- I'm very pleased to welcome you
to this public talk sponsored
by the Department of Biochemistry,
the great Department of Biochemistry.
And we're thrilled to have Svante Paabo
here with us this afternoon.
This talk is part of the Biochemistry Colloquium's
International Steenbock Lectureship,
and that's funded by the estate of Harry Steenbock.
Svante Paabo is a world-renowned researcher
from the Max Planck Institute
for Evolutionary Anthropology in Germany.
He's a founder of the field of paleogenetics,
the study of ancient DNA.
He uses DNA obtained
from ancient bones to piece together human origins
and the history of how we spread across the globe.
He has shown how much DNA we share with Neandertals,
and how some genetic variance from the Neandertals
are beneficial, while some are involved in disease.
And my colleague Aseem Ansari, Professor of Biochemistry,
will tell you more about Svante's work
and introduce him, thank you.
[applauding]
- Thank you, Marsha.
This is the first International Steenbock Symposium Lecture
series and it has been an unusual one
because this is the first time we've actually
had a second lecture in the Historical Society.
So that tells you of the broad appeal
of the deep and abiding question,
the mystery that Professor Paabo is investigating.
That is, of our origins, of our human origins.
Where did we start?
What other types of archaic humans might have been?
And where are we today?
How do they contribute to our being here?
He started this, I first noticed his papers from 1987,
where he was among the first people to clone
a mummified DNA from Egyptian mummies.
And from then onwards it has been just an intellectually
stimulating series of contributions,
both scientific and
making it accessible to general audiences.
That's what you're seeing today.
You can see much of that work in over 290 papers
that he's published, most of them
in some of the world's best journals,
but even more interesting I recently discovered
I had not seen this before
but I recently discovered his book The Neandertal Man.
This tells you about his personal journey as he traveled
through those 30 years, making his way,
in the last few years deciphering the Neandertal genome,
incredible resolution, you hear about it today.
As well as Denisovan genome and other archaic
[mumbling] that he's pursuing.
With that I would also like to say, those 30 years,
the advancements that he's made,
both scientific and conceptual,
have brought him numerous awards.
Yesterday when I tried to introduce him,
I sort of mixed things up because they were just so many.
So today I decided not to try and list all the awards
that he's won, except to say that he's won
some of the most prestigious awards
and is a member of some of the most prestigious
societies and national academies.
Most people work a lifetime to be a member
of one national academy.
He's a member of a dozen, including
the US National Academy of Sciences, German,
Swedish, Finnish, Russian.
Uncommon to have that.
He has been widely recognized for his amazing
and penetrating work.
I would also like to point out that he has had
a direct impact on UW,
he's contributed to UW in many ways.
First of all, bringing the science
and the humanities communities here together.
General audience.
This is one very clear evidence
of his impact on our community.
The second one is Jesse Dabney
and his mentor Bill Aylward, who's studying Troy.
Where is Jesse, Jesse, stand up.
There he is, stand up, stand up.
Jesse is Paabo's student.
He did his PhD work at the Institute, the Max Planck,
that Marsha just mentioned.
And he is now here with William Aylward,
trying to essentially build the Molecular Archaeology Group.
This is an attempt to bring together chemists,
genomicists, biomathematicians, anthropologists,
archaeologists, et cetera.
So already you can see Svante's immediate
impact on our community.
We look forward to all sorts of wonderful things
that this Molecular Archaeology Group will do
for us with Jesse and William at its helm.
With that, let me invite Professor Paabo to tell us
about the amazing stuff that he's done
over the last several years.
[applauding]
- Thank you very, very much
for the very generous introduction.
I'm both pleased and honored to be here
for this first Steenbock symposium.
I have had two wonderful days on campus talking to many,
many people and learning many things.
So what I then wanted to do is
to talk to you a bit
about how we have been able to reconstruct
the genome of Neandertals, relatives of Neandertals,
what we learned from that, talk a little bit
about what we begin to learn from studying
the genomes of very early modern humans outside Africa
and in the end talk a bit about functional
implications of this.
Functional implications of the contribution
from Neandertals and Denisovans their relatives
to present-day humans.
And what we can learn maybe about what's specific
to humans relative to Neandertals.
Let me start out by pointing out what you already know,
I think, that our genetic materials,
DNA stored on chromosomes in all cells in our body
so we can study our genome looking at DNA
from such chromosomes from any cells.
