What I want to talk to you about is what we can learn from studying the genomes of living people and extinct humans. But before doing that, I just briefly want to remind you about what you already know: that our genomes, our genetic material, are stored in almost all cells in our bodies in chromosomes in the form of DNA, which is this famous double-helical molecule. And the genetic information is contained in the form of a sequence of four bases abbreviated with the letters A, T, C and G. And the information is there twice -- one on each strand -- which is important, because when new cells are formed, these strands come apart, new strands are synthesized with the old ones as templates in an almost perfect process.
Hoxe quero contarlles que podemos aprender do estudo do xenoma de persoas vivas e de humanos extintos. Pero antes diso quero lembrarlles brevemente algo que xa saben: que o noso xenoma, o noso material xenético, está almacenado en case todas as nosas células, nos cromosomas, en forma de ADN que é a famosa molécula de dobre hélice. A información xenética está contida baixo a forma dunha secuencia de 4 bases abreviadas coas letras A, T, C e G. A información está dúas veces: unha en cada cadea; algo importante xa que cando se forman novas células estas cadeas sepáranse e sintetízanse novas cadeas a partir das vellas nun proceso case perfecto.
But nothing, of course, in nature is totally perfect, so sometimes an error is made and a wrong letter is built in. And we can then see the result of such mutations when we compare DNA sequences among us here in the room, for example. If we compare my genome to the genome of you, approximately every 1,200, 1,300 letters will differ between us. And these mutations accumulate approximately as a function of time. So if we add in a chimpanzee here, we will see more differences. Approximately one letter in a hundred will differ from a chimpanzee.
Pero, claro, na Natureza nada é totalmente perfecto así que ás veces cométese un erro e incorpórase unha letra errónea. E podemos ver o resultado desas mutacións ao compararmos secuencias de ADN entre as persoas da sala, por exemplo. Se comparamos o meu xenoma co seu veremos unhas 1 200 ou 1 300 letras de diferenza entre nós. E estas mutacións acumúlanse aproximadamente en función do tempo. Se incorporásemos agora un chimpancé veríamos máis diferenzas. Máis ou menos unha letra de cada 100 vai ser diferente das do chimpancé.
And if you're then interested in the history of a piece of DNA, or the whole genome, you can reconstruct the history of the DNA with those differences you observe. And generally we depict our ideas about this history in the form of trees like this. In this case, it's very simple. The two human DNA sequences go back to a common ancestor quite recently. Farther back is there one shared with chimpanzees. And because these mutations happen approximately as a function of time, you can transform these differences to estimates of time, where the two humans, typically, will share a common ancestor about half a million years ago, and with the chimpanzees, it will be in the order of five million years ago.
E se nos interesa a historia dun fragmento de ADN, ou do xenoma enteiro, é posible reconstruír a historia do ADN a partir desas diferenzas que se observan. En xeral, representamos as nosas ideas sobre esta historia con árbores coma esta. Neste caso é moi simple. As dúas secuencias de ADN humano chegan ata un devanceiro común de hai pouco tempo. Máis atrás hai un compartido cos chimpancés. E debido a que estas mutacións ocorren máis ou menos en función do tempo un pode transformar estas diferenzas para estimar o tempo en que estes dous humanos, en xeral, compartían un devanceiro común hai medio millón de anos; e cos chimpancés, hai arredor dos 5 millóns de anos.
So what has now happened in the last few years is that there are account technologies around that allow you to see many, many pieces of DNA very quickly. So we can now, in a matter of hours, determine a whole human genome. Each of us, of course, contains two human genomes -- one from our mothers and one from our fathers. And they are around three billion such letters long. And we will find that the two genomes in me, or one genome of mine we want to use, will have about three million differences in the order of that. And what you can then also begin to do is to say, "How are these genetic differences distributed across the world?" And if you do that, you find a certain amount of genetic variation in Africa. And if you look outside Africa, you actually find less genetic variation. This is surprising, of course, because in the order of six to eight times fewer people live in Africa than outside Africa. Yet the people inside Africa have more genetic variation.
