Svante Paabo: “Neanderthal Man: In Search of Lost Genomes” | Talks at Google


MALE SPEAKER: Svante Paabo got
his PhD from the University of Uppsala Or is it Uppsala? SVANTE PAABO:
Yeah, it’s Uppsala. MALE SPEAKER: Uppsala in Sweden. And did four years
post-doc at Berkeley. So he’s been in the
Bay Area before. He’s actually the founder of
the field of ancient DNA, who even when he was
a doctoral student was working on sequencing
DNA from Egyptian mummies without telling his
adviser in his spare time. But fortunately it
worked out well. And much later, any time
you read about Neanderthals and whether they mated with
humans, where they came from, chances are it came from his
lab, the Max Planck Institute in Leipzig, Germany. So please welcome Svante Paabo. [APPLAUSE] SVANTE PAABO: OK, so do
that afterwards if you think it’s– So, yeah, what I wanted
to do though was then talk a bit about what we can learn
about the origins of modern humans, so the origins of the
type of humans that exist all over the planet today,
from studying the genome of our closest extinct
relative, the Neanderthals. And the technology and
the ability to do this have come about over 30
years of development. And the history of
how that happened is what’s described in this
book that just appeared. It discusses not
only the science, but a bit how this
came about, including the conflicts and the mistakes
I made on the way and things like that. But I don’t want to recount
here exactly what’s in the book. What I’d rather do is talk a
bit about the insights that have emerged over the
years about human origins from this work. And in the end,
a bit about where we want to go in the future,
in the next five or 10 years or so. But just before we start,
let me then remind you about what you
all know, I think, that our genome,
the DNA, is stored in almost all
cells in our bodies on these chromosomes in
the form of the famous DNA, this double helix. As you also know,
the information is there in the
sequence, in the form of a sequence of
these four bases, As, Ts, Cs, and whatever. I forgot [INAUDIBLE]. And it’s there twice, so to say,
and in a complementary form. So whenever there’s
an A on one strand, there’s a T on the other. When there’s a G there,
there’s a C there. And that’s really important. Because whenever a cell
divides, particularly then in the germ line when new
individuals may be formed, there are enzymes that
unwind those strands, and two new strands
are synthesized with the old as a template. So you get two fairly extract
copies again of the genome. But nothing is, of
course, perfect in nature. So sometimes an
error may be made. And if that ever is not
repaired quickly enough before the cell
divides again, that will appear then as a mutation,
a new version of the DNA sequence. So any baby that’s born
as in the order of 100, 200 new mutations that’s
there neither in the father nor in the mother. And we can detect the
effects of those mutations in the population. If you compare DNA sequences
of two people in the room, we will find a difference every
1,200, 1,300 bases between us. If we add in a chimp, we
will find a difference every 100 bases or so. So if you want to reconstruct
the history of a piece of DNA, what you do is use
our best models for how these mutations happen
and reconstruct the history and depict it in the
form of a tree like this normally where in this
case it’s super simple. The two genome sequences go
back to a common ancestor rather recently. And much further back is
a very common ancestor shared with the
chimpanzees also. And as you also
know, our genome is a bit over 3 billion base pairs. So if we compare two genomes–
either the two genomes you carry from your two parents
or two people in the room, we have an order of
3 million differences between two individuals. So there is quite a
lot of information there to reconstruct
the history with. And if you do this on a global
scale, what you will find is that in Africa you have more
variation than outside Africa. So although there are only 700
million people or something like that living in Africa,
and almost 7 billion people living outside Africa, we
have more genetic variation among those Africans than
among all the non-Africans taken as a group. And not only that,
most of the DNA variants we find
outside Africa, we find closely related
forms also inside Africa. But in addition, then,
there is a component of the variation in
Africa that’s not outside. So the interpretation
of that is then that modern humans
evolved, emerged in Africa, accumulated variation there,
and a part of that variation went out and colonized
the rest of the world. And by genetic tricks, you can
also figure out approximately when this happened by
looking at how big chunks, over how big distances
are things associated on the chromosome
and things like that. And you find that
that’s fairly recently, in the order of 100,000
years or even a bit less do people start
expanding out of Africa. So this is the origin of