And this DNA molecule, as you know,
let's see if I, I do have a pointer here
this DNA molecule is double-stranded, as you know.
The information is encoded in a sequence
of four letters or nucleotides.
And the two strands are really important
because when a cell divides there are enzymes
in the cell that take these strands apart
and you synthesize.
New strands with the old as a template in a very exact
process but there are then errors
that are sometimes made.
Sometimes a wrong base is built in.
You have a mutation.
And if this happens in the germline and it's not repaired
before the next separation comes,
it will appear in the next generation as a mutation
that you can detect in the form
of a difference between two human DNA sequences
that you compare.
If you compare two genomes of people in this room,
you have a difference about every 1200, 1300 letters,
there's a difference between two genomes.
And these mutations rain down on our genomes
approximately as a function of time.
So if we add in here a chimpanzee,
you will have more differences.
You will have about a difference every 100 bases or so.
If you're now interested in the history of our genomes
or the history of a DNA sequence,
what you will do is study these differences,
use the best models that we have for how these mutations
accumulate, and reconstruct the history,
and depict it in the form of a tree like this.
Very simple in this case.
The two human sequences go back to common
ancestors recently, much further back once shared
with the chimpanzees.
And you know also that we have three billion bases
in our genome.
So a difference every thousand or so means there are
three million differences between any two genomes,
also between the two genomes inherited from your father
and your mother, so there's a lot of information
to reconstruct history here.
If you now do that and look on this variation world-wide,
what you will find is that you find
most variation in Africa.
And you take the entire world outside Africa,
although there are a lot more people living outside
Africa than inside Africa,
because you have less variation there.
And in addition, most of the DNA sequences
you find outside have close relatives inside Africa.
But there is a component, if you like,
of the variation inside Africa
that have no close relatives outside.
So the interpretation of this pattern
is then that modern humans,
that is the direct ancestors of people living today,
evolved in Africa, accumulated variation there,
and a part of that variation went out
and colonized the rest of the world.
You can also estimate approximately when that happened.
And it's rather recently in sort of evolutionary terms
within the last hundred thousand years or so.
When these modern humans then came out of Africa
they must have met other forms of humans
that existed since a long time in Eurasia.
Neandertals to western Eurasia,
other forms farther east in Asia.
And we are then, our lab, is sort of, if you like,
sort of obsessed with these Neandertals.
You may then ask, well, first of all remind you
about the fact that Neandertals are then
this sort of robust humans.
They appear in Europe and western Asia
about 400,000 years ago and exist
there until around 40,000 years ago
when they become extinct.
And around that time then modern humans appear on the scene.
And you may then ask why should we be
so interested in Neandertals?
And I think there are two major reasons for that.
The first one is that they are the closest evolutionary
relatives to all present-day humans today.
If we sort of should define ourselves as a group,
it's them from a genetic perspective
or biological perspective.
It's them that we should compare ourselves to.
The other thing, interesting thing, is, of course,
that they were here rather recently.
Like 3000 generations ago or so there were
Neandertals in Europe.
You may ask what happened to them?
How are we related to them and things like that.
So that's something that, the latter question,
has been debated a lot in paleontology.
What happened when modern humans came out of Africa?
Did they totally replace the Neandertals
so there would be no contribution whatsoever
from Neandertals to present-day people?
Or is there mixing up to sort of a suggestion
of that Neandertals would be the direct
ancestors of Europeans?
A sort of 100% contribution, if you like.
So we sort of got a chance to then start asking
this question in the 90s when we got access
to the Neandertal type specimen.
This is a fossil that was found in 1856
and gave its name to this group of hominids, Neandertal.
It was actually the first time that one realized
there had been other forms of humans
around before present-day people.
So we took a sample of this thing here,
a rather big piece we needed at that time.
We use much less now and we could then build
on already 10 years' or more experience of trying
to retrieve DNA from ancient remains.
Work that then started with studying ancient Egyptian
mummies and showing that sometimes
there could be DNA preserved in them.
But also realizing very rapidly after the first
sort of results that there are lots of problems with this.
One problem is that the ancient DNA degraded
to really small pieces.
So 50, 60 bases-long,
whereas you have 10-, 20,000 bases,
base-pairs-long pieces if you extract
DNA from a blood sample of you.
There are chemical modifications here.
And there is, of course, a lot less preserved per gram
of tissue, on the order of 10,000 million-fold less
than you would have in a fresh bone.
There are other problems too.