O que aconteceu nos últimos anos é que apareceron tecnoloxías que permiten ver moitos fragmentos de ADN moi rapidamente. Agora podemos, en cuestión de horas, determinar un xenoma humano completo. Todos nós temos, claro, dous xenomas humanos: o que vén das nosas nais e o que vén dos nosos pais. Teñen unha lonxitude duns 3.000 millóns de letras. E descubriremos que os meus dous xenomas, ou un xenoma meu que queiramos usar, terá uns tres millóns de diferenzas, nesa orde. E o que se pode comezar a facer é describir a distribución destas diferenzas xenéticas no mundo. E ao facelo un acha unha certa cantidade de variación xenética en África. E se miramos fóra de África atopamos menos variación xenética. Isto é sorprendente, por suposto, porque hai de 6 a 8 veces menos xente vivindo dentro ca fóra de África. Aínda así, as persoas de África teñen máis variación xenética.
Moreover, almost all these genetic variants we see outside Africa have closely related DNA sequences that you find inside Africa. But if you look in Africa, there is a component of the genetic variation that has no close relatives outside. So a model to explain this is that a part of the African variation, but not all of it, [has] gone out and colonized the rest of the world. And together with the methods to date these genetic differences, this has led to the insight that modern humans -- humans that are essentially indistinguishable from you and me -- evolved in Africa, quite recently, between 100 and 200,000 years ago. And later, between 100 and 50,000 years ago or so, went out of Africa to colonize the rest of the world.
Ademais, case todas estas variantes que vemos fóra de África teñen secuencias de ADN máis estreitamente relacionadas que as de África entre si. Pero se vemos en África hai unha compoñente de variación xenética que non ten parentes próximos fóra. O modelo que explica isto di que unha parte da variación africana, pero non toda, saíu colonizar o resto do mundo. E xunta estes métodos de datación das diferenzas xenéticas isto conduciu á idea de que os humanos modernos, humanos que en esencia son indistinguibles de vostedes e de min, evolucionaron en África hai moi pouco tempo; entre 100.000 e 200.000 anos. E despois, hai entre 100.000 e 50.000, saíron de África para colonizar o resto do mundo.
So what I often like to say is that, from a genomic perspective, we are all Africans. We either live inside Africa today, or in quite recent exile. Another consequence of this recent origin of modern humans is that genetic variants are generally distributed widely in the world, in many places, and they tend to vary as gradients, from a bird's-eye perspective at least. And since there are many genetic variants, and they have different such gradients, this means that if we determine a DNA sequence -- a genome from one individual -- we can quite accurately estimate where that person comes from, provided that its parents or grandparents haven't moved around too much.
Por iso moitas veces gústame dicir que, desde un punto de vista xenómico, todos somos africanos. Ou vivimos hoxe dentro de África ou somos exiliados moi recentes. Outra consecuencia desta orixe recente dos humanos modernos é que as variantes xenéticas están en xeral amplamente distribuídas polo mundo, en moitos lugares, e tenden a variar como gradientes polo menos miradas a vista de paxaro. E dado que hai moitas variantes xenéticas e teñen diferentes gradientes, se determinamos unha secuencia de ADN, un xenoma dun individuo, podemos estimar con bastante precisión de onde vén esa persoa sempre que seus pais ou seus avós non se moveran demasiado.
But does this then mean, as many people tend to think, that there are huge genetic differences between groups of people -- on different continents, for example? Well we can begin to ask those questions also. There is, for example, a project that's underway to sequence a thousand individuals -- their genomes -- from different parts of the world. They've sequenced 185 Africans from two populations in Africa. [They've] sequenced approximately equally [as] many people in Europe and in China. And we can begin to say how much variance do we find, how many letters that vary in at least one of those individual sequences. And it's a lot: 38 million variable positions.
Pero, significa isto, como moita xente adoita pensar, que hai grandes diferenzas xenéticas entre grupos de persoas nos distintos continentes, por exemplo? Ben, podemos empezar a facer estas preguntas. Por exemplo, hai en marcha un proxecto para secuenciar o xenoma dun milleiro de individuos de diferentes partes do mundo. Secuenciáronse 185 africanos de dúas poboacións en África. Secuenciáronse outros tantos máis ou menos en Europa e na China. E podemos empezar a contar cantas variacións atopamos, cantas letras varían, polo menos nunha destas secuencias individuais. E son unha chea: 38 millóns de posicións variables.