this recent African origin model of modern humans. But there is, of course,
a problem with that. And that is that we
know from finding bones that there were
other forms of humans around since a long time, since
2 million years at that time. So most famously,
there were Neanderthals in Europe and Western Asia. In Eastern Asia,
there were other forms of now extinct humans that
are less well described. So the big question is sort
of what happened with them? How are we related to them? Did they contribute to us? So but to study
their DNA, you would have to go back in
the bones, of course. And that, of course,
is a bit difficult. And this then goes back to where
it started in the ’80s, where I started and studied
Egyptology, actually, and then ended up in graduate school
studying molecular genetics. So I knew there were thousands
and thousands of mummies of animals and humans around
that look very well preserved. I thought perhaps there’s
DNA preserved in them and started looking in
the microscope at tissues and such remains. And that turned out to
the very frustrating. So this is a muscle from
a present-day person. You see the muscle fibers. You see these black dots, which
are the cell nuclei, where the genome is stored. And this is a muscle from
a 2,000-year-old mummy, much like the one
we looked at there. So you barely see there
are muscle fibers there. You see no cell nuclei. There’s no DNA preserved But it’s not always
that depressing to look at these things. So as also described
in the book, I’ll have at that time in
the ’80s lived in Sweden. So you had rather
good connections to communist countries. We were able to get
mummies from East Berlin. And one of the mummies there,
this 2,400-year-old child, you could in the basal levels
of the skin see some things that looked like cell nuclei. You could actually stain
it and show DNA is there, and go on to extract the DNA,
replicate it in bacteria, and show that some of
it came from human. So in hindsight, I really
believe this microscopy that the cell
nuclei here contain DNA that’s for sure
DNA from that mummy. The DNA I replicated
and published is for sure a contamination. It’s for sure DNA from
[INAUDIBLE] Berlin or something like that. Because what has
since become clear is that there’s
generally very little DNA preserved in such remains. It’s degraded and
chemically modified. So whereas, say, from
a gram of tissues, you might extract a micro gram
of DNA from a blood sample or from a present-day
tissue, for example, a 10,000-fold to a million-fold
less in such old remains. And the vast majority
of the DNA here comes from bacteria and things
that have grown in the tissues since it died. So if you have tiny
amounts of contamination from present-day
humans here– so, say, skin fragments in a room like
this where people are around, dust particles or to big
extent, skin fragments that do contain a lot of DNA. So if such comes into
present-day experiment, it will be swamped
out by the billions of copies of the
modern DNA there. But in these
ancient experiments, if a dust particle
lands, it can easily overwhelm the whole experiment. So it’s also described
there how we over the years become more and more
paranoid about this until when we today now work
in spacesuit-like things in rooms with high
pressure and filtered air so dust doesn’t get in,
pretty much like a chip factory or something like that, to avoid
contaminating the experiments. Also focused a lot on
not the nuclear genome that comes from
the moms and dads, but the tiny part of the
genome outside the cell nuclei that comes
only from the mother, the mitochondrial genome
because there are many, many copies of it
per cell, so a bigger chance that a
little bit survives. And worked ourselves
back in time. So we started when I
was here at Berkeley. There There were actually
zoological collections. At the museum at the university
there, were these kangaroo rats from the Mohave Desert,
that had been collected 70, 80 years ago. So we went out and set
traps with the field maps from that time and
collected rats now, and could follow the populations
then over 70, 80 years. To a bit older,
extinct animals– marsupials wolves, say,
that became extinct about 100 years ago from
over-hunting in Australia, or things that disappeared
in the last glaciation. So these giant ground
sloths, for example, were in the North and
South America, or mammoths and mastodons and
things like that. But our big interest
was, really, Neanderthals as our closest relatives. And so Neanderthals appear
300,000, 400,000 years ago, and then exist in
Europe and Western Asia until they become extinct
something like 30,000 years ago in connection with that
present-day humans appear. So a big question is
then what happened when modern humans
encountered these guys? And there are two
ideas about this that one was fighting about in
paleontology, vicious fights that paleontologists can
have over 30 years, where one idea is modern humans
come out of Africa, meet these guys in
Europe and Asia, and replace them with