One problem is that the DNA here is present in a vast excess
of microbial DNA, DNA from bacteria and fungi
that colonized the bone when it was in the ground.
And all this leads to that if you have tiny amounts
of present-day human DNA that you may have in,
say, dust particles in a room like this with many people,
a large part of the dust is actually
skin fragments from people.
And one such dust particle may easily contain much more
DNA than you have in your experiment here.
And these small amounts, when you study present-day DNA,
are so small so they wouldn't at all disturb
or show up when you study DNA from a fresh blood sample.
But in this situation here the same amounts
can totally overwhelm your experiments.
So actually the very first mummy DNA that I cloned
and published in Nature in hindsight
was sure of contamination from myself.
[laughing]
But we don't talk about that.
That's secret. [laughing]
So then I developed over the years lots
of funny things to avoid contamination.
You dress up in funny clothes,
you work in a room with filtered air,
irradiate your equipment and UV light, and so on.
At the time, we focused on a tiny part of the genome
that is inherited from mother to offspring,
the mitochondrial genome.
The advantage of that for this work is that it occurs
in many copies per set.
There's a much bigger chance
that some fragments would survive of it.
So we reconstructed part of the mitochondrial genome
and estimated such a phylogenetic tree
as I illustrated in the beginning.
All present-day mitochondrial genomes go back
to a common ancestor quite recently, 100,
200,000 years ago.
And what we found was that the Neandertal mitochondrial
genome goes much further back, half a million years or so.
And since then one has studied more Neandertals
and 10s of thousands of humans,
and it's very clear there's no modern human today
on the planet that runs around
with a mitochondrial genome from a Neandertal.
So in this sense of things it is total replacement.
But it is also clear that this is a very
small part of the genome.
The big story is in the nuclear genome
that's inherited both from mothers and fathers
and that has a lot more information.
And I think I am on the published record
in some newspaper 10 years ago or 11 years ago
saying we will never be able to sequence
the nuclear genome of a Neandertal.
There's too little there.
It's chemically modified.
It can't be done.
And I guess it goes to say you should never make
negative predictions like that in science
because you're generally overtaken by things.
What often overtakes you is technical
developments, of course.
And what I hadn't anticipated that came along
was High Throughput DNA Sequencing.
The ability to sequence millions and billions
of molecules really rapidly.
So you then can take all the DNA from such a fossil,
sequence all the molecules, make your database,
and start comparing it to the human genome.
This worked for the first time from the site
in southern Europe, Croatia from this bone
that's about 40,000 years old.
And, indeed, the fragments are very short
what you get here, 40, 50 base pairs.
The very best bones have something like
three or 4% endogenous DNA, all the rest is microbial.
And we worked very hard for a few years on improving
the methods of extracting these things,
converting into form that can get into
the sequencing machines.
Looked at many sites and many bones to find the ones
with the most Neandertal DNA in them.
Focused on three fragments of bones
from three different individuals.
You may notice that these are sort of tiny
fragments of things.
In fact, there is very good evidence that in this cave
and in many other caves where Neandertals lived,
they consumed each other.
So, say, the long bone, such as tibia, this one,
the shinbone, have been crushed to get to the bone marrow
in the bone to eat it.
There are cut marks where muscles attach and so on.
That is probably the key also to why the DNA
is so well preserved in those bones
because when you have burials we begin to have less
good DNA preservation.
I think if you bury a body you have mounds
of microbial activity that consumes the body.
If you sort of cut it up, chew off all the bone,
and throw the bone in the corner of the cave,
it dries out rapidly.
Less microbial activity.
So I think we actually have cannibalism
to thank for that this project worked so well.
So we sequenced a little over a billion fragments from this,
most of them bacterial, mapped into the human genome,
taking into account the typical errors
we see in this ancient DNA,
and then had slightly over half the Neandertal genome
in 2010 when we had the first draft.
So we then asked this question.
Would there have been a contribution to present-day people?
We asked it in different ways.
The most direct way was the same to say
that if modern humans coming out of Africa
meet Neandertals in Europe and mix with them,
then we would expect Europeans today to share
more genetic values with the Neandertals
than Africans today, where there had never been
Neandertals in Africa.
There's no reason to assume that Africans should have any
special relationship to Neandertals.
So it is this idea simply, if there is no contribution here,
then Neandertal is just as far from someone
in Africa as someone in Europe.
If there is a contribution, there should on average
then Neandertal should be closer to people in Europe today.
