Europe and to us -- sorry, that is actually the Neanderthal
we sequenced, one person from Europe, here, and to us, of course, our typical European
is a French person, so this is a French person here.
[laughter]
We have two African individuals, one person from China, and one from Papua New Guinea.
And then we did a very simple analysis where we just took two of these modern genomes to
test it first to Africans and looked for all positions where those two present-day Africans
differ from each other. And we'd take the Neanderthal and count how often does a Neanderthal
match that African or that African? And it would be 50/50 right because Neanderthals
had never been in Africa, there is no reason to assume that it would be closer to one African
than the other. And indeed, it's about a little less than 100,000 matches to this one and
Then we do the same analysis with a European individual and an African individual. And
to my surprise, I would say, we actually found statistically significantly more matching
to the European individual than the African individual. Even more surprising to me was
that when we looked in the Chinese individual there was again more matching than to the
African, and even in Papua New Guinea that was also the case. So I was actually biased
when we started doing this, thinking there had been no mix with the Neanderthals, but
if there was one, I would expect it in Europe, where the Neanderthals had actually lived.
But we now found that in China and in Papua New Guinea.
So the model is sort of supposed to explain that, that has since been borne out by work
by others, is that if you assume that modern humans came out of Africa, the first -- they
probably passed through the Middle East and we know there were Neanderthals in the Middle
East. So if these modern humans there mixed with Neanderthals and then went on to become
the ancestors of everyone that live today outside Africa, they would have sort of carried
with them this Neanderthal contribution out to the world, [unintelligible] the parts where
there were no Neanderthals to the extent that up to a maximum, perhaps 2-and-a-half percent
or so of the genomes of people outside Africa come from the Neanderthals.
We could also calculate with various tricks about when this inflow from the Neanderthals
had happened between 40 and 90,000 years ago, fitting with the time when we believe modern
humans came out of African and started spreading seriously over the world. And there has since
been a lot of follow-up work of this by other scientists, but I can sort of never stop myself
from pointing out that the public is also very interested in what we do, and started
writing to us in 2010. Many people wrote to us and self-identified as Neanderthals.
[laughter]
And after a while I started seeing a pattern in this correspondence. It was almost exclusively
men who wrote to me.
[laughter]
And there were very few women who self-identified as Neanderthals.
[laughter]
So I do no real lab work myself anymore, so I presented this to my group as sort of my
research counting emails.
[laughter]
And they're, of course, very critical particularly when I present something. So they said this
is just as a payment, women are not interested -- less interested in molecular genetics than
men, so only men will write to you.
[laughter]
But I went back to my correspondence and found that that was not at all true because there
were plenty of women who wrote to me and said their husbands were Neanderthals.
[laughter]
Whereas, not a single man has written and said that his wife is a Neanderthal.
[laughter]
And this is, of course, extremely interesting for geneticists so that's sort of something
I have to look into.
But we, of course, do a few other things than counting emails. So something we're interested
in is other forms of extinct humans. There are, of course, many, many forms of humans
that we don't find in the fossil record and we don't really know how they're related to
present-day people and to Neanderthals. And we are particularly lucky to work together
with Professor [unintelligible] Yankel [spelled phonetically] and his associate, Professor
[unintelligible] excavated many sites in Siberia, particularly they excavated this site in southern
Siberia on the border to Mongolia and China. It's a beautiful place and they excavate since
a number of years. And in 2008, they were actually very skilled, I think, to find and
recognize a tiny little bone and realize that it might come from a human. So it's a fragment
of the last phalanx of the pinkie.
So we extracted the DNA from this bone and found, to our surprise, that it was extremely
well-preserved. As I said, our best Neanderthal bones are 4 percent indigenous to [unintelligible]
70 percent. So it allowed us to produce a genome from this individual about the same
quality as the Neanderthal genome. And to our great surprise we found that it was not
really Neanderthal. It went back to common ancestor shared with Neanderthals but far,
far back. Neanderthals had a long, independent history, longer than say the history deepest
divergence as we have among present-day people. So we defined this as a sort of new group
of extinct [unintelligible] and based just on the genome sequences and we named them
denisovans after the Denisova cave, where they were first found just like Neanderthals
are then called Neanderthals after Neanderthal, where they were first found.
What has then happened in the last three years since that time is that we have improved our
methods for retrieving tiny amounts of damaged DNA very much. There are many parts to that,
but one particularly interesting one is that you extract across a double-stranded DNA from
your fossil. And normally you then try to modify the [unintelligible] so that you can
go on and sequence it. But many of these molecules are chemically modified so that you cannot
actual replicate them or sequence them. So something that [unintelligible] in the laboratory
invented was that he actually starts by separating the two DNA strands, then ligate on the synthetic
piece of DNA and immobilize it here so that each of the two strands independently have
a chance to end up being sequenced. So that means if you have a chemical modification
of one strand that inhibits analysis, the other strand can still make it.
So with this method and other modifications we've been able to go on in the denisovan
genome first that you have this slight overview over where many pieces were missed, to now
sequence it so deeply so that we actually see all the positions to which we can map
these short fragments, which is about two-thirds of the genome, but with great accuracy. So
you can do a lot of things then when you have a very accurate genome. You can, for example,
distinguish the two variants that this individual inherited from its mother and its father.
Just to illustrate that there is a genetic variant at high frequency in Asia and Native
Americans that's responsible for straight hair and some other sort of texture of the
hair. It's very common among people in China and East Asia today. It's not in Europe or
Africa and when we now look at this denisovan individual it doesn't carry it either. And
that's actually a common pattern. This individual doesn't seem to have any special relationship
to people in Asia today.
But you can do much more than that. Since we have the sequence of the two chromosomes,
we can sort of estimate for a part of the genome here the time back to common ancestor
by making a little tree like that. And you can then go across a genome and do that for
many, many parts of the genome. And you can then use by a method developed by Hennly [spelled
phonetically] and Richard Durbin this to estimate population size over time. Because when you
have two chromosomes like that, when they go back to common ancestor they would be more
likely to go back to common ancestor at a time when the population was small. So in
this example here we would expect the population size to have been small at this time where
many of the chromosomes have a common ancestor.