no mixture whatsoever. That there’s no contribution
from Neanderthals to Europeans today, for example. And the other idea is that
when modern humans come to these regions, they do
eventually replace this forms, but they do mix with them. So that Neanderthals
would have contributed genetically to present-day
Europeans and these other forms in Asia, the present-day Asians. So you can see this as a sliding
scale from total replacement, 0% contribution from
these earlier guys, to a sliding scale to
more and more of that. So our first chance to
test this came in ’96 when after a lot of
intrigues we got access to this specimen,
which is a Neanderthal, but it’s not just
any Neanderthal. It’s the Neanderthal that was
found in 1856 in the Neander Valley and gave its name
to this group of humans. And we were really
lucky, I think, that the first
Neanderthal we studied was really the
type specimen that gave its name to these guys. Because whatever
Neanderthal we since have studied, that there’s
always some paleontologist who comes and say, ah, it’s
a little too gracile, a little too robust. It’s not quite typical. But if this is
not a Neanderthal, then Neanderthals don’t exist. So with the technology
at the time, we retrieved a part of
that mitochondrial genome with great effort, short little
pieces, many, many times over, looking for the things that
were consistently there, and then reconstructed
such a phylogenetic tree for the mitochondrial DNA then,
this tiny part of the genome. And what we saw was
what was already known, that all mitochondrial
DNA of everybody living today go back
100,000, 200,000 years, to a common ancestor of all the
mitochondria that exist today. But Neanderthal
mitochondrial DNA go much further back to
a common ancestor, half a million years or so. So they look quite different
in their mitochondrial genome. So in this sliding scale of
things, it’s really here. There are no humans
today that run around with a Neanderthal
mitochondrial genome. It’s total replacement,
no contribution. So that was then the picture
for this mitochondrial genome. And we couldn’t get
to the nuclear genome. And I think I’m on the
published record eight years ago or something like that
of saying we will never see the nuclear genome
of Neanderthals. And you should, of course,
never make negative predictions like that because
you’re generally overtaken by history and
by technology, actually. And in this case, what
I didn’t anticipate was really high
throughput DNA sequencing that came around in the
early 2000s, the ability to sequence millions
of DNA molecules really rapidly
and inexpensively. So instead of trying to find
some little piece you’re particularly interested
in, you could simply extract all the DNA from
such a fossil sequence, all the molecules
you time in there, make your little data bank,
and start comparing it to the human genome that
had then become sequenced, and say what has similarity
to the human genome that presumably comes
from the Neanderthal. So the first place
for this work was from a cave site in southern
Europe, in Croatia, this place, from this bone that’s
38,000 years old, from this little fragment
of the bone here. And the first
thing you then find is that the fragments
of DNA are really small. So whereas from present,
from a blood sample from me, you would extract
things that are 10,000, 20,000 base pairs
long, here it’s really 50, 60 base pairs,
tiny little fragments. And the vast majority
of the DNA doesn’t come from the
Neanderthal at all, but from bacteria and fungi
that colonized the bone when it was lying there in the
sediments in the cave. So our very best
Neanderthals have sampling like 3%,
3.5% [INAUDIBLE] DNA. So we then managed to raise
some money to over five years work a lot on the technology
from which we can extract the DNA from the bone and
manipulate it into a form that you can feed into
the sequencing machines. And we have gotten a lot
more efficient than that, something like 500-fold more
efficient over this time. And the machines have also
gotten better in how much they can sequence. We looked through a lot of
different Neanderthal sites and bones to find the ones
with the most DNA in them. And it described a
lot of little problems in running a group of
different forms of expertise to actually get this done. We identified then three bones
that were particularly good that we used for this and
sequenced a bit over a billion DNA fragments from these
bones, which at the time was quite a lot, vast
majority, of course, not from the Neanderthal, as
I said, but from bacteria. But we could then
match the ones that had similarity to
the human genome with computer programs we
developed to the human genome, taking various types of errors
that occur in these sequences and so on into account. And we ended up with a first
view or the Neanderthal genome in 2010, then where we had
seen a little over half of the genome at least
once from these fragments. So we could begin
asking questions. And that then involved a lot