So we can compare the Neandertal genome then to genomes
of people today that we sequenced
and make very simple tests.
If you start by testing this in taking two Africans,
finding all places where they differ from each other,
and then take the Neandertal genome
and see how often does the Neandertal match
the variant this African has or this African.
Since Neandertals are not expected to contributed
to Africans, there is no reason to assume
that Neandertal is closer to one African
than the other African, right?
And that's indeed what we see.
Statistically speaking, no difference here.
But that was then, to my surprise, different
when we looked at a European versus an African.
We find more matching to a French person here
than an African person.
Even more surprising, a Chinese person
versus an African person, again, more matching.
And finally, even Papua New Guinea,
where for sure there have never been Neaderthals,
we find more matching.
So, the sort of idea that came out of this was to say,
to explain why we find a contribution also in parts
of the world where Neandertals have not lived.
Was to say that these early modern humans
that come out of Africa, they go through the Middle East
and we know there are Neandertals there,
if they mix with Neandertals early on
and then move out in the world, they will sort of carry
with them this contribution out to the rest of the world
to the extent, then, that one or 2% of the genome,
if your roots are outside of Africa, come from Neandertals.
So we published this in 2010.
There was a lot of sort of scientific follow-up over
this general model, a sort of too simple a course,
but overall it has held up pretty well.
It was very satisfying.
But very soon after we published this I also started
realizing that the general public was very interested
in what we were doing.
I can never stop myself from sort of pointing out,
then, that we started getting a lot of correspondence
also from the public.
E-mails and letters from people
who self-identified as Neandertals
and offered us sort of hair samples
and blood samples to study.
And after a while I started sort of noticing
a pattern in this correspondence,
and that was only almost men who wrote to say
they were Neandertals and very few women
who said they were Neandertals.
I sort of presented this to my research
group as my research.
I count mails, I also do something useful.
And they were, of course, hyper-critical as they are always
of anything I say.
They say this is just entertainment.
Men are more interested in molecular genetics.
They will write to you, women don't.
I went back to my mails and found that that is not
at all true because there were plenty of women
who said they were married to Neandertal men
[laughing]
and so far not a single
man who claims that he is married to a Neandertal woman.
So that's, of course, very interesting, as a geneticist,
a transmitted pattern like that.
So that is sort of one thing to follow up.
Well, we do a bit of other things too.
We work with colleagues in Russia that excavate
particular in Siberia, in particular this site
on the border to Mongolia and China, Denisova Cave.
It's Professor Derevianko, who leads
these excavations and finds amazing things.
This is the site, and they found this bone in 2010.
It's a phalanx of the toe.
It turned out to come from and Neandertal.
We were able to sequence the genome to very high quality.
So we sort of have covered every position
to which we can map this toe fragment 50 times over.
So we really have everything of this genome.
So you can begin to do more detailed things.
You can look at a certain chromosome
that you are interested in, say, in different people
today and mark in red here the fragments
that come from Neandertals.
And you will see that different people have different
fragments from the Neandertals,
but indeed, over all it adds up to about
one or 2% of the genome of a person from Asia or Europe.
You could ask then.
Is that a lot or a little?
A sort of stupid question, what is a lot or a little.
But just to give a perspective
on this might be to say,
of course, if you think of your own family tree.
You have 50%
of your DNA from your mother
and from your father, 25% from a grandparent,
one more generation back 12%, 6%, 3%,
and on average one and 1/2% six generations back.
So quantitatively speaking, in terms of the amount of DNA,
it's as if you have one Neandertal ancestor
six generations back.
But that would of course have been in big chunks
since this is smaller chunks, but in terms
of amount that's sort of what it is.
You can say how much of the Neandertal genome
still lives on today?
So since we have different fragments here you can
sort of go along the chromosome and parcel
together a bigger piece of the Neandertal genome
in the computer by jumping
from person to person in this room.
And it turns out that it's in the order of something
like 40% or 50% of the Neandertal genome
is still walking around on two legs today sort of in people.
But they found other things also and still find
things there in this cave site.
They found this other very small fragment.
It's part of the last phalanx on the finger of a child.
We sequenced a good genome from that one too.
And we were very surprised to find that it was not
a Neandertal, not a modern human,
but something very distantly related to Neandertals.
So, say about four times deeper than the deepest
split between any human population when you look
at this bit to Neandertals.
There is a distant relatives to Neandertals.