So from a single individual the two genomes and that we can estimate the population history
of the entire population from which this individual derives. So if we do this for present-day
people you will see very nicely it's past here, you go to the present here, and everybody,
no matter where we live on the planet, share a reduction in population size, an increase
in population size, and only the last 100,000 years or so do we start seeing a difference
between Africans we have more variation than non-Africans due to this bottleneck of coming
out of Africa. And we could now add this individual and look what its population history was.
You then find that, if anything, it's a bit bigger population size there for a time, but
then it crashes and goes down and becomes extinct. So this was very fascinating to me.
This individual had a very different population history from anybody who is around today on
the planet.
Something else we can do when we have very accurate genome sequences, is that we can
begin to see that this individual lived long ago, so actually it's missing mutations when
we compare to present-day humans. So we could see that it missed something like 1 to 1.3
percent of the mutations relative to present-day humans here. So we can then if we assume that
the common ancestor with the chimp is 6.5 million years, we'd miss 1.2 percent of the
mutations here. We can estimate how old this bone is. And in this case it would be something
like 60 to 80,000 years old. Now there are many caveats about this, particularly about
sequencing errors among present-day human genomes. They actually vary in age by about
20 percent of this here or that we know they all live today. But I think it's an indication
of what will come in the future, that when we handle genome sequencing even better than
now, that from bones where we can retrieve a genome, we can actually date them. And in
this case even more from a bone so small that you could actually not use carbon dating,
for example, on it. So we can, of course, with a genome ask just for the Neanderthals,
have these denisovans contribute to present-day people and indeed they have. But surprisingly
not in central Asia or Siberia, but out in the Pacific, particularly aboriginal Australians,
Papua New Guineans, and so on. So this then suggests that probably these denisovans were
more widespread in the past and was also in Southeast Asia.
So this is a copy again of this bone. And I think it sort of indicates something that
will become more common in archeology in the future. They're from tiny, little remains
like this. You can reconstruct a lot of population history, even dates and often frustratingly.
Like in this case we don't know how these denisovans looked morphologically or what
stone tools they made or any other things we would traditionally know.
So, just to summarize before coming to the last part here what we think we know then
about the origin of Neanderthals and modern humans. And Denisovans -- we think that Neanderthals
and Denisovans have a common ancestor sometime in the order of half a million years ago in
Africa. They come out, they evolve in Western Eurasia to what we call Neanderthals. In Eastern
Eurasia somewhere to what we call Denisovans. This is not to say that they were this widespread,
also not that they were the only hominins there at that time. We know there were other
hobbits *** floresiensis in Indonesia, for example. We also don't know the border between
these two groups. We do know that in this region in the Altai Mountains, at sometimes
there were Neanderthals, at another time, Denisovans. Then modern humans evolved in
Africa come out and presume [spelled phonetically] in the Middle East mix with Neanderthals.
They continue to spread around, and there is now a paper that appeared in January that
convincingly showed that there seems to have been a second occurrence or mixing with Neanderthals
in -- somewhere in Central Asia or so because people in China, for example, have slightly
more Neanderthal contribution in their genome than people in Europe. There is then this
mixture with Denisovans, presumably somewhere in Southeast Asia by people that then spread
out in to the Pacific.
And these archaic humans then become extinct, but they live on a little bit today if you'd
like so that something like 1 to 2-and-a-half of percent of the genomes of people in Eurasia
comes from them. And you add on another 5 percent from Denisovans in the Pacific.
Now we've sequenced two genomes from extinct hominins, found two cases of that mixture.
I wouldn't be surprised if, for example, in China one found other cases. I also don't
think there is an absolute difference between Africans and non-Africans in that Africans
would not have a contribution. Clearly, Neanderthals -- sort of modern humans appeared somewhere
in Africa and also spread across Africa. And there is some indication from present-day
variation that there might have been a contribution from earlier forms of hominins also there.
So we've clearly rejected the sort of total replacement model for modern human origins.
We have up to 7 and a half percent contribution from other forms. But the big picture is still
one of replacement. So we has to sort of have a name for this. I find sort of lethal replacement
perhaps a good idea.
[laughter]
So I would then like some bring up three things that are sort of in the works. The first one
is actually now accomplished; we need a good Neanderthal genome. And we know have that
since January when we published it. It's again from the same site in the Altai Mountain from
Denisova Cave. We even found a finger bone, and deeper down, two years later, they found
a toe bone that looks like this. And we sequenced the DNA from it, and again to our surprise,
it was not Denisovan, but it was very close to other known Neanderthals there. So this
is a Neanderthal, and we sequenced this genome to high coverage, again very high quality.
We can compare it to present day people. For example, look over all how much variation
is it between the two genomes these individuals have inherited from their parents. So here
are Africans that have more variation than non-Africans today. And these are the Denisovan
finger bones and the Neanderthal toe bone that have dramatically less variation. But
not only that, we also found something very surprising.
When we worked along the chromosomes in this Neanderthal genome on the bottom here, we
found large stretches, one here, of 19 million base pairs where the two chromosomes were
absolutely identical. And this of course indicates that the parents of this individual was -- were
closely related. So you can -- where we find much less of that in the Denisova finger.
So you can then model what relationships must have occurred [spelled phonetically] been
the case for the parents of this individual here, the Neanderthal individual. The parents
have been either, say half sibs or grandfather granddaughter. Don't ask me to explain what
double for double fir castles [spelled phonetically] --
[laughter]
-- this because I can't. But one of these four scenarios must have been the case. So
you begin to get some idea about socially what happened in that cave quite a long time
ago. And I think it would be very interesting in the future to see in other Neanderthal
sites if this is a typical pattern for Neanderthal or something special here. You could, again,
do the same analysis with a Neanderthal here, comparing it to present day humans and Denisovans.
And its population history matches that of the Denisovans very closely. This difference
here is probably just due to that this bone is actually older than the Denisovan bone,
but we don't know how much older it is.
We now then have two good genomes of a Denisovan, of a Neanderthal. We have some sort of overview
genomes from Croatia and a place in the Corcuses [spelled phonetically]. So we can now begin
to look at interactions not only the present day people but also with anon between Neanderthals
and the Denisovans. So if we do that, we find this contribution from Neanderthals to present
day people outside Africa that we know about or wanted to present contribution from Denisovans,
the people out in the Pacific of about 5 percent. We now find a tiny contribution Denisovans
also from mainland Asia in China for example of .2 percent. So a lot less. But we also
see a contribution from Neanderthals to Denisovans, and quite interestingly we see an old component
in the Denisovan genome that we do not see in the Neanderthal genome that comes from
something else, that diverged much earlier than these guys want to 4 million years ago
from the human lineage.