But we can then ask: Are there any absolute differences between Africans and non-Africans? Perhaps the biggest difference most of us would imagine existed. And with absolute difference -- and I mean a difference where people inside Africa at a certain position, where all individuals -- 100 percent -- have one letter, and everybody outside Africa has another letter. And the answer to that, among those millions of differences, is that there is not a single such position. This may be surprising. Maybe a single individual is misclassified or so. So we can relax the criterion a bit and say: How many positions do we find where 95 percent of people in Africa have one variant, 95 percent another variant, and the number of that is 12.
Pero podemos preguntarnos: hai diferenzas absolutas entre africanos e non africanos? Se cadra a maioría de nós pensamos que hai unha gran diferenza. E con diferenza absoluta quero dicir unha diferenza en que a xente de África teña unha posición todos os individuos, o 100%, teñan unha letra e todos fóra de África teñan outra diferente. E a resposta a esa pregunta, entre eses millóns de diferenzas, é que non nin unha posición en que iso ocorra. Isto pode ser sorprendente. Se cadra, un individuo está mal clasificado. Por iso podemos relaxar algo o criterio e dicir: cantas posicións atopamos en que o 95% da xente de África teña unha variante e o 95% fóra de África teña outra, e o total son 12.
So this is very surprising. It means that when we look at people and see a person from Africa and a person from Europe or Asia, we cannot, for a single position in the genome with 100 percent accuracy, predict what the person would carry. And only for 12 positions can we hope to be 95 percent right. This may be surprising, because we can, of course, look at these people and quite easily say where they or their ancestors came from. So what this means now is that those traits we then look at and so readily see -- facial features, skin color, hair structure -- are not determined by single genes with big effects, but are determined by many different genetic variants that seem to vary in frequency between different parts of the world.
Isto é moi sorprendente. Iso significa que ao observarmos persoas e ver unha de África e unha de Europa ou Asia non hai ningunha posición no xenoma para a que poidamos predicir ao 100 %, a súa carga xenética. E só para 12 posicións podemos esperar estar seguros ao 95 %. Isto pode sorprender porque, obviamente, podemos mirar para eles e dicir facilmente de onde veñen eles ou os seus devanceiros. Xa que logo, isto significa que eses trazos que ao mirarmos vemos tan facilmente... trazos faciais, cor da pel, estrutura do cabelo... non están determinados por xenes únicos con grande influencia, senón por moitas variantes xenéticas diferentes que se presentan con frecuencias diversas en diferentes partes do mundo.
There is another thing with those traits that we so easily observe in each other that I think is worthwhile to consider, and that is that, in a very literal sense, they're really on the surface of our bodies. They are what we just said -- facial features, hair structure, skin color. There are also a number of features that vary between continents like that that have to do with how we metabolize food that we ingest, or that have to do with how our immune systems deal with microbes that try to invade our bodies. But so those are all parts of our bodies where we very directly interact with our environment, in a direct confrontation, if you like. It's easy to imagine how particularly those parts of our bodies were quickly influenced by selection from the environment and shifted frequencies of genes that are involved in them. But if we look on other parts of our bodies where we don't directly interact with the environment -- our kidneys, our livers, our hearts -- there is no way to say, by just looking at these organs, where in the world they would come from.
Hai outra cousa en relación con estes trazos que observamos con facilidade nos outros que me parece digno de mención: nun sentido moi literal, están realmente na nosa superficie corporal. Son, como acabamos de dicir, trazos faciais, estrutura do cabelo, cor de pel. Hai tamén unha serie de características que varían entre continentes, coma as anteriores, que teñen que ver con como metabolizamos os alimentos que inxerimos ou coa forma en que o noso sistema inmune enfronta os microbios que tratan de invadir os nosos corpos. Pero todas esas son partes do corpo coas que interactuamos directamente co medio, en confrontación directa, se se quere. É fácil imaxinar como esas partes do corpo se viron rapidamente influídas pola selección do medio ambiente, o que alterou as frecuencias de xenes involucradas nelas. Pero se observamos outras partes do corpo coas que non interactuamos directamente co medio -riles, fígados, corazóns- non hai xeito de dicir só mirando eses órganos de que parte do mundo veñen.