We debated a lot about what to call them
and ended up calling them Denisovans after the site,
Denisova Cave, where they were found.
You can ask for these groups in Asia,
have they contributed to present-day people?
Indeed they have.
You find a little bit, way less than 1%, in mainland Asia,
nothing in Europe, and out in the Pacific
you find up to about 5% of the genome in people
in Papua New Guinea or aboriginal Australians
come from these Denisovans.
To summarize then what we think we know
about the origin of Neandertals and Denisovans
and modern humans from studying genomes,
we sort of think that they have some origin in Africa,
the Neandertals and Denisovans.
They come out and evolve then in western Eurasia
to what we call Neandertals and in eastern Eurasia
to what we call Denisovans.
It's sort of a megalomaniacal thing to put them
all over Asia.
We don't know how they were distributed.
There were for sure other forms of hominids there too.
There were hominids in Indonesia for sure
and other things in China.
But we do know that at some point they were at this site,
the Denisova Cave.
There were Neandertals at some time
and at some other time Denisovans there.
Then modern humans have an origin in Africa,
start spreading out of the Middle East seriously
50, 60,000 years ago.
They mix early on with Neandertals, continue to spread.
And there is now good evidence that there was later mixing,
say, in the ancestors of Asians
because they have a bit more Neandertal ancestry.
Somewhere in Southeast Asia presumably modern humans
mix with the Denisovans and continue out in the Pacific.
And these other groups disappear and become extinct
but live on then in the form of one to 2% in Europeans
and Asians and another 5% on top of that
in Papua New Guinea.
Now we sequenced two archaic genomes.
We found several cases of interbreeding with modern humans.
I wouldn't be surprised say in China in the future
one would find other cases with other groups.
And indeed when modern humans spread across Africa,
I wouldn't be surprised if one mixed with other forms
there too since one did it outside
and one might find that in the future.
So you may then ask, what happens with this contribution
of Neandertal DNA in modern humans?
We now begin to be able to follow that
because there is now more and more work on really early
modern human genomes too, particularly in Europe.
So there was a project where we were involved
and David Reich's group at Broad and Johannes Krause's
groups in Jena studying 51 early modern human individuals
between 45,000 years ago and about 10,000 years ago.
So you can then look on how much Neandertal DNA
did you have in these early modern humans.
If you go back in time and these are people today
having one to 2%, and then we go back in time
and we then find sort of a steady increase
in amount of Neandertal DNA as we go back, suggesting,
and there's other lines of evidence too,
suggesting that there is selection against this
in a human population, that this Neandertal variance
often or slightly disadvantageous
and we are slowly sort of losing them over time.
But in this study we found also a surprise.
One of the 51 individuals was totally different
from the others, had a lot more here.
And this individual is this,
it's a mandible from Romania.
It's 40,000 years old.
It's a very early modern human, found from this cave site.
And if we just look at, say, one chromosome here
and compare this individual to other early modern humans
and present-day humans have fragments
of Neandertals indicated in color, this individual,
then, has a lot more.
And in reality, these black spots here
we have no information since it's such
a very low-quality genome.
So it seems that over half this chromosome
is solidly of Neandertal origin.
And genome-wide we find a seven such large, large readings.
And this then suggests that this individual
had an Neandertal ancestor very recently.
So of course if you have a Neandertal
and a modern human and they have a baby,
the baby will have one chromosome of Neandertal
origin and one of modern origin.
If this baby now goes on to live in the modern human
population and has children,
it will have children and start recombining here.
So there will be big chunks in the first generation
of Neandertal origin, and as the generations
go on these chunks will become smaller
and smaller due to recombination.
So from the size of these we can then estimate
how far back in the family tree
was there an Neandertal here?
And there's [inaudible], but you can say that six, five
or four generations back there must've been
a Neandertal ancestor here.
So, we've sort of almost caught them in the act
of doing it with a Neandertal here, within six generations.
We know that there has been local mixing here too.
So, very clearly we have rejected this idea
that there was total replacement.
We have rejected this idea.
There is this contribution,
but it's sort of a small contribution, less than 10% or so.
The big picture is still our variation comes out of Africa.
So we like to call this a leaky replacement,
saying most of our variation comes out of Africa.
There's a little bit of contribution from other groups.
So just to give you a feeling for where one can go now
with early modern humans then,
if you look at these 51 individuals that we studied
in this age range, you can sort of begin to ask
lots of questions about what happened after Neandertals
disappear and when these modern humans come here.