So it's very tempting to speculate that this is ***-erectus or something like that in
Asia that contributes to the Denisovan genome. And I think future work will look more into
that. So a conclusion from this is that human forms have always mixed with each other at
least to some extent. We find no, sort of wholesale contributions of 30, 40 percent
from one into the other. It seems to be generally small extent.
What you can also do now then, and there were two papers that appeared in January. One of
them we were involved in, and the other was one from Josh Akey's group in Seattle where
they had looked at contributions in present day European genomes and East Asian genomes
from Neanderthals. And they then find in some regions high contributions from Neanderthals,
very high percent of present day people carry fragments from Neanderthals in certain regions
of the genome. And if you look what genes are particular present in such areas, one
group of such genes are those that are involved with structured proteins in the hair and the
skin. So there seems to be that Neanderthals have contributed something in the skin or
hair to quite a lot of people that exist today.
And now the group of genes that come from Neanderthals and Denisovans was shown already
in 2011, but Peter Parham's group that they're involved in regulation of the immune system.
So I can imagine that there were sort of Neanderthals had resistance to certain infectious diseases
that they had adapted to over hundreds of thousands of years. And when modern humans
from Africa picked up this variance, they were of advantage to them, so they increased
in frequency.
I was quite fascinated by a paper that appeared from David Altshuler's group, a big consortium
that appeared in December where they found a new risk allele for Type 2 diabetes, the
type of diabetes you get in old age. And that risk allele was existed at high frequencies
in East Asia and in Native Americas. And when you look at this -- a tree of this risk allele
versus non-risk alleles, you find that the Neanderthal allele is right in there. So this
is a variance that one has picked up probably in Asia from Neanderthals into high frequency,
perhaps because its variance were of an advantage in a situation of starvation. And today when
we have ample nutrition all the time, it results in type two diabetes. So some of the sort
of contributions may actually have consequences also, medical consequences today.
What you can also look across is genomes of present day people. They stand for areas where
there is no contribution from Neanderthals, so areas that seems to be resistant to Neanderthal
contribution when we would expect statistically to see Neanderthal DNA in some people, but
we don't see it. They are of course interesting because they might point to things that we
sort of don't accept from Neanderthals in the modern human gene pool. And if we look
in such regions of the genome for what genes are particular present there, it turns out
that is genes that are expressed in the male germ [spelled phonetically] and in testicles.
So it makes it very tempting to suggest that in the hybrids -- Neanderthal-human hybrids,
there may have been a problem with male fertility. And that's actually not uncommon when closely
related species or populations come together and make hybrids, be that say donkeys and
horses. It's a male offspring that's infertile, and the female offspring generally is fertile.
So it may actually be that there was some biological problems when this happened.
So something else that we then work on is to apply this super sensitive techniques,
particularly that single strand library techniques to all the remains of hominins. So far we've
sort of always said that we have to stay within the last 100,000 years or so of human history.
But we now apply this and try older things, and we've been very lucky to work at a site
in Spain called Cema de Luesos [spelled phonetically] in Atapuerca. It's a deep cave, 30 meters
down, so it's very constant conditions where they find very many bones of something that
most people would call Homohydobergensas [spelled phonetically], so maybe an ancestor of Neanderthals.
And from this femur here, we were able to get -- we got samples, extracted DNA and are
very degraded, very short pieces. We have so far been only able to retrieve this mitochondrial
genome that exist in many cultures per cell. And just to give you a feeling for this, we've
sequenced about 500,000,000 DNA sequences from this bone, and sift them down to be in
the end analyzed in the order of 10,000 to reconstruct the mitochondrial genome. But
we were able to do that. And quite surprisingly we found that this mitochondrial genome was
related not to the mitochondrial genomes of Neanderthals, but to the Denisovan mitochondrial
genomes, but far back here of course. So it's very surprising, of course, that we now find
in Spain something that's related even though far back to the Denisovan mitochondrial genome
and not those of the Neanderthals that have been sequences.
So one explanation for this may be that 400,000 years ago, we're simply so far back. So we're
somewhere in the common ancestral populations of Denisovans and Neanderthals and modern
humans that they have variance, that they're related to all of these. We may see other
types of mitochondrial DNA when we sequence more individuals from there. Another possibility
is that this actually comes from gene flow from some other group of humans into the ancestors
here in Cema de Luesos. And it's them only the nuclear genome that would be able to clarify
that. And we're sort of working hard to try to retrieve at least parts of the nuclear
genome.
But what is really exciting to me is that these techniques now allow us to go further
back. Somewhere maybe to within the last million years or so in the rare sites that well enough
preserved for this.
So finally then, the third thing that has [spelled phonetically] a very excited about
is to actually look on the sort of functional implications for modern humans from what we
can now see from the genomes. So for example looking in this regions that lack Neanderthal
contributions to see what hides there more than this male gene's expressed in male germ
line. So looking for things and that has appeared in humans very recently since we separated
from Neanderthals. In particular, those things that have become fixed and are present in
all humans today. So if we take a very strict criterion and say what changes in the genome
can we find that exist to -- in everybody today, no matter where we live on the planet,
but where the Neanderthals, Denisovans look like the apes. So things that changed here
and spread to everybody. That's if you like a genetic recipe for being a fully modern
human when we then compare ourselves to our very closest relatives.
The interesting thing that this catalog of such changes that flow could define us genetically
as a species relative to Neanderthals and Denisovans is not very long. It's not very
long. It's a total of a bit of over 30,000 single nucleotides that have changed, and
some insertions and deletions. So you can actually look through it in an afternoon in
the computer. You can then of course say some of these we have some inkling what they may
be involved in. So there are something like 3,000 changes in well-defined regulatory regions.
And if we look at things that change amino acids in our proteins in our body, we'll focus
on that for a minute just to give you a sense for how we can look this now. It's just 96
amino acid changes that have changed. And they occur in just 87 different proteins because
some of them have multiple changes. So it's of course very interesting to look at this
and say is there some function that hides that may be behind what set modern humans
on this very special trajectory: the fact that we are 7 billion people on the planet,
and not in the hundreds of thousands that -- the hundreds of thousands that the Neanderthals
were.