So there's another interesting thing that comes from this realization that humans have a recent common origin in Africa, and that is that when those humans emerged around 100,000 years ago or so, they were not alone on the planet. There were other forms of humans around, most famously perhaps, Neanderthals -- these robust forms of humans, compared to the left here with a modern human skeleton on the right -- that existed in Western Asia and Europe since several hundreds of thousands of years. So an interesting question is, what happened when we met? What happened to the Neanderthals?
Hai outra cousa interesante que deriva desta constatación de que os seres humanos teñen unha orixe común recente en África: cando eses seres humanos apareceron hai uns 100.000 anos non estaban sós no planeta. Andaban arredor outras formas de humanos, os máis famosos, se cadra, os neanderthais, --esas variedades robustas de humanos da esquerda comparadas cos esqueletos modernos da dereita-- que existiron no oeste de Asia e en Europa desde hai centos de miles de anos. Así que unha pregunta interesante é: que pasou cando nos atopamos? Que lles sucedeu aos neanderthais?
And to begin to answer such questions, my research group -- since over 25 years now -- works on methods to extract DNA from remains of Neanderthals and extinct animals that are tens of thousands of years old. So this involves a lot of technical issues in how you extract the DNA, how you convert it to a form you can sequence. You have to work very carefully to avoid contamination of experiments with DNA from yourself. And this then, in conjunction with these methods that allow very many DNA molecules to be sequenced very rapidly, allowed us last year to present the first version of the Neanderthal genome, so that any one of you can now look on the Internet, on the Neanderthal genome, or at least on the 55 percent of it that we've been able to reconstruct so far. And you can begin to compare it to the genomes of people who live today.
E para empezar a responder estas preguntas o meu grupo de investigación traballa --desde hai máis de 25 anos-- en métodos para extraer ADN en restos de neanderthais e animais extintos que teñen decenas de miles de anos. Isto implica unha chea de cuestións técnicas sobre a forma de extraer o ADN, sobre como convertelo en algo que poida secuenciarse. Hai que traballar con moito coidado para evitar a contaminación dos experimentos co ADN propio. E así, xunto con eses métodos que permiten secuenciar moi rapidamente moitas moléculas de ADN, permitiunos presentar o ano pasado a primeira versión do xenoma neanderthal de xeito que calquera de vostedes pode agora velo en Internet, ou polo menos o 55% do total que fomos quen de reconstruír ata agora. E pódese empezar a comparalo cos xenomas da xente que vive na actualidade.
And one question that you may then want to ask is, what happened when we met? Did we mix or not? And the way to ask that question is to look at the Neanderthal that comes from Southern Europe and compare it to genomes of people who live today. So we then look to do this with pairs of individuals, starting with two Africans, looking at the two African genomes, finding places where they differ from each other, and in each case ask: What is a Neanderthal like? Does it match one African or the other African? We would expect there to be no difference, because Neanderthals were never in Africa. They should be equal, have no reason to be closer to one African than another African. And that's indeed the case. Statistically speaking, there is no difference in how often the Neanderthal matches one African or the other. But this is different if we now look at the European individual and an African. Then, significantly more often, does a Neanderthal match the European rather than the African. The same is true if we look at a Chinese individual versus an African, the Neanderthal will match the Chinese individual more often. This may also be surprising because the Neanderthals were never in China.
E unha pregunta que poden querer formular é... que ocorreu cando nos coñecemos? Mesturámonos ou non? E a maneira de responder esa pregunta é observar os neanderthais procedentes do sur de Europa e comparar os seus xenomas cos da poboación actual. Así, buscamos facer isto con pares de individuos empezando con dous africanos, observando dous xenomas africanos, atopando lugares onde difiren un do outro, e en cada caso preguntámonos: a quen se parece o neanderthal? Con cal dos africanos coincide? O esperable sería non achar diferenzas porque os neanderthais nunca estiveron en África. Deberían ser iguais, non hai razón para que estean máis cerca dun africano ca do outro. E así é na realidade. Estatisticamente falando, non hai diferenzas na frecuencia en que os neanderthais coinciden cun africano ou con outro. Pero as cousas cambian se comparamos un individuo europeo e un africano. Entón, con moita máis frecuencia o neanderthal coincide co europeo antes ca co africano. E o mesmo pasa se comparamos un individuo chinés cun africano: o neanderthal coincidirá máis a miúdo co individuo chinés. Isto tamén pode sorprender porque os neanderthais nunca estiveron en China.