You can look at your genetic relationships
among these early modern humans.
And a way to illustrate that is simply to list
all the modern humans here and there
and do a matrix where the more yellow you are,
the more closely you're related overall in the genome.
Just to illustrate this, if we take Chinese
and a sort of southern Chinese individual,
you find that they are particularly related to other
Chinese and Native American individuals.
The colors don't come through so well,
but this is more yellow than other things.
If we now first look here on the very old individuals
we have, this 40,000-year-old from Romania
and a 45,000-year-old person from Russia,
the striking thing here is that they seem to be related
to no one else.
There's no yellow in this comparison here.
So these early guys, this one and this one,
the very earliest modern humans we have is of these
individuals seem to be related to no one else today really.
So it really seems that the very first modern humans
that come, say, to Eurasia either become extinct
or absorbed into Neandertals.
These early pioneers are not ancestors of anybody today.
That, then, changes from 37,000-year-old.
This is the earliest individual we looked at
that actually is an ancestor to people today.
It's from this site in western Russia here, Kostenki.
This individual is related to people today.
So from 37,000 years ago, all individuals we've looked at
so far actually have at least some ancestry
they contributed to Europeans today.
You can then move forward a time a bit
to a 35,000-year-old individual from Belgium.
You can see how that individual here is related
and particularly actually to people from this later group
of closely-related individuals.
So, these are individuals that live a lot later,
like 15,000 years later.
So you can begin to look at this.
You have this person 35,000 years ago in Belgium
is sort of particularly related to someone in Spain
18,000 years ago, and then to people even younger
that are in middle Europe again.
And of course what happens in this time
is the Ice Age, right?
So what we are looking at here is really the retraction
of populations to the south during the Glacial Maximum
and then recolonization of Europe again.
So we see population movements within Europe at this time.
We see no influence from outside Europe actually.
So, if we do an analysis here
where we sort of illustrate
how many alleles one shares with ancient individuals
with different places in the world,
for example the Near East that is of relevance.
Around Syria you see no special relationship
with the Near East.
And that then changes when you come to around
14,000 years ago. From 14,000 years ago
you suddenly start seeing
a special relationship with the Middle East.
And it's this group of people named after this
site in Italy then.
Around 14,000 years ago there is some kind of influx
of genes from the Middle East to Europe.
And that is sort of the first time one sees that.
It's also interesting that nothing that had been suggested
by archaeologists or so that there was something
happening at that point.
I think also for later times this study of genetic history
actually comes up with quite a few surprises.
To just sort of illustrate then what we know
about European history of modern humans,
we have this earliest period where modern humans come
but disappear, no relatives later on.
Then we have a period of 38 to 15,000 years ago
where there's sort of movements within Europe
but you see no influx into Europe.
That then changes after that with this
Near Eastern connection, and there's lots later
then influx from the East and from many places.
If we then come back to the Neandertals
and the Neandertals mixing with present-day people,
one thing you may ask is,
Does that matter?
Is there anything functionally relevant to us today
from this contribution from Neandertals?
You can work over the entire genome here in Europe,
say, or in Asia and look for part of the genome
where many people today have something,
where like 50% of people have a Neandertal contribution
here that's shared with Asia.
There are other things here that's unique to Asia
or unique to Europe.
If you just ask statistically what links are there,
that's then as a group, that's genes keratin,
sort of involved in skin and hair.
So we don't know functionally what that means,
but we will probably in the future learn that there
is some aspect of physiology or morphology,
the hair and skin, of people in Europe
and Asia that comes from these extinct hominids.
There are other more for functionally interesting things.
There is, for example,
a risk variant of the gene,
risk for type II diabetes, that turns out to be
quite high-frequency over in Asia and Native Americans.
About 25% allele frequency.
That variant comes from Neandertals very clearly.
You may sort of ask why is it that something
that gives you a problem today, that gives you diabetes,
comes over from Neandertals and rises to high-frequency?
The speculation there would be that that has to do,
that variance that may cause diabetes today
when you eat too much during your whole life,
may actually help you in a period of starvation.
So it may be that this is some kind of Neandertal
adaptation to starvation.
Denisovans have also contributed to things
that are functionally relevant.
The most spectacular example, I think, is in Tibet,
where people are adapted to living at high altitudes,
to have less complications in pregnancy, for example,
than other people who move there.
It was already known that a major component
of that adaptation is a variant this gene here, EPAS1.
