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What I want to talk to you about

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is what we can learn from studying the genomes

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of living people

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and extinct humans.

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But before doing that,

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I just briefly want to remind you about what you already know:

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that our genomes, our genetic material,

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are stored in almost all cells in our bodies in chromosomes

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in the form of DNA,

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which is this famous double-helical molecule.

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And the genetic information

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is contained in the form of a sequence

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of four bases

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abbreviated with the letters A, T, C and G.

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And the information is there twice --

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one on each strand --

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which is important,

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because when new cells are formed, these strands come apart,

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new strands are synthesized with the old ones as templates

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in an almost perfect process.

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But nothing, of course, in nature

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is totally perfect,

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so sometimes an error is made

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and a wrong letter is built in.

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And we can then see the result

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of such mutations

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when we compare DNA sequences

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among us here in the room, for example.

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If we compare my genome to the genome of you,

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approximately every 1,200, 1,300 letters

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will differ between us.

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And these mutations accumulate

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approximately as a function of time.

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So if we add in a chimpanzee here, we will see more differences.

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Approximately one letter in a hundred

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will differ from a chimpanzee.

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And if you're then interested in the history

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of a piece of DNA, or the whole genome,

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you can reconstruct the history of the DNA

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with those differences you observe.

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And generally we depict our ideas about this history

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in the form of trees like this.

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In this case, it's very simple.

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The two human DNA sequences

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go back to a common ancestor quite recently.

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Farther back is there one shared with chimpanzees.

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And because these mutations

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happen approximately as a function of time,

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you can transform these differences

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to estimates of time,

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where the two humans, typically,

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will share a common ancestor about half a million years ago,

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and with the chimpanzees,

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it will be in the order of five million years ago.

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So what has now happened in the last few years

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is that there are account technologies around

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that allow you to see many, many pieces of DNA very quickly.

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So we can now, in a matter of hours,

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determine a whole human genome.

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Each of us, of course, contains two human genomes --

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one from our mothers and one from our fathers.

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And they are around three billion such letters long.

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And we will find that the two genomes in me,

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or one genome of mine we want to use,

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will have about three million differences

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in the order of that.

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And what you can then also begin to do

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is to say, "How are these genetic differences

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distributed across the world?"

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And if you do that,

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you find a certain amount of genetic variation in Africa.

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And if you look outside Africa,

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you actually find less genetic variation.

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This is surprising, of course,

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because in the order of six to eight times fewer people

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live in Africa than outside Africa.

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Yet the people inside Africa

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have more genetic variation.

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Moreover, almost all these genetic variants

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we see outside Africa

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have closely related DNA sequences

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that you find inside Africa.

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But if you look in Africa,

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there is a component of the genetic variation

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that has no close relatives outside.

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So a model to explain this

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is that a part of the African variation, but not all of it,

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[has] gone out and colonized the rest of the world.

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And together with the methods to date these genetic differences,

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this has led to the insight

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that modern humans --

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humans that are essentially indistinguishable from you and me --

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evolved in Africa, quite recently,

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between 100 and 200,000 years ago.

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And later, between 100 and 50,000 years ago or so,

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went out of Africa

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to colonize the rest of the world.

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So what I often like to say

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is that, from a genomic perspective,

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we are all Africans.

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We either live inside Africa today,

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or in quite recent exile.

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Another consequence

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of this recent origin of modern humans

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is that genetic variants

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are generally distributed widely in the world,

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in many places,

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and they tend to vary as gradients,

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from a bird's-eye perspective at least.

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And since there are many genetic variants,

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and they have different such gradients,

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this means that if we determine a DNA sequence --

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a genome from one individual --

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we can quite accurately estimate

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where that person comes from,

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provided that its parents or grandparents

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haven't moved around too much.

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But does this then mean,

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as many people tend to think,

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that there are huge genetic differences between groups of people --

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on different continents, for example?

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Well we can begin to ask those questions also.

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There is, for example, a project that's underway

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to sequence a thousand individuals --

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their genomes -- from different parts of the world.

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They've sequenced 185 Africans

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from two populations in Africa.

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[They've] sequenced approximately equally [as] many people

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in Europe and in China.

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And we can begin to say how much variance do we find,

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how many letters that vary

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in at least one of those individual sequences.

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And it's a lot: 38 million variable positions.

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But we can then ask: Are there any absolute differences

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between Africans and non-Africans?

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Perhaps the biggest difference

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most of us would imagine existed.

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And with absolute difference --

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and I mean a difference

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where people inside Africa at a certain position,

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where all individuals -- 100 percent -- have one letter,

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and everybody outside Africa has another letter.