We're particularly interested of course in things expressed in the brain. So it was quite
interesting to see that if we look for those 87 proteins and see where they're expressed
in the developing human brain, we actually see an enrichment of them in the proliferative
zone in the developing brains where new neurons are born in fetal development.
And quite surprisingly, of these seven genes that are expressed here, three of them actually
turn out to be part in the machinery that pull chromosomes apart during cell division.
So that was quite surprising to me. I thought that was a very concerred [spelled phonetically]
function that would not have changed recently in human history. But there also indications
that how cells divide, how the stem cells divide in the developing brain, determines
what types of neurons are form and how many of them you form. So it may actually be that
these three genes are particularly interesting, that one should now go on study, but that's,
of course, work that will be very -- take a lot of work over many years by many biologists
to do that.
But I just wanted to end up saying how would we do that? How would we take the next step
to investigate such human-specific traits? Because the problem is, of course, we have
no animal models. When we now want to study something that's unique to humans. So I've
gone a long sort of that is the question. And I've sort of spent many years going around
making jokes when I give talks and saying what we want to do is put Neanderthal variance
into transgenic humans. And human variance into transgenic chimps, and then analyze them.
And I've sort of said that that is impossible --
[laughter]
-- and would never be done. But this is sort of subtly not so much of a joke anymore because
there are people, there's even a very famous professor of genetics in Harvard, George Church,
that goes around and suggests that one should go much further than what I suggested here.
We should clone Neanderthals. We should engineer all these changes we found in the Neanderthal
genome into human stem cell and create a Neanderthal. And I think I'm sort of tired of discussing
it. I think it's technically impossible and ethically totally, absolutely impossible.
So why are we really thinking about it?
But it's, anyway, a serious question. How will we go on with this? And I think there
are some ways that I just want to mention. I think that the human genome and I think
Eric is a perfect person to discuss this is a small enough place that all mutations that
are compatible with human life actually exist there out in the population. Every baby that's
born has something like 50 or 100 mutations -- new mutations that are not there in the
father nor the mother. The genome is 3 billion base pairs, we are 7 billion people on the
planet, everyone has 50 or 100 mutations. So we will -- in the future when we sequence
millions and millions of people when you just walk into your doctor's office, I think we
will be able to find back mutations to the ancestral state. And probably it will be possible
to work out ethical ways to then study that.
Something else that will come and we and others are already in the process of doing it is
engineering these interesting changes into human stem cells and differentiate in two
different forms of cells in the tissue culture in the laboratory and study their effects
in cells in culture. And I think something else one would also be able to do is sort
of put them into mice, maybe several of them together to study the effects of particular
biological systems.
Before ending, I should also say there have been many, many people involved in this. Many
more people than I can mention. I then just want to put up one person here, Matthias Meyer,
who developed the single strand library method that -- without which we would never have
been able to get these high quality Neanderthal and Denisovan genomes. It's really transformed
what we can do. Many people have helped in analyzing this, particularly Jim Mullikin
at the NHGRI here in the TESTA [spelled phonetically].
And before ending, I should also say that some of the things I've described is also
in a book where I sort of also describe the dirty, little secrets of how this all happened.
And I thank you very much for your attention.
[applause]
[laughter]
[inaudible commentary]
Male Speaker: Very good. Am I on? Do -- hear me okay? Excellent,
excellent. Terrific Svante, and my head is swimming, not because of the complexity of
the subject, but because that it's been done [laughs] and is continuing to go on. And I
just can't -- personally, I can't wait to see what a Neanderthal mouse looks like.
[laughter]
The -- so what we'll do here is we'll have about 20 minutes of conversation and maybe
before our -- as we're winding that part of it up, I'll mention that if you have questions,
we have two microphones that are available. Don't get up now and get there -- and line
up for your question yet, but I'll announce when we're going to start to take questions
from the audience.
I love the idea of liki [spelled phonetically] replacement with regard to the variety of
models that you've suggested. And, you know, I'm a bones and stones person. And those of
us in that area of paleoanthropology -- we love our categories. We like to slap the species
name on things. And I think that most people also enjoy, you know, what box do I put things
in? Whether it be a woman put her -- putting her husband in a Neanderthal category, or
whatever, which is terrific. In any case, to what degree would you then say that Neanderthals
-- that the Neanderthal lineage and the lineage of living people were reproductively isolated?
Because I think this is one of the questions that as -- in our hall of human origins that
I get, that our volunteers who are the docents who work there get a lot. Do we call ***
-- do we call Neanderthals ***-neanderthalensis as a separate species? And particularly of
interest to me is that for about -- what was it, be about 10,000 years that -- or maybe
15,000 years that Neanderthals and *** sapiens were both in Europe. But apparently you see
no evidence, no echo of interbreeding during that time?
Svante Pääbo: Yeah, so -- I mean we see this what I found
it very fascinating this thing that we do see something that the most reasonable explanation
was that there was some problem with fertility in the offspring, probably that the men had
reduced fertility. So it wasn't just a sort of two groups that totally -- they were perhaps
even on the verge of becoming reproductive isolated that when they came together. Then
it's another thing that we as humans and perhaps particularly as professors in academics you
want to put things into boxes and feel very uncomfortable if you can't put everything
in boxes. To some extent I would say it's a sterile discussion. Are we calling them
a species or a sub species if we now describe that they contributed 1 or 2 percent to the
genomes of people today. In a way that is the interesting information. I think it's
up to everybody if you want to call them one or the other. We actually -- I never use these
Latin names because then I have to take a stand on it. I have the feeling if I say Neanderthals,
if I say Denisovans, modern humans, people know pretty much what I'm talking about and
I don't need to have a long discussion --
Male Speaker: Yeah. [laughs].
Svante Pääbo: -- but is chickening out.
Male Speaker: So noted [laughs] as a paleoanthropologist.
I'm interested in the matter of the chromosomal evolution that has occurred in humans since
the separation from our last common ancestor with a living species, chimpanzees. And all
of the great apes have 48 chromosomes, 24 pairs; humans have 46 chromosome, 23 pairs.
And as I understand it, the change that occurred was where two chromosomes both that have -- that
are the strands are joined together at the end merged into one that joins at the middle:
a fusion of two chromosomes into one. Are we pretty certain that the Neanderthals had
23 pairs of chromosomes as you've shown? And how would we be able to detect? And do you
have ideas about when that possibly very important change in genetic evolution but at the chromosomal
level occurred?