And a group at Berkeley showed then that this variant
is very common in Tibet, hardly present anywhere else.
That comes over to the ancestor Tibetans from Denisovans.
So that is something then that is quite important
for the ability to live at high altitudes in the Himalayas.
There are other things, receptors important
in immune systems, defense against viral infections
that come both from Neandertal and Denisovans,
and are associated in populations today, for example,
in resistance to bacterial infection that gives you ulcers.
So if you don't have an ulcer you might thank
the Neandertals perhaps for that.
But these same variants are then associated
with an increased risk problem with allergic diseases.
Allergists may sort of blame the Neandertals perhaps.
Overall, there is quite
a lot of things genome-wide
that seem to be positively selected
that come from Neandertals.
Many of them have to do with immunity
and many with skin and pigmentation actually.
There is sort of a picture emerging then where these modern
humans come out, meet these groups that have lived
for hundreds of thousands of years
in the environment in Eurasia.
These groups are adapted to things
there in their environment.
Some of the variants come over to modern humans,
are positively selected, and rise in frequency
in present-day humans.
Something you could call adaptive introgression, or so.
But you should not lose track of the fact
that most Neandertal variants that we know
what they do or are associated with today actually
come from studies in medical genetics
and are just associated with either the risk for disease
or reduced risk of disease and we don't really know.
They don't seem positively selected
or anything like that.
And this involves many diseases by now, say, blood clots,
skin diseases, even things like tobacco use,
or depression, or things like that.
The last thing I sort of wanted to bring up
is another aspect of this.
And that is to say what was not contributed by Neandertals.
What is unique to modern humans?
You can sort of look chromosome-by-chromosome here,
indicated in red in Europe and green in Asia,
frequency of contributions from Neandertals.
And then you can say, are there parts of the genomes
where we statistically would expect to see
a contribution from Neandertals but we don't?
And, yes, there are such regions.
You can say, what is hiding in those regions
where we seem to select against something from Neandertals?
One way to ask that is simply to say,
genes in those regions, where are they expressed
in the body more than you would expect by chance?
And if you ask that question there is only one tissue
that stands out, and those are testicles.
So, the male germline.
So that then is very suggestive that there was some problem
maybe in the hybrids with sort of male fertility.
And of course it could be that these hybrids
had reduced male fertility.
And that sort of fits with the pattern
in biology where you have closely related
populations of species that have hybrids.
It's generally the heterogametic sex in males,
that have a problem with fertility.
In mules, as you may know, the males
are infertile and the females sort of can at least
some time have offspring.
So it may actually be that Neandertals
and modern humans were on the verge of sort of
becoming reproductively isolated when they came together,
and we have some indication of that here.
That is one insight from those regions.
Another one is to say,
are there things hiding here
that are really unique functions for modern humans?
Saying things that changed here
and that are typical of modern humans.
There are at least in my opinion then it's a sort of
interesting question because it's of course the fact
that modern humans rather than Neandertals or Denisovans
or any other extinct forms of humans,
after a while at least, start to develop technology,
things that change very rapidly.
Neandertal technology is homogeneous
over their whole distribution.
It's also very constant over hundreds of thousands of years.
In modern humans technology starts changing rapidly.
You also see that it becomes regionalized.
Stone tools in Central Asia are different from in Europe.
Modern humans are the first ones that do art,
at least art that depicts things
that we can recognize as art.
And that comes quite early on.
And modern humans are the first ones
to sort of spread across open water,
where you don't see land on the other side.
So for two million years other forms of humans
live in Africa, Asia, and Europe.
They don't come to the Americas and don't come to Australia.
They don't come to Madagascar.
There's actually no evidence that they ever crossed water
where you don't look over and see land.
So they were not mad.
Then come modern humans.
And whereas other guys didn't do it for two million years,
in 50,000 years they come to America, to Madagascar,
to Australia, and to every little speck of island
in the Pacific to Easter Island, right?
So how many people must not sort of sail out on the Pacific
and just perish before they found Easter Island?
There is some madness there.
It has to do with technology, of course,
because they were building boats and things.
But it's also something about attitude, I think.
And we can never stop, right?
Now we go to the moon, we go to Mars.
There's sort of no stopping.
It's very tempting to say that this has to do
with why modern humans spread,
became so numerous that it's changed a large part
of the biosphere today and so on.
A dream now for the future is that some of the secrets
to this lie in the genetic changes here.
And the really cool thing is of course that we now have
the Neandertal genome.