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And the answer to that, among those millions of differences,

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is that there is not a single such position.

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This may be surprising.

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Maybe a single individual is misclassified or so.

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So we can relax the criterion a bit

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and say: How many positions do we find

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where 95 percent of people in Africa have

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one variant,

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95 percent another variant,

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and the number of that is 12.

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So this is very surprising.

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It means that when we look at people

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and see a person from Africa

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and a person from Europe or Asia,

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we cannot, for a single position in the genome with 100 percent accuracy,

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predict what the person would carry.

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And only for 12 positions

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can we hope to be 95 percent right.

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This may be surprising,

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because we can, of course, look at these people

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and quite easily say where they or their ancestors came from.

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So what this means now

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is that those traits we then look at

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and so readily see --

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facial features, skin color, hair structure --

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are not determined by single genes with big effects,

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but are determined by many different genetic variants

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that seem to vary in frequency

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between different parts of the world.

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There is another thing with those traits

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that we so easily observe in each other

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that I think is worthwhile to consider,

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and that is that, in a very literal sense,

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they're really on the surface of our bodies.

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They are what we just said --

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facial features, hair structure, skin color.

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There are also a number of features

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that vary between continents like that

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that have to do with how we metabolize food that we ingest,

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or that have to do

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with how our immune systems deal with microbes

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that try to invade our bodies.

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But so those are all parts of our bodies

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where we very directly interact with our environment,

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in a direct confrontation, if you like.

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It's easy to imagine

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how particularly those parts of our bodies

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were quickly influenced by selection from the environment

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and shifted frequencies of genes

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that are involved in them.

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But if we look on other parts of our bodies

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where we don't directly interact with the environment --

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our kidneys, our livers, our hearts --

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there is no way to say,

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by just looking at these organs,

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where in the world they would come from.

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So there's another interesting thing

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that comes from this realization

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that humans have a recent common origin in Africa,

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and that is that when those humans emerged

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around 100,000 years ago or so,

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they were not alone on the planet.

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There were other forms of humans around,

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most famously perhaps, Neanderthals --

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these robust forms of humans,

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compared to the left here

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with a modern human skeleton on the right --

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that existed in Western Asia and Europe

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since several hundreds of thousands of years.

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So an interesting question is,

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what happened when we met?

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What happened to the Neanderthals?

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And to begin to answer such questions,

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my research group -- since over 25 years now --

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works on methods to extract DNA

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from remains of Neanderthals

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and extinct animals

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that are tens of thousands of years old.

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So this involves a lot of technical issues

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in how you extract the DNA,

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how you convert it to a form you can sequence.

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You have to work very carefully

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to avoid contamination of experiments

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with DNA from yourself.

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And this then, in conjunction with these methods

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that allow very many DNA molecules to be sequenced very rapidly,

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allowed us last year

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to present the first version of the Neanderthal genome,

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so that any one of you

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can now look on the Internet, on the Neanderthal genome,

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or at least on the 55 percent of it

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that we've been able to reconstruct so far.

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And you can begin to compare it to the genomes

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of people who live today.

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And one question

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that you may then want to ask

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is, what happened when we met?

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Did we mix or not?

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And the way to ask that question

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is to look at the Neanderthal that comes from Southern Europe

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and compare it to genomes

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of people who live today.

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So we then look

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to do this with pairs of individuals,

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starting with two Africans,

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looking at the two African genomes,

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finding places where they differ from each other,

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and in each case ask: What is a Neanderthal like?

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Does it match one African or the other African?

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We would expect there to be no difference,

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because Neanderthals were never in Africa.

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They should be equal, have no reason to be closer

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to one African than another African.

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And that's indeed the case.

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Statistically speaking, there is no difference

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in how often the Neanderthal matches one African or the other.

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But this is different

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if we now look at the European individual and an African.

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Then, significantly more often,

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does a Neanderthal match the European

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rather than the African.

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The same is true if we look at a Chinese individual

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versus an African,

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the Neanderthal will match the Chinese individual more often.

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This may also be surprising

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because the Neanderthals were never in China.

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So the model we've proposed to explain this

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is that when modern humans came out of Africa

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sometime after 100,000 years ago,

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they met Neanderthals.

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Presumably, they did so first in the Middle East,

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where there were Neanderthals living.

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If they then mixed with each other there,

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then those modern humans

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that became the ancestors

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of everyone outside Africa

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carried with them this Neanderthal component in their genome

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to the rest of the world.

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So that today, the people living outside Africa

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have about two and a half percent of their DNA

283
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from Neanderthals.