of population– yes, please? AUDIENCE: With fragments
just being 20 bases, are they unique
enough to figure out whether something is
the same gene or– SVANTE PAABO: Yes. AUDIENCE: Or could
the Neanderthals have had the genes which
are completely different from humans
but which are– SVANTE PAABO: Yeah. So first of all, if
Neanderthals had something that at all doesn’t exist
in the human genome today, we would be totally blind to it. But that is probably very
little such material there. If you compare to
the apes for example, there’s hardly any such things. But a big, big challenge is
this matching of these fragments because, yes, we have
a [INAUDIBLE] for 30. We don’t regard
anything below 30. But also there is
an issue about we have a vast majority
of bacterial DNA that can have spurious
similarity to places in the human genome. We certainly
mis-map some things. But, yes, so that this
one of the big things, is actually an
informatics problem here. But so we then involved a
lot more population genetics, modeling people. Particular, I should mention
Monty Slatkin and his group at UC-Berkeley, and David
Reich and Nick Patterson at the Broad
Institute in Boston, to analyze these genomes. And one of the first
questions was, of course, what happened when modern
humans came out of Africa and met Neanderthals? Did one mix or not? And we addressed that
in many different ways. But one way, the
most intuitive one, is to say, well, if there was a
contribution from Neanderthals to present-day people in
Europe, we would, of course, expect Europeans today to
share more genetic variance with Neanderthals
than people in Africa, where there have never
been Neanderthals. So they couldn’t have
contributed there. So this is this
idea, again, saying if there’s no
mixture whatsoever, then the Neanderthal is just
as far from people in Africa as people in Europe. If there is a contribution,
on average Neanderthals were more similar to Europeans
that to people in Africa. So we then had the
Neanderthal genome. And we needed to compare
to present-day genomes and look for small signals. We were, of course,
very scared of errors in the sequencing or
differences in ever profiles in different genomes. So we went out to sequence
five genomes total in parallel from
present-day people ourselves to know we
had the same error profiles in them all. So wanted one European
person to ask. Of course, the archetypal
European person is someone from France. We sequenced a French person. We sequenced two people
from Africa, one for China, and one from Papua New Guinea. And then we did a
very simple analysis. So we had to test
this first, say we compare the two present-day
people to Africans, then find all the places where
they differ in their genome. And then we [INAUDIBLE]
for the Neanderthal. How often does it match one
African and the other African? Since Neanderthals had
never been in Africa, there is no reason
for Neanderthal to be more close to one
African than another African. It should be equally distant. And indeed,
statistically speaking, it’s 50/50 of 99,000 or
100,000 matches there. When we do this with
the European person and African person, then we
found, to my surprise actually, statistically significantly
more matching to the European than the African individual. Even more surprising was that
in China relative to Africa, we again find it. And in Papua New Guinea, again. So this really surprised me. I was biased after the
mitochondrial genome was saying that there had been
no contribution. But if there was one,
I would, of course, expect it where Neanderthals
had existed in Europe. But we found it in China, where
most people agree Neanderthals had never been, and in Papua
New Guinea where everyone agrees Neanderthals
had never been. So the model we then ended
up suggesting that’s since been borne out by other
work is to suggest that when modern humans
came out of Africa, they presumably passed
by the Middle East. And we know that in the Middle
East, there were Neanderthals. So if these early modern
humans mixed with Neanderthals and then became the ancestors
of everybody outside Africa, they can sort of carry with
them out into the world this Neanderthal
contribution also to regions where Neanderthals never existed
to the extent that 1% to 2% of the genome of
the DNA of people in this part of the world
come from Neanderthals today. Why didn’t we find any
mitochondrial contribution when we now see it in
the nuclear genome? I think the simplest,
boring answer is that it can be
simply by chance. The mitochondrial genome
is inherited as one unit. And it can just be
lost [INAUDIBLE]. But it is, of course, also true
that the mitochondria genome is maternal inherited. So we get it from our mothers
and not from the fathers. So if it was particularly
Neanderthal men who contributed to the modern
human gene pool, it would also bias against
mitochondrial DNA. And, of course, you can say
even by normal consideration, saying if you have hybrids,
you would, of course, expect the babies to stay
