CARTA: The Origin of Us – Richard “Ed” Green: Interbreeding with Archaic Humans outside Africa

you I'm gonna tell you a little bit about the technology used to sequence the genome of Neanderthal and this Denis of an individual and what we have learned from doing that so before I start I just show the pictures and names of many of the key players and that's the collecting these data has really been kind of a lifelong project of this visionary sponte Pavo who was one of the first to imagine that DNA might stick around and very very old fossil material and invented many of the ways of getting that DNA out and sequencing it and many of the other people who helped in analyses along the way so Neanderthals by now need no introduction they were morphologically very similar to us yet distinct enough that from the early days it was known that they were something different they have many many distinguishing characteristics that other experts here could go over in great detail I just want to put this in some context that we look morphologically at the crania of Neanderthals and nearly contemporaneous modern human compared to our closest living relative the chimpanzee one can probably find many more similarities here than differences if you put it in context with this out-group the chimpanzee so Neanderthals show up classical Neanderthals that everyone would agree is in the and earth all maybe a few hundred thousand years ago and they disappear mysteriously from the fossil record about thirty thousand years ago they are known mainly from their bones and their stone tool technology from Europe and the Middle East but we know their range extends into Asia and I agree that it is really an open question how far to the east that they went perhaps one day we will find Neanderthals from China it would not at all be surprised by that sequencing their genomes is largely in a success story that follows on the heels of advances in high-throughput sequencing there are several companies now that will sell you machines that will sequence DNA hundreds of thousands of times faster and cheaper than what we could do ten years ago one of these companies Illumina is kind of the leader in the field now they are based here in San Diego and are pretty much the the world leader in this DNA sequencing technology and it's what we largely used a sequence DNA that comes out of old bones so the first really genome scale data set from Neanderthals came from these three bones that were dated to about 38,000 years ago that were excavated from this cave the Vindhya cave in Croatia in 1980 they were chosen from amongst hundreds of bones that sponte and his co-workers had screened through to look for the presence of some surviving DNA and the absence of contaminating modern human DNA which is a large problem with bones that have after all been touched by many people who go and dig them out of the ground and museum curators who handle them so these were found to be largely free of contaminating modern human DNA and have lots of DNA that can be sequence so a few years ago we accumulated a little over 1 billion base pairs from each of those 3 bones and a little bit of DNA from some other bones so that on average we had a little more than one full coverage of the genome of the Neanderthal one immediate surprise from this dataset was that when one sequences all of the DNA that comes out of an old bone very little of it is actually from Neanderthal at all most of it identified by sequence similarity is likely from soil living microbes that have colonized the bone in the time that has been sitting in the ground and in fact most of those microbes we've never sequenced so we don't see any similarity in terms of DNA sequence so we can just assume these are some microbes that live long ago in the past and we focus really on the things that look like primate look like a Neanderthal so another thing that we have for sometime is that DNA as it's sitting around for tens of thousands of years it sustains chemical damage and this is the main chemical damage that happens cytosine will spontaneously dominate to uracil so it's chemically different and then the polymerase is the enzyme that we use to read the DNA will read this uracil as Athena Dean so where this Neanderthal when he was alive walking around had a cytosine we will read this often as thymidine this process is happening all the time it happens in your cells it's happening right now but we have energy dependent repair mechanisms that will detect this cytosine deaminase in and fix it they're not perfect but they're good enough to keep us alive through our lifetime but as soon as we die this process goes on unchecked and cytosine accumulates damage so that the longer the DNA has been sitting in the ground the more we will see this c-to-t difference we were able to see early on as we started accumulating data that this c-to-t damage pattern was concentrated on the ends of reads and learned a lot about the process of diagenesis how the DNA changes over time the spatial pattern wound up being very important to learn about and so once we had learned what we could learn from that we started doing data analysis and this is a figure of a broad scale view of the genetic difference between Neanderthals human and chimpanzee so we have a reference human genome we know there's DNA sequence variation amongst human but the reference sequence the one that we have known and in some form for about ten years now is what we all use to compare other humans that we might sequence to see where they are different from this reference this one instance of the human genome we have something similar for the chimpanzee so if we just align the Neanderthal the human the reference human and the reference chimpanzee we can ask for each of the three bones where do we see some difference where is the chimpanzee difference and the Neanderthal and the human are the same or where as the Neanderthal different and the human and the chimpanzee are the same or where's the human difference where the Neanderthal and the chimp are the same and one thing that kind of stands out and in each of these bar charts I'm just showing what the difference is so for example here the Neanderthal and the human have a G but the chimpanzee has an A so doing this kind of analysis you can see that these types of differences happen faster than these types these are transitions these are trans versions this is a description of molecular evolution these things happen faster than these things the same pattern is here over in the differences that are just specific to human but the neanderthal pattern is very very different we see this huge excess of G 2 a and c 2 t as we know to expect from DNA that has been damaged so in this first data set that we published a little over two years ago now it was the case that what we could learn about human evolution from Neanderthal DNA was nothing really about this lineage here nothing about Neanderthals themselves and that's because we know that most of the differences that are specific to Neanderthals are in fact errors they're errors in the DNA that have accumulated while the DNA was sitting in the ground or they're the machine error the background sequencing error that we have when we are sequencing DNA and having only one fold coverage of the genome it's rife with errors so we see something like a hundred and thirty thousand transversions on this lineage and only thirty thousand on the human lineage and we know that we should accumulate basically the same amount of differences yet there's this huge excess over on the Neanderthal side so at that point what we could do with the Neanderthal genome is really define this point here that is find the positions where the Neanderthal matches the chimpanzee but the human is different that is ask what changes have happened in the human genome since we diverged from Neanderthal but all of the questions about specific changes in the and Earth all would have to wait better technology which skipping ahead a little bit has come online and we'll get to that in a minute but before I start talking about the contrast that we want to make between Neanderthals and humans and answering the questions we can answer with Neanderthal DNA I'm going to do a very brief primer on genetics and sexually reproducing diploid x' like us if you imagine yourself as the current generation which I used to do less and less I do but you're in the current generation here you have you know you get your genome two copies of the genome one copy you get from your father and one copy you get from your mother so of each of your chromosome pairs one of those pairs came directly from the sperm and your dad and one from the individual egg and your mom that would eventually yield you what you may not know or think about all the time is that that chromosome that your dad bequeathed to you or your mom bequeathed to you did not exist in your dad or your mom it was a special version of the two chromosomes that existed in your dad or your mom that were recombined together stitched together and put in that single sperm that would become you or that single egg that would become you and each sperm and each egg are different so my brothers and sisters are different so this recombination denoted by the little X here shows that this chromosome inherited from the father has the front tip here from the chromosome that he got from his mother and the back part from the chromosome that he got from his father so in you the current generation is the physically melded manifestation not of your parents but of your grandparents so this is