Svante Pääbo: Yes, they're more actually now sure that that
fusion that created our chromosome two had happened before we separate from Neanderthals.
Because we can find this junction fragment that of course created a piece of DNA that's
unique to humans relative to the apes. Where one chromosome ends, the other one start and
fuse to each other. And we can look in our high quality genomes, but the reads we have
there for this junction fragment, and we find it many, many times over. So that had actually
-- so from that point of view -- if two groups of different chromosome numbers have offspring,
you'll often also have problems in fertility in the hybrids. But that is not a risk-taking
-- [spelled phonetically].
Male Speaker: [affirmative] And do you -- are you quite
certain at this point that in the Atapuerca material that goes back to about 400,000,
that again the chromosomal fusion occurred before then?
Svante Pääbo: That we don't know. That there we have so
little information. We only have the mitochondrial genome. But there are studies on that sort
of fusion region that suggests that this is at least 700,000 years ago or more.
Male Speaker: [affirmative] The number that you put up here,
and there were a lot of numbers that we've heard tonight. But one of the ones that I
think may be surprising to many people. I find that when I crib from your articles and
things like this and mention this to people that people are quite amazed at the number
of base pairs in our DNA and that, as I understand it, between any two individuals, there would
be about 3 million base pair differences. Could you put a number on the number of base
pair difference between any two Neanderthals? And what does that indicate about the genetic
diversity of Neanderthals compared with the genetic diversity of human beings today?
Svante Pääbo: Yeah, so as I showed there, there is much
less genetic diversity among Neanderthals than among present day people. Now that said,
we sort of study late Neanderthals here, of course. So it may -- but they have something
like -- I shouldn't put a number on this because I don't really have it in my head. But they
have something like a third of the variation that we have today. They are among the least
variable groups of organisms we have among mammals so far. But again, these are late
Neanderthals. Some of it is rather extreme as we saw the perils of this in Neanderthals
where [inaudible]. And there is also indication that there have been close relatives further
back in the generations of this individual also.
Male Speaker: Well, that's interesting, because one of the
things that as I understand it come out from the study of genetics of all living people
is that the genetic diversity of living humans is actually quite small relative to other
primates. And it is been speculated that -- not speculated exactly, but one part of the spectrum
of thinking on that is that there is -- was a genetic bottleneck in the evolution of our
own species. Others might see that it was a low population size over a long period of
time. Do you think that the Neanderthals also underwent a genetic bottleneck? And might
this be a fairly common phenomenon for the precarious nature of human evolutionary history?
Svante Pääbo: Yes, but sort of with a caveat that I don't
know if that bottleneck had to do with the origin of Neanderthals or say, the last Asian
[inaudible]. We also see that we have now Neanderthals from Spain; we have them Croatia;
we have them from the Corcuses; we have them from the Altai Mountains. But not only do
they have little variation, they also are quite distinct from each other. I mean, our
interpretations relay that they've been quite small but separated, isolated groups from
each other.
Male Speaker: [affirmative] The idea of cloning a Neanderthal
-- I'm glad you mentioned what you did and had your thoughts about this. There is a gentleman
named -- who's quite famous named Stuart Brand who's also very strongly in favor of well,
let's bring back -- let's bring back the extinct forms of organisms. And one day at -- about
three years ago at dinner, he said, "You're a paleoanthropologist. Don't you want to see
a Neanderthal?" And I said, "Well, yeah. I would love to see a Neanderthal, but give
me -- give me a time machine to go back rather than trying to bring one up to speed now."
I'm interested that George Church at Harvard also is in favor of this. You mentioned that
you thought not only is it ethically questionable at best, but is it technically possible given
that every aspect of biology needs an environment? Even the genome needs a molecular environment
in which to actually produce the organism for which those instructions have evolved.
And is it possible to actually take the genome of the Neanderthal that you and your team
and others around the world have produced -- and is it technically possible to bring
back a Neanderthal?
Svante Pääbo: First of all, as I said at one point there,
what we study is actually the single copy part of the inner parts of the genome that
occur only once -- that's where we're going to have this very accurate sequence now. For
about a third of the genome is actually repeated; the sequences occur twice or more times; [unintelligible]
fragments where they fit, to which copy they fit. So we can only statistically say there
were this many copied numbers of this version, but we don't know how they are arranged. And
we know that those parts of the genome are also very important in many respects. So for
a third of the genome we cannot do it at all. For the other parts, I mean, in reality we
struggled just to put in two or three changes today, accurately in a stem cell. We can do
it in one with great effort; putting in more is much, much harder. And we're now talking
about putting in, say, 30,000 back to the common ancestors and another 30,000 to make
the Neanderthal and put them in on both chromosomes. I mean, this is way [unintelligible] what
George Church can do.
Male Speaker: Have you just said, "never"?
Svante Pääbo: I haven't said quite never, but yes.
Male Speaker: I thought I should ask. Okay, I'll have perhaps
one or two more questions. If you'd like to think about questions you'd like to ask Dr.
Pääbo. We have the two microphones here and you can -- please stand up, don't be shy,
and go to a microphone and ask your question. And one of the final questions I have that's
on my mind is that, as a person who does his research largely focused, not entirely focused,
but largely focused in Africa, you know, we tend to think that Africa is the happening
place for changes for the developments in human evolutionary history that have been
so important related to the origin of our species. And, yet, there are problems, as
I understand it, in warmer climates with regard to DNA degradation. Are there some steps,
do you see some technologies that you see clearly, or vaguely, down the road that can
help deal with that? And allow the rich fossil record of Africa and other tropical areas
to be decoded?
Svante Pääbo: So, of course with these new sensitive methods,
some things work that have previously not worked for us. I think it's still the situation
that there have been very disappointing to try things in the Middle East, for example.
I would really hope for areas of Africa with a colder climate, be that southern South Africa,
or Ethiopian Highlands, or deep cave sites, if there are such things, with constant conditions,
would probably be the best things.
Male Speaker: Right, right. I had the pleasure of visiting
Svante's lab several years ago and bringing a fragment of our Shanidar 3 Neanderthal from
Shanidar Cave in northern Iraq to his lab, but unfortunately there were only contaminates
or hardly any DNA in it at all. What was there proved to be contaminates. So that's the fossil
that you can see out in the human origins hall there, but, you know, with the kinds
of remarkable developments that you and your team and others around the world have been
able to make, I remain, at least hopeful that and other bones from more southerly locations,
more near the equator locations will someday be susceptible to study in this way.