with their mothers. And we know that these
individuals contributed stayed in the modern human
population because they in turn had kids and contributed
to people today. So maybe we’re
particularly picking up the cases where the
mother was modern human and the father
was a Neanderthal. But both are possible. So we’re blind to contribution
in the other direction, into Neanderthals, simply
because we would then have to find a
Neanderthal that lived at the right place and
late enough in time that its ancestors had
met the modern humans. So in reality, we
have only something like 300 Neanderthal
individuals or so distributed over hundreds of
thousands of years of history. So we would be extremely lucky
to find someone like that, I think. So we haven’t done that
and perhaps we will never. Maybe in the Middle East
or something like that. Can we differentiate
against a scenario where, yes, modern
humans and Neanderthals have a more recent common
ancestor than we think? We see this difference
between Africa and non-Africa. We see that overall in the
genome we’re closely related, including all people
in Africa, of course. But people outside Africa
have this extra component in their genome, a tiny little
part that is deeper diverged, yet very similar to
the Neanderthal genome. So that’s really the only
reasonable explanation for that is [INAUDIBLE]
from Neanderthals. So the question is, all
three must have been fertile, and can we estimate
how fertile they were? So the only thing we can say
about that– that’s very recent work now– where two groups, one
project where we were involved together with people at Broad
and another group in Seattle, have independently now designed
a pretty efficient algorithm to go over present-day
human genomes and say which parts actually
come from Neanderthals. And if you do that in
thousands of genomes of present-day people, you
will find regions nowadays where we see no Neanderthal
contribution although we would expect it from the distribution
across the whole genome. But then there are
what we call deserts, where there suddenly is no
Neanderthal contribution. So that’s interesting
because you could imagine there are hiding
something that really defines us as modern humans
that selected against an account
from Neanderthals. And you could then look at
what genes are in such regions and where are they
expressed in our body. The only significant
over-expression of the genes are in the male urine
line, in testicles. So it really suggests
that there may have been some problem in the
hybrids with male fertility. And that’s actually
a rather common thing when closely related
species or groups mix, that the male hybrids have
problems with fertility. So horses and donkeys
and mules, the males are infertile but the
females are fertile. So it seems to have gone
on something like that. It may have been
that the boys didn’t do well in
reproduction at least. But that’s really the only
thing we can at the moment say about that. But there seems some to have
been some incompatibility there biologically, really. So I can never stop myself
from also pointing out that there has been a lot
of scientific interest in this, lots of
follow-up things. But the public is
also very interested. And lots of people write to us. And a lot of people write and
self-identify as Neanderthals or volunteer to give us
blood samples or things. And after a while,
reading this mail, I started seeing a pattern. And that was that it’s
mainly men who write to us and self-identify and very few
women who write and say they are Neanderthals. And so I presented this as
my research to my group, in counting emails. And they said, ah, it’s
just ascertainment. It’s just because men
are more interested in molecular genetics that
they would write to you. Women would not write to you. But that’s not true. Because I went back and
looked at the emails again. And there are
plenty of women who write and say they are married
to Neanderthals actually. [LAUGHTER] Whereas so far not a
single man has claimed he’s married to a
Neanderthal woman. We’re very interested in
other forms of humans, also. So there are lots of other
forms of Neanderthals one finds that one
can hope to study now. And we work together
with Russian colleagues that excavate in
Siberia and particularly then in this cave, Denisova
Cave, in southern Russia on the border to
China and Mongolia. And it’s a very beautiful area
in this cave where they in 2008 found a tiny little bone that
they were actually extremely skilled in realizing that
it might a human bone. So it’s a fragment
of the last phalanx of a pinkie from a little girl. So we got this bone, and
we extracted DNA from it. And we were surprised to find
it was very much endogenous DNA. It was like 70%, very different
from the Neanderthal samples, the best Neanderthal samples. AUDIENCE: Meaning? SVANTE PAABO: Meaning really
coming from this individual. And we don’t know why
it’s so well preserved. It’s not permafrost here. It’s not frozen. But we were able to sequence