So the model we've proposed to explain this is that when modern humans came out of Africa sometime after 100,000 years ago, they met Neanderthals. Presumably, they did so first in the Middle East, where there were Neanderthals living. If they then mixed with each other there, then those modern humans that became the ancestors of everyone outside Africa carried with them this Neanderthal component in their genome to the rest of the world. So that today, the people living outside Africa have about two and a half percent of their DNA from Neanderthals.
Así que o modelo que propuxemos para explicar isto é que cando os humanos modernos saíron de África hai uns 100.000 anos atoparon aos neanderthais. Supoñemos que ocorreu por primeira vez en Oriente Medio onde vivían neanderthais. Se alí se mesturaron uns con outros entón eses humanos modernos que acabaron sendo devanceiros de todos nós fóra de África levaron consigo no seu xenoma o compoñente neanderthal ao resto do mundo. Así que hoxe, a xente que vive fóra de África ten preto do 2,5% do seu ADN de orixe neanderthal.
So having now a Neanderthal genome on hand as a reference point and having the technologies to look at ancient remains and extract the DNA, we can begin to apply them elsewhere in the world. And the first place we've done that is in Southern Siberia in the Altai Mountains at a place called Denisova, a cave site in this mountain here, where archeologists in 2008 found a tiny little piece of bone -- this is a copy of it -- that they realized came from the last phalanx of a little finger of a pinky of a human. And it was well enough preserved so we could determine the DNA from this individual, even to a greater extent than for the Neanderthals actually, and start relating it to the Neanderthal genome and to people today. And we found that this individual shared a common origin for his DNA sequences with Neanderthals around 640,000 years ago. And further back, 800,000 years ago is there a common origin with present day humans.
Ao termos hoxe un xenoma neanderthal dispoñible como punto de referencia e ao termos as tecnoloxías para observar restos antigos e extraer deles o ADN, podemos empezar a aplicalas en calquera lugar do mundo. E o primeiro lugar onde o fixemos foi no sur de Siberia, nas montañas Altai, nun lugar que se chama Denisova, nunha cova desa montaña na que en 2008 os arqueólogos acharon un anaquiño de óso --velaquí unha copia-- e decatáronse de que proviña da última falanxe dun maimiño humano. E estaba tan ben conservado que foi posible determinar o ADN deste individuo incluso nunha extensión maior que para os neanderthais, e comezouse a relacionalo co xenoma neanderthal e co de persoas de hoxe. E descubrimos que este individuo compartía unha orixe común para as súas secuencias de ADN cos neandertais de hai preto de 640.000 anos. E máis atrás, hai 800.000 anos hai unha orixe común cos humanos actuais.
So this individual comes from a population that shares an origin with Neanderthals, but far back and then have a long independent history. We call this group of humans, that we then described for the first time from this tiny, tiny little piece of bone, the Denisovans, after this place where they were first described. So we can then ask for Denisovans the same things as for the Neanderthals: Did they mix with ancestors of present day people? If we ask that question, and compare the Denisovan genome to people around the world, we surprisingly find no evidence of Denisovan DNA in any people living even close to Siberia today. But we do find it in Papua New Guinea and in other islands in Melanesia and the Pacific. So this presumably means that these Denisovans had been more widespread in the past, since we don't think that the ancestors of Melanesians were ever in Siberia.
Este individuo provén dunha poboación que comparte unha orixe cos neanderthais pero indo cara a atrás, ten unha longa historia independente. Chamámoslles a este grupo de humanos, que describimos por vez primeira a partir deste diminuto anaco de óso, denisovanos, polo lugar onde se descubriron por primeira vez. Podemos preguntarnos sobre os denisovanos o mesmo que fixemos sobre os neanderthais: mesturáronse con devanceiros dos humanos actuais? Si nos facemos esa pregunta e comparamos o xenoma denisovano co dos humanos de todo o mundo atopamos con sorpresa que non hai evidencia de ADN denisovano nin sequera entre as persoas que hoxe viven preto de Siberia. Pero atopámolo en Papúa Nova Guinea e noutras illas de Melanesia e o Pacífico. Isto significa, probablemente, que estes denisovanos estiveron máis dispersos no pasado porque non cremos que os devanceiros dos melanesios estiveran en Siberia.