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So having now a Neanderthal genome

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on hand as a reference point

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and having the technologies

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to look at ancient remains

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and extract the DNA,

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we can begin to apply them elsewhere in the world.

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And the first place we've done that is in Southern Siberia

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in the Altai Mountains

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at a place called Denisova,

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a cave site in this mountain here,

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where archeologists in 2008

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found a tiny little piece of bone --

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this is a copy of it --

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that they realized came from the last phalanx

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of a little finger of a pinky of a human.

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And it was well enough preserved

300
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so we could determine the DNA from this individual,

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even to a greater extent

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than for the Neanderthals actually,

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and start relating it to the Neanderthal genome

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and to people today.

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And we found that this individual

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shared a common origin for his DNA sequences

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with Neanderthals around 640,000 years ago.

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And further back, 800,000 years ago

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is there a common origin

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with present day humans.

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So this individual comes from a population

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that shares an origin with Neanderthals,

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but far back and then have a long independent history.

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We call this group of humans,

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that we then described for the first time

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from this tiny, tiny little piece of bone,

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the Denisovans,

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after this place where they were first described.

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So we can then ask for Denisovans

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the same things as for the Neanderthals:

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Did they mix with ancestors of present day people?

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If we ask that question,

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and compare the Denisovan genome

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to people around the world,

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we surprisingly find

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no evidence of Denisovan DNA

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in any people living even close to Siberia today.

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But we do find it in Papua New Guinea

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and in other islands in Melanesia and the Pacific.

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So this presumably means

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that these Denisovans had been more widespread in the past,

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since we don't think that the ancestors of Melanesians

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00:14:11,000 --> 00:14:13,000
were ever in Siberia.

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So from studying

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these genomes of extinct humans,

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00:14:18,000 --> 00:14:21,000
we're beginning to arrive at a picture of what the world looked like

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when modern humans started coming out of Africa.

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In the West, there were Neanderthals;

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in the East, there were Denisovans --

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maybe other forms of humans too

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that we've not yet described.

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We don't know quite where the borders between these people were,

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but we know that in Southern Siberia,

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there were both Neanderthals and Denisovans

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at least at some time in the past.

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Then modern humans emerged somewhere in Africa,

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came out of Africa, presumably in the Middle East.

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They meet Neanderthals, mix with them,

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continue to spread over the world,

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and somewhere in Southeast Asia,

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they meet Denisovans and mix with them

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and continue on out into the Pacific.

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And then these earlier forms of humans disappear,

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but they live on a little bit today

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in some of us --

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in that people outside of Africa have two and a half percent of their DNA

357
00:15:14,000 --> 00:15:16,000
from Neanderthals,

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and people in Melanesia

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00:15:18,000 --> 00:15:21,000
actually have an additional five percent approximately

360
00:15:21,000 --> 00:15:24,000
from the Denisovans.

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Does this then mean that there is after all

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some absolute difference

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00:15:28,000 --> 00:15:31,000
between people outside Africa and inside Africa

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in that people outside Africa

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00:15:33,000 --> 00:15:35,000
have this old component in their genome

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00:15:35,000 --> 00:15:37,000
from these extinct forms of humans,

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whereas Africans do not?

368
00:15:39,000 --> 00:15:42,000
Well I don't think that is the case.

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Presumably, modern humans

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00:15:44,000 --> 00:15:46,000
emerged somewhere in Africa.

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They spread across Africa also, of course,

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and there were older, earlier forms of humans there.

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And since we mixed elsewhere,

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I'm pretty sure that one day,

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when we will perhaps have a genome

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00:15:58,000 --> 00:16:00,000
of also these earlier forms in Africa,

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00:16:00,000 --> 00:16:02,000
we will find that they have also mixed

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00:16:02,000 --> 00:16:05,000
with early modern humans in Africa.

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00:16:06,000 --> 00:16:08,000
So to sum up,

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00:16:08,000 --> 00:16:10,000
what have we learned from studying genomes

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00:16:10,000 --> 00:16:12,000
of present day humans

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00:16:12,000 --> 00:16:14,000
and extinct humans?

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00:16:14,000 --> 00:16:16,000
We learn perhaps many things,

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but one thing that I find sort of important to mention

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00:16:21,000 --> 00:16:24,000
is that I think the lesson is that we have always mixed.

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00:16:24,000 --> 00:16:26,000
We mixed with these earlier forms of humans,

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00:16:26,000 --> 00:16:28,000
wherever we met them,

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and we mixed with each other ever since.

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Thank you for your attention.

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(Applause)