So, why don't we begin, and we'll just go back-and-forth, and why don't we start over
here. Please, sir.
Male Speaker: Yes, you showed the nice little pinky bone
from the Denisovans. Can you say something about what fraction of that tiny bone you
actually had to destroy in order to do this experiment? And will there be plenty of that
left in the future for, let's say a decade from now when even your techniques will be
more highly developed?
Svante Pääbo: So we used almost all of that. We used a sterile
dentistry drill and we drill inside; we just barely kept the surface of it. Of course we
do micro-CT on things before so that the more [unintelligible] is at least sort of preserved.
Now actually there's another part of the story, too, that I don't know if I dare tell, but
it's in the book, so I can also still say it. There was another part of that bone that
was given to another laboratory and so there is, but nothing ever really came out of that,
but there is another part of that bone that could perhaps be used for other analysis.
There's also been two teeth found in the cave that we have shown contained Denisovan DNA,
but much, much less than the finger bone. So we have some idea about the dental morphology
of this Denisovans.
Male Speaker: Please.
Female Speaker: Thank you for a lovely talk. In written human
history, we know that infectious disease has had a major role in forming societies and
really having major impacts on different populations around the world. And I was really heartened
to see that you were analyzing aspects of the Neanderthal and Denisovan genomes that
involve the immune loci. Can you, maybe, tell us what you can extract as information for
how perhaps infectious disease may have impacted these early hominids as well?
Svante Pääbo: Yes. That sort of is a good question. We can
of course imagine that infectious disease has played a big role. We have not anything
really to say about this. It's quite hard to study this immune responses because they
are so repeated it's just sort of really hard to see which fragments come from which. And
Peter Parham's group at Stanford are really the experts in these groups of these and it's
their study I had that figure [unintelligible] from there.
The problem is a disease has genes that regulate an immune response, it's a count of high frequency,
but you do not know what pathogens [unintelligible] that were responsible for this. There has
been work recently from a previous student of mine who is now a professor who studies
the DNA of infectious diseases of the Yersinia pestis, for example, and of other pathogens.
So it might be the chance there are, for example, some Neanderthal remains with what seems to
be tuberculosis lesions. So, it may well be that one will be able to study the evolution
of these pathogens even back to part of our archaic continents. But unfortunately I have
nothing really concrete to say.
Male Speaker: I was wondering if the geographic range of
the Neanderthal extended into areas were then and maybe still are permafrost? What I'm getting
at is there a finite, but maybe infinitesimal possibility a preserved body could be found
or maybe an Ӧtzi or maybe a bog person in a temperate climate?
Svante Pääbo: I [unintelligible] find a permafrost Neanderthal
is the question. I think there is a realistic chance of that. Unfortunately, one has not
done that yet. But, if of course things are melting, we've actually started collecting
bones from people who collect mammoth ivory from the river systems in Siberia. They find
a lot of bones on the banks of a river; they are there for the ivory. But one can sort
of get them to sort of pick-up what looks like human bones and it might be that we'll
find things there that are of interest. That's not permafrost, but yes.
Male Speaker: Actually, as a follow-up to that, I'm wondering
is there any possibility ever, do you imagine, of finding DNA say to the place where you
hold a stone tool?
Svante Pääbo: Yes, maybe, I would be skeptical. Or from
blood stains on stone tools or things like that, maybe, maybe.
Male Speaker: Dr. Pääbo, thank you again for such a lovely
talk. And, it's very now interesting to think about what it means to be a modern human considering
your findings. And I was wondering, in reference, this is more of a philosophical question,
I guess. In reference to the findings that you identified, there are contributions of
Neanderthals and Denisovans that have been made to our modern genome and considering
that some of the subpopulations of modern humans have these while others don't, I was
wondering what sort of implications, if any, does this have for the definition of what
it means to be a modern human?
Svante Pääbo: Yes. To me, the definition of being a modern
human must be in the parts that we don't have from Neanderthals. In those regions when Neanderthals
don't seem to contribute, the Denisovans also don't contribute. It must, in a way, be in
this catalog we presented there; that is now a very strict catalog saying, "This would
be genetic changes that are there, as far as we can tell today, in 100 percent of humans
on the planet." Can I of course relax that to say 90 percent then that catalog gets about
a bit more than twice as long, but it's in that catalog I would see the genetic definition
of it being a fully modern human. Because all of us, that is to say, we are all modern
humans, right, even if you don't have any Neanderthal contribution, if you are from
Africa and don't have any Neanderthal contribution, right. But this is a surprisingly short list
to me. It is extremely interesting if some of these have functional consequences I think.
And I think many people work on this other than us in the world.
Female Speaker: When I was a student, Neanderthals were depicted
as being these hairy, shambling, brutes with low brows and corresponding low IQs. I was
wondering from your studies, and this is highly speculative, if you clean them up and put
them in a suit and so forth and put them on the metro, would they stand out? [laughs]
What would people say, "This is a human being or this is a, I don't know what this is"?
Svante Pääbo: Probably you are better than I can answer
this.
[laughter]
I would tend to think one would look twice.
Male Speaker: Yes. I would agree with that.
Svante Pääbo: Maybe not in a New York subway.
[laughter]
Male Speaker: Thank you. I happened to have bought your
book and read it and it's fascinating. I would invite everybody [unintelligible] I would
invite everybody to read it. It's very interesting. Thank you.
My question is more on the statistical side. Both in your presentation and your book and
what you say, it appears that you have very, very fine statistics. And we're talking about
one out of 10,000 or 1 percent, half a percent. I come from the engineering side and the financial
side and these are just, in my universe, just not significant. The likelihood of error,
the lack of certainty on such a fine number of differences over a very large population,
I've done a bit of statistics, leads me to think that the statistics that you use must
be very, very precise or powerful. So, my question is very simple, do you really trust
the statistics and why do you trust them when they are so fine as to be infinitesimal?
Svante Pääbo: Yes, [unintelligible] of course should be
skeptical about this. Of course, in the statistics, we sort of try have as good models as we can.