So from studying these genomes of extinct humans, we're beginning to arrive at a picture of what the world looked like when modern humans started coming out of Africa. In the West, there were Neanderthals; in the East, there were Denisovans -- maybe other forms of humans too that we've not yet described. We don't know quite where the borders between these people were, but we know that in Southern Siberia, there were both Neanderthals and Denisovans at least at some time in the past. Then modern humans emerged somewhere in Africa, came out of Africa, presumably in the Middle East. They meet Neanderthals, mix with them, continue to spread over the world, and somewhere in Southeast Asia, they meet Denisovans and mix with them and continue on out into the Pacific. And then these earlier forms of humans disappear, but they live on a little bit today in some of us -- in that people outside of Africa have two and a half percent of their DNA from Neanderthals, and people in Melanesia actually have an additional five percent approximately from the Denisovans.
Así, a partir do estudo destes xenomas de humanos extintos estamos a empezar a ter unha imaxe de como era o mundo cando os humanos modernos saíron de África. En Occidente había neanderthais; en Oriente había denisovanos... e se cadra tamén outras variedades de humanos que aínda non describimos. Non coñecemos ben as fronteiras entre estas xentes pero sabemos que no sur de Siberia había tanto neanderthais como denisovanos, polo menos nalgún momento do pasado. Os humanos modernos xurdiron nalgún lugar de África; saíron de África, probablemente cara ao Oriente Medio. Atoparon os neanderthais, mesturáronse con eles, continuaron estendéndose polo mundo e nalgún lugar no sueste de Asia atoparon os denisovanos e mesturáronse con eles e continuaron cara ao Pacífico. Despois estas formas temperás de humanos desapareceron pero hoxe viven un pouco nalgúns de nós nesas persoas de fóra de África que teñen o 2,5% do seu ADN de orixe neanderthal e nas persoas de Melanesia que teñen máis ou menos un 5% adicional de orixe denisovana.
Does this then mean that there is after all some absolute difference between people outside Africa and inside Africa in that people outside Africa have this old component in their genome from these extinct forms of humans, whereas Africans do not? Well I don't think that is the case. Presumably, modern humans emerged somewhere in Africa. They spread across Africa also, of course, and there were older, earlier forms of humans there. And since we mixed elsewhere, I'm pretty sure that one day, when we will perhaps have a genome of also these earlier forms in Africa, we will find that they have also mixed with early modern humans in Africa.
Significa isto que existe a pesar de todo algunha diferenza absoluta entre as persoas de fóra de África e as de dentro no feito de que as persoas de fóra de África teñan este compoñente ancestral no seu xenoma con orixe nestas formas humanas extintas mentres que os africanos non? Ben, non creo que sexa así. Probablemente, os humanos modernos xurdiron nalgún lugar de África. Espalláronse por África, claro, e había alí formas humanas máis vellas, máis temperás. E como nos mesturamos nalgún lado estou bastante seguro que un día cando quizá teñamos un xenoma destas formas temperás de África imos atopar que tamén se mesturaron con humanos modernos temperáns en África.
So to sum up, what have we learned from studying genomes of present day humans and extinct humans? We learn perhaps many things, but one thing that I find sort of important to mention is that I think the lesson is that we have always mixed. We mixed with these earlier forms of humans, wherever we met them, and we mixed with each other ever since.
Para resumir: que aprendemos ao estudar xenomas de humanos actuais e humanos extintos? Se cadra, aprendemos moitas cousas, pero unha que me parece importante mencionar é que creo que a lección é que sempre nos mesturamos. Mesturámonos con estas formas temperás de humanos onde for que nos atopamos e mesturámonos uns con outros desde aquela.
Thank you for your attention.
Grazas pola súa atención.
(Applause)
(Aplausos)