the genome from this girl, too, and were quite surprised
to see that it was not the Neanderthal and
not the modern human. It has a common origin with
Neanderthals, but far back, 200,000, 250,000 years back. And since then,
Neanderthals have a long, long
independent history. So this is the first
time, actually, that only based on the
genome sequence we define a new group of extinct
humans that we then called the Denisovans, after
this Denisova Cave where they were found. Just like Neanderthals
were named after the first place
where they were found. And since then, we have
worked on new techniques to be even more efficient in
extracting tiny amounts of DNA. So we now have a very
good genome from both. From this girl,
we have sequenced every position many, many
times over in the genome. It’s actually better
quality than most genomes sequenced from people today. So we can begin to see, when
you have some good genomes, you can see cool things. We can, for example, see
missing mutations here. This person lived tens of
thousands of years ago. So compared to us
today, they have experienced fewer mutations. And we can actually
measure that. So relative back to the common
ancestor with the chimp, there’s a little over
1% of the mutations that are missing here. So if we now say that’s
6.5 million years ago, we can actually date the
bone to approximately 60,000 to 80,000 years ago. So it’s fascinating to me. That’s from a bone that’s too
small to do a carbon date. When we can sequence
the genome, we can actually now begin to
date it from the genome. There are still
caveats about this, particularly error rates
in the present-day genomes confuse this number. But it’s certainly something
that will come in the future. We can ask, as for
the Neanderthals, did they contribute [INAUDIBLE]
to present-day people? And yes, they did in
Oceania, not in Siberia. So this then suggests
that they were more widespread in
the past, I think, that they’ve been also here
meeting ancestors in that area. I think it’s sort of
an indication of what will come in the future. This is a copy of this tiny
little bone, where we can then get a whole genome sequence. We can date it. We can re-construct a lot about
the history of this group. But we don’t know how
their skeletons looked. We don’t know what
stone tools they made. And I think it’s
something we’ll see a lot more in the
archaeology in the future. So we shouldn’t be too long
where from this cave also then found a little
toe bone that turned out to be Neanderthal. So we now have a very
good Neanderthal genome also that we’ll
sequence many times over to very high quality. One of the cool
things we find, then, is that you can, of course,
then invoke over chromosomes and find where there are
differences between the two genomes that this
person inherits from their mother
and their father. And what we then find
in this Neanderthal is that we find huge segments–
this is 19 million bases here– where the two chromosomes
are identical. And we found much
less of those in this than this of our
present-day people. And this, of course, means that
the patterns of this individual were very closely related. So we can reconstruct
the relationships that must have been. One of these four
relationships must been for this
Neanderthal individual. The parents must have been half
sibs, or, say, grandfather, granddaughter. Don’t even ask me what
double first cousins are. I can never reconstruct it. But they were clearly
closely related. So it would be very
interesting to see if that’s a general pattern
in Neanderthals when we get more genomes
in the future. So we have now a bit
more things there. We can actually see
how these things are mixed with each other. Then Neanderthals
to modern humans, Denisovans to modern humans. We can see on mainland Asia
also a bit of a contribution from Denisovans. And we can see quite
interesting a contribution from something else,
a deeper divergence into Denisovans, not into
Neanderthals– probably homo erectus or so in Asia. So let me accelerate
a little bit. I’ll not do this. I want to just encounter
where we go now. So just to wrap that up. We have excluded this absolute,
no-contribution, total replacement. But we see a bit of replacement
from these earlier forms to present-day humans. But the big picture
is, of course, still replacement
coming out of Africa. So just a term for this, I
suggest Leaky replacement. So the big picture
is replacement. There’s a bit of contribution
from these earlier forms. And what can we now
do with these genomes? I think when we now have
high-quality from our closest relatives, the
really cool thing is we can focus on
these [INAUDIBLE] changes here, things that we
all have in common on the planet today but where the
Neanderthals and Denisovans look like the apes. So things that appeared
in modern humans and spread to everybody
in the last little segment of our history. And why is that
particularly interesting? Well, I think there