So we can ask, genetically what are the changes
here that are here in all of us today no matter
where we live on the planet but not in the Neandertals?
The Neandertals looked like the apes.
So make a catalog of this, and that's not a very large
list of things.
It's just around 30, 32,000 changes in the genome.
You can look through that list in an afternoon
on the computer.
You have only one problem, you have no clue
what you sort of look at or what this means
because a little dirty secret of genomics is in a way
that are incredibly bad at inferring a function
from any one change we see in the genome.
I think this is really the challenge for the future.
How will we now study this?
In some sense you can say here lies maybe
the most important fundamental historical question
you could ask, what is it in our biology that set us
on this trajectory to this enormously unique history
that humans have?
I have gone around for 10 years or something making jokes
and talks saying what we want to do, of course, to make
put Neandertal alleles into transgenic humans
and we want to put human alleles into trangenic chimps
and then we want to test their abilities in language
and commission and things like that.
And we have a problem because we have ethics committees
and things that we can't do it.
But it's sort of not just a joke, of course.
This is what we would do [inaudible] mice
or so where we would study this.
So there is a brief just this story-telling in the future.
And the joke is not so much a joke anymore
because now there are even people who say we have
this list with 30,000 changes, we should go even further.
We should put them all into single stem cells
and then have an adventurous woman give birth
to an ancestral human.
We should clone Neandertals, if you like.
George Church in Harvard, nonetheless.
And I think we have exactly the same problems.
Technically impossible for reasons we cannot discuss.
It's ethically totally impossible to think about this.
But what can we do, what is reasonable to think?
Well, I think one thing we can hope
to do in the next 10 years
is to look for backmutations in humans.
The human genome is, of course, such a small place
three billion base pairs.
Every baby that's born has 50 or 100 new mutations
that was not there in its mom or dad.
Just seven billion humans or 14 billion genomes out there.
Every place in the genome that's compatible
with human life is mutated in the current population.
And at very low frequency.
But of course in the future where we will all have
our genome sequenced as soon as we go to the doctor,
we will begin to find these backmutations.
And I think one can design ethical ways to then study that.
So I think that will certainly be something
that will come in the future in this area.
Another area to sort of
study put these ancient things
into human stem cells and differentiate
them in vitro into different
tissues or cells and study that.
And I think there is evidence from other work
that one could also use laboratory animals.
You can humanize aspects of mouse biology
in Neandertal mice, if you like.
Aspects of mouse biology and study that.
I think that is sort of the direction
this work will be going.
The most exciting thing, if you like, for the future.
Sorry this was sort of, [mumbling to himself].
I will accelerate and not talk about that.
I thought I could jump with this computer but I can't.
Sorry about that.
So I wanted to end then on another question and that is,
how far back in time can we go?
Can we do older hominids?
The oldest DNA that has been retrieved today
is around 700,000 years old,
but that is in the permafrost and it's a horse genome
that they used in Denmark that's done.
So outside the permafrost, we have been very lucky
to work at a site in Spain in Sima de los Huesos,
which is about 430,000 years old,
where they find deep caves sites.
Find large amounts of sort of hominid remains.
There we've gone back now since it is so badly degraded
to study mitochondrial genomes first.
And just to give you a feeling for this,
we sequenced half one billion DNA molecules
from these bones and find around 15,000 mitochondrial
fragments in here.
So you have to do a lot of sequencing to arrive at this.
And then reconstruct the mitochondrial genome of this thing,
and you see is quite a short branch.
It's extremely old, et cetera.
Recently, we've then been able to retrieve a bit
of nuclear DNA also.
This falls clearly sort of early on
on the Neandertal lineage.
So this means that 430,000 years ago
there was already something there in Europe
that was sort of an ancestor of Neandertals.
And I think this is hopefully just the beginning.
That sort of in other sites outside the permafrost
we can go back maybe approaching half a million years or so.
So I think that we can hope.
I had sort of thought that was really limited
to the last hundred thousand years.
I think we can really hope to go further back.
Maybe approaching a million years
or so in the next few years.
Many people have contributed to this work,
more than I can mention.
Many people contributed to the analysis of the genomes too.
I will mention one person particularly, Matthias Meyer,
who discovered or invented a way to do various libraries
from extremely small amounts of DNA.
Without his work we would not have had
the high coverage Neandertal genomes have now
and make all these things possible.
And with that, I then thank you for your attention.
[applause]