But it's of course not just a statistical thing we have. You can also go in the genome
and find pieces of DNA that are 30, 40, 50 thousand [unintelligible] that are almost
identical to the Neanderthal genome, where the eye, for example, is almost identical
to the Neanderthal genome and very different from other people from over in Europe. So,
you can sort of actually see with your own eyes that there is evidence of this and that
you don't find this in African genomes. So that is sort of [unintelligible] intuitively
direct answer to your question. We can also formalize that more where we, for example,
do analysis where we see that if you walk across a genome of me and I sort of plot when
I get closer and closer to the Neanderthals, most of that is simply a counterpart of genome
with a mutation, right, is rather low, but then I see that in those regions where I get
closer and closer to Neanderthal, I also get closer and closer to you because we just have
a low mutation rate in those parts. But then when I get to the regions where I'm very close,
almost identical to Neanderthal, I'm suddenly very different from you. So that also convinces
us that there is a population of sequences there that is really derived from Neanderthals.
There are several lines of evidence like that, actually. And I mean, this is so [unintelligible]
I've almost waited for someone in the world to publish something and say it's wrong.
[laughter]
Male Speaker: Now there's a challenge, isn't it? Please.
Female Speaker: Thank you for coming tonight, I really enjoyed
your talk. And first off, I'd like to tell you the Arkansas definition of a double first
cousin, brothers marry sisters, their offspring are double first cousins. Two brothers marry
two sisters, each set has children, the cousins are then first cousins from both sides.
Svante Pääbo: These are double first cousins?
Female Speaker: Arkansas double first cousins.
[laughter]
Svante Pääbo: Ah, yeah, cool.
Female Speaker: My question is --
Male Speaker: Someone write that down, please. --
[laughter]
Female Speaker: -- a lot of the mutations, you said, are transferred
from Neanderthal to modern human being with the immune system. Do you think there's any
way we can maybe pull some more out and have maybe some new gene therapies and stuff to
fight disease; Alzheimer's, cancers, whatever.
Svante Pääbo: I don't -- so the question is, do we think
that we can somehow learn from these variants?
Female Speaker: Maybe even manipulate modern human to go back
to Neanderthal to fight off things maybe, you know.
Svante Pääbo: Yes, I would be extremely, yes, for all these
reasons that we don't clone Neanderthals; I would also not go and manipulate the genomes.
Even with the view to fighting diseases like that.
[inaudible commentary]
Svante Pääbo: That maybe something that's an earlier branch
off [unintelligible] the real sort of attempt to do that, after lots of discussions and
negotiations with six, seven years ago, to drill a little bit in the root of a tooth
and we couldn't get any DNA out of that at that time. Now that said, we are better at
it now, but it's also very humid, and very warm. I suspect it's actually not preserved.
The majority of fossils, especially from such climates, don't contain any DNA. That's not
that this can be applied to everything, unfortunately.
Female Speaker: Hi, I have a question about another human
ancestor that's also a recent new comer to our whole hominid species, Australopithecus
sediba. So, I've been teaching anthropology at the high school level for eight years and
it's been really exciting because we keep getting new species, like sediba. And so I
heard, it's almost like rumors, that there might be on some of those fossils some actual
flesh or they think there might be a little bit of something like that, and so would you
be able to get DNA out of that? If that, sort of rumor, is actually true?
Svante Pääbo: So what was the rumor?
[laughter]
Female Speaker: So, I've heard, I just took, actually, a course
through Coursera with John Hoch at the University of Madison and so he interviewed somebody
who was working with the sediba fossils and they think there might be some bit of, you
know, actual material --
Svante Pääbo: Soft tissue --
Female Speaker: -- yeah, soft tissue.
Male Speaker: And that rumor is true in that it is a rumor.
Svante Pääbo: I mean, I would still think, so how old is
sediba?
Male Speaker: 1.9 million years.
Svante Pääbo: I would be very skeptical. I don't think it
would be justified to sort of sacrifice any of it to try to get DNA. But animal remains
from similar place, [unintelligible] attempt but I would almost think it was a waste of
your time to do that today.
Male Speaker: So we know the Neanderthals buried their dead;
we know that they created musical instruments; we know that they painted; do you have sense
of that portion of the non-African population, what the DNA, the genomes contributed to modern
people? So, blonde hair? Blue eyes? Musical ability?
Svante Pääbo: No, actually. All we know almost is just what
I presented there, unfortunately. I think there will be a lot more knowledge in the
future. I know that there are studies underway, for example, where [unintelligible] look at
cranial forms, [unintelligible] what Neanderthals looked like from FMRI studies, medical studies.
We also have genome sequence from individuals to look at and now look at what Neanderthal
proportion part of the genome that people have and does it correlate with the features
in the cranial [unintelligible]. So I think there will be some things like that that will
be known in just the next few years. But there has been a claim that red hair came from Neanderthals.
There's even a, sort of study, so, but those mutations in the Neanderthal genomes we have,
we don't see the mutations that now give red hair in Europeans, so far.
Male Speaker: So it's a kind of a parallel evolution of
red hair, is what you're suggesting?
Svante Pääbo: A parallel? I mean, we don't know if Neanderthals
had red hair.
Male Speaker: Ah, right, okay. Please.
Female Speaker: Hi, my question may be a little bit similar.
I'm actually a cultural anthropologist so I'm a little of my realm here. But, is there
any potential benefit to having either Neanderthal or Denisovan DNA. And, for example, if I'm
looking for a husband, should I seek out or avoid men with Neanderthal or Denisovan? [laughs]
It's more about, is there any potential benefit? Is there any something different about people
who have the Neanderthal?
Svante Pääbo: No, everyone we've looked at outside of Africa
have Neanderthal contribution, but we have different pieces, each of us, right. So you
can actually walk around people in this room and parcel together the Neanderthal genome
by jumping from person to person, so to say. And you can get something like 35 percent
of the Neanderthal genome that way. But, yes, we're just at the beginning of associating
any of the variants with anything in how we look, or behave, or things you might look
for in your husband.
[laughter]
Male Speaker: That may not have been a question a scientist
would ask, but it certainly is a very human question. Please.
Male Speaker: My understanding is you worked primarily with
mitochondrial DNA?
Svante Pääbo: Not anymore. Whenever we can, we really try
to look at the nuclear genome because it gives us so much more information.
Male Speaker: I wonder is it possible to use the male chromosome?
Is that accessible, I mean, is it preserved enough to use?