are a number of things that changed in modern humans. A big thing is
technology, of course. Neanderthals appeared
350,000 years ago, disappeared 30,0000 years ago. The stone tools they make in
the beginning of their history and the end of their history
are pretty much identical. Modern humans appear,
say, 100,000 years ago. And I think we agree,
particularly at this place, for example, I think,
that technology today is different from
100,000 years ago. So technology started changing
rapidly with modern humans and could become
regionalized, for example. Neanderthals made
the same stone tools wherever they were, from
Central Asia to Western Europe. With modern humans,
it changes so rapidly. So when you don’t have
much communication, technology really becomes being
different in different regions. Art that really depicts things
comes only with modern humans. And modern humans,
of course, start spreading across
the whole globe. These other forms of humans
have lived in Africa and Eurasia for 2 million years. They never made it to Americas,
never to Australia, never to Madagascar in
2 million years. Modern humans
started spreading out of the Middle East
60,000 years ago, and in those 60,000 years
come to every speck of land, not only the big continent,
but every little island out in the Pacific. So there’s actually no
evidence that Neanderthals or the other early humans
ever spread across water where you don’t see
land on the other side. So they were not mad. But modern humans,
how many people must not sail out on the Pacific
before you found Easter Island and just perished? And we can never stop. Now we go to the moon,
and we go to Mars. So there is some craziness
there also, not only technology, I think. So we can look in the genome
now for all of the things that we have in
common that is not shared with the Neanderthals. So if we take the
strict approach and say thanks to the
best our knowledge, 100% percent of
humans have today, but Neanderthals and
apes don’t have it, then that’s not a
long list of things. It’s surprisingly short. It’s something like 30,000
changes in the genome. So whereas I differ from
an individual in this room by 3 million differences or so. If we say things
that we all have in common and the
Neanderthals are difference, it’s just 30,000. So you can scroll
through them in two hours and look at them
actually in the computer. So for example,
it’s just 96 changes in proteins of amino acids. So this is a list
of all the genes that have such differences. The dirty little
secret of genomics is, of course, that
we’re incredibly bad at predicting what
such changes would have for consequences. But we were, of
course, particularly interested in things
expressed in the brain. And we and many others will
now start to look at that. So just to give you a
feel for this, if we just look in different
layers of the brain during development in
the fetus, the one area within the red
[INAUDIBLE], we see a significant
over-representation of those proteins
that had differences to the Neanderthals, is
in the proliferative zone, where the neuronal
precursor cells divide to make neurons for our brain. And actually three
of those 87 proteins are expressed in the spindle
and the parts of the cell that pull the chromosomes
apart in cell division. And it’s known that the plane,
how these cleavages take place here, determine
what type of neurons will be formed during
brain development. So these three
genes, for example, are particularly
interesting to study. And I think we and many others
will now start doing that. So just to end, then,
what we then want to study is human-specific changes. So how will we do that? Because it’s, of
course, a problem. And no animal model, really. So there are people like
George Church at Harvard who have suggested we
should clone Neanderthals. We should engineer these changes
into the modern human stem cell and have babies born that
are essentially Neanderthals. And I think there
are many reasons to say it’s actually
both technically not feasible in my mind. But leaving that apart,
it’s ethically, of course, totally unthinkable. But what can we do? I think something that will come
is, of course, the genome is a small place, after all. 3 billion bases. I already told
you that there are 200 new mutations in
each baby that is born. Just 7 billion people. So every position
in the genome that can change and is
compatible with human life exists out there
in the population. But [INAUDIBLE] low frequency. But in a future where we will
all have our genome sequenced when we just walk into
the doctor’s office, who will have millions and
millions of DNA sequences, we’ll be able to start finding
people who have back mutations to an ancestral
state and study them. So that will become possible. You can, of course, also
engineer in these changes, into stem cells,
and differentiate tissues, nerve cells,
liver cells, in test tube, in the lab. And we and others are
starting to do that. And you can start putting
these things into mice and start humanizing part
of the mouse brains, say, or something like that. So just to end up, think
that I have convinced you that if you’re interested
in what makes humans unique, particularly this last
part of human history that set us on this very
unique trajectory of spreading across the whole globe,
coming to dominate even parts of the
biosphere today, then it’s very useful to now
have the genomes of our very close relative,
the Neanderthals, but to now go on to
understand those changes. It will not be enough to
just stare at the genomes. We have to do functional work. I think one of the
most realistic ones is actually this thing
to humanize mice. So that was it. I would be glad to
answer more questions. [APPLAUSE] AUDIENCE: How much of
a sample do you use up? And how much do you leave
for future technology? SVANTE PAABO: Yeah,
so, to just test if there is DNA preserved
that one could study, we use like 50, 100 milligrams,
so very, very little, actually. But then, if there is DNA
there and one wants to go on, then it really depends on
the preservation state. If there is very little
DNA, we would need more. But we never work with more
than half a gram or maybe up to a gram of bone material. So it’s not that we use
up enormous amounts. AUDIENCE: Excuse me. How many individual Neanderthal
genomes do we have sequenced? SVANTE PAABO: So we have only
one really good quality one. We have then this
low-quality one from Croatia and one from the Caucasus
that I didn’t talk about. So we have three
genome sequences. We have some exome
sequences, too. We just have the protein coding
parts on two more individuals. AUDIENCE: Could you use
this to create technology for archaeologists, like
fish stains or something to help them find
more Neanderthal DNA? SVANTE PAABO: Yes. So what we can do is
to take small samples and determine the
species of bone where don’t know what it is. And we begin to do
that, the vast majority, of course, animals. But now and again we then
find new Neanderthal bones. And then you’re in
a good situation. Because then you
can really argue, if you didn’t even know
what species it is, it can’t be very valuable
to you, this bone. You should give it to me. AUDIENCE: Yes, have there
been any specific interesting insights about the
X or Y chromosomes of Neanderthals
compared to ours? SVANTE PAABO: Very curiously,
these are female individuals so far, we have happened to
hit in those three individuals. So in the X chromosome, we
see very little contribution from Neanderthals. It’s probably again
to present-day people. So it’s almost like a
desert, the whole chromosome, which is probably also
compatible with that the men had particular problems. Of course, there are
extra, many genes on the X that has to do
with reproduction. And males are, of course,
slaves to their X chromosome, if you like. Men have only one X chromosome. So if they get bad alleles,
they are in trouble. Whereas females have two
chances also on the X. So it’s probably again
a reflection of that the men may have had a
problem in the hybrids. That’s the only thing at the
moment we can say about that, I think. AUDIENCE: The contaminant DNA
that you found in the samples, was that contemporaneous with
the death of the individual? SVANTE PAABO: The bacteria
that are there, we don’t really know. There are typical chemical
modifications of the old DNA. And in some specimens, most of
the bacteria have such things. So they are at least
thousands of years old. But we don’t know
how much of that goes back to really 60,000
years ago and how much can be– AUDIENCE: Presumably
you couldn’t look at the gut micro
biota because that would have been completely
eroded away, not in the skeleton? SVANTE PAABO: I
would think so, yes. But yes, it’s an
interesting question. And we’ve talked about studying
the bacteria from the soil you just outside the bone and inside
the bone, and comparing that and see if one can
fish out something AUDIENCE: So since the
DNA or the bone fragments were found in Europe,
how do you know that the contamination is
not from European humans? How do you control for that? SVANTE PAABO: That add
mixture signal, yes. So I mean, there are
a lot more analysis than what I present here
that really indicate that. For example, if you look
in the present-day humans, in the fragments
that are particularly close to the Neanderthal,
say, in an individual, in me, those fragments are
also particularly different from everyone
else in Europe. So if you just
plot, say, fragments where I’m closer and closer
to Neanderthal, most of that is simply due to that
these are regions of the genome that
change slowly. But then I also get closer
and closer to other Europeans today. These are assay regions
that change slowly. But when I get really close
to the Neanderthal, then suddenly I’m more different
from everyone else. So that’s another
line of evidence to say that these are really
things from the Neanderthal. MALE SPEAKER: Let’s thank
him for coming here. [APPLAUSE]

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