Svante Pääbo: So, by funny quirk of nature, these are females
in the Denisovan high-coverage genome and Neanderthal high-coverage genome, but when
we find a male and we have one in Spain now, one will be able to study the Y chromosome.
At least those parts of them that are single copy, the large part of them that are repeated
we'll have problems with.
Male Speaker: Thank you.
Male Speaker: We'll take two more questions. Eric Green
has a question.
Eric Green: So I'm going to actually ask a question of
the moderator because I actually have something that I think you might be able to answer to
shed some light on. Everything Svante talked about has been made possible because of remarkable
technological breakthroughs in DNA sequencing to allow exquisite sensitivity to be able
to reconstruct genomic information from highly degraded bits of DNA. But, he'd be the first
to admit, you even heard in some of his answers, that what limits him now, will be some technical
advances and computational methods will get better, but really what limits him from doing
some things that even come up in the questions and answers of "wouldn't it be great if?"
are better specimens and better preserved materials. And one can't help wonder if somewhere
in this earth are better preserved samples where the DNA is more intact and we can get
much more accurate and complete genomic information from those specimens. But, we can't find it.
So just as we've seen genomic technologies advance this field significantly, are there
new technologies on the horizon for finding better specimens that can then be analyzed?
Male Speaker: Yeah, that's a good question. Well, if you
look at the comparison of the extent of genomic coverage of the Denisovan DNA compared with
others from Vindija Cave, caves are a good place to look. Caves in colder environments,
so far, have been very good to look. I know that in our excavations right near the equator
in Kenya that there have been times when I have been excavating, for example, the fossil
elephant butchery site that's featured in one of the snapshots through time in our exhibit
on human origins, whereas while we were digging we were actually seeing oxidation of plant
roots, of ancient plant roots right before our eyes as we were digging. At that point,
we changed over to excavating with gloves, sterile gloves and implements that we have
not excavated with before or handled in order to try to see is there something from the
stone tools that we could recover. And we were able to actually see amino acids related
to keratin in hair on them. So that's an example of something where if you, and this has gone
on in one of the Spanish sites where you've worked on the Neanderthals, El Sidrón, is
that the name of it?
Svante Pääbo: Yes.
Male Speaker: Where people went in there, the excavators
went in there with gloves in sterile conditions in order to recover these things. I would
say that the best place to look would be caves. And the question is whether there are caves
that have been sealed enough in areas that are closer to the equator, places in Africa
for example, where one might try to look, but I think it's, you're work has shown, that
it's a little bit like looking for a needle in a haystack.
Eric Green: Are there better imaging technologies that
are becoming available that can allow you to find the sites to then try to dig --
Male Speaker: Yeah, I mean, satellite technology has been
great to be able to see exposed sediments; exposures of sediments; places where the vegetation
coverage is such that you can actually go and you can see eroded hills and gullies to
recover things. But, even there, when you get to outcrops where you can dig, where nature
does the first excavation, and you go in and you help nature along by excavating a bit,
we find the degradation of pollen; we find the degradation of organic materials; and
so one of the questions that could be really, you know, that would get around that is if
you could drill down like we've drilled a core for environmental purposes out of the
east African rift valley. But, the chances of hitting hominid bone in a drill core that's
four centimeters in diameter going down are quite remote, so there's going to have to
be some continued luck on the paleo-anthropological side and where possible, the use of sterile
techniques.
Yes, last question.
Male Speaker: Thank you very much for an excellent presentation
and also for an excellent book that you wrote that talked about the decades of effort it
took to develop these techniques, especially dealing with such small fragments of DNA and
the extensive amount of contamination. Early in your book you talk about the examination
of Ӧtzi, the Paleolithic man that was found in Europe, but you don't follow-up with what
we've learned later. And, I assume we've learned a great deal. One of the interesting questions
perhaps you could shed some light on is, to what extent is Ӧtzi different from us? He's
clearly not a Neanderthal, he's much closer to us, but is there a field of study of worth
in looking at human beings using the techniques you've developed since the last breaks 3,000
plus years ago now that you've got these techniques to the point where they can look so specifically
at individual genes and get pretty good DNA registers and apply them perhaps on things
in the last five to seven thousand years.
Svante Pääbo: Yes, I think that's a sort of area that's
expanding very drastically. There are many laboratories now that study sort of Neolithic,
Paleolithic, the transition to agriculture in Europe. So I think that will be extremely
illuminating and [unintelligible] first insights are coming suggesting there's quite an influx
of populations that came with agriculture. But, in northern Europe, there's also big
contribution from earlier hunter/gatherers to present day populations. So I think there
will be a lot of things in that timeframe that will come. That is obviously very, very
close to us today compared to Neanderthals, particularly. Had we sequenced this [unintelligible]
person today, we would not have reacted and said this couldn't be a person on the street
today.
Male Speaker: In addition to the fossil Neanderthal from
Shanidar Cave that we have on display, we do have, here in the department of anthropology
in this museum, one other fossil hominid from a site in Afghanistan. And, I'm glad to say
Svante's going to, I think, go away with it in his luggage in a couple of days.
Svante Pääbo: You'll get most of it back. You'll get most
of it back.
Male Speaker: We don't know how old it is. It comes from
a site called Dari Ekor and there's a plan to date the specimen and have to Svante's
group sample the bit of cranial bone and see what it means for, not only our collections,
but for the study of human evolution. As a follow-up to that, I just have a question.
How many fossil human specimens do you have in your lab right now that you're working
on?
Svante Pääbo: We have milligrams of bone material from hundreds
of specimens that we have had. But many sites are of course many, many bones for example.
Male Speaker: Where can one get your book?
Svante Pääbo: In a bookstore.
[laughter]
Svante Pääbo: Amazon.
Male Speaker: And there is a bookstore in this museum and
of course all around. Are you doing a signing by any chance, while you're here?
Svante Pääbo: Not that I know of.
Male Speaker: Not that you know of. Okay. So in any case,
well, I hope that we have it in our bookstore. Does anyone know whether...
Audience: Yes.
Male Speaker: We do, okay, good, good, excellent. That's
a thumbs-up on that. So, well, in any case, I can say it, Svante can't, go buy his book.
I want to thank you all for coming out on a snowy evening and contributing to a great
evening here together. And a tremendous thanks to Dr. Svante Pääbo.
[applause]
[end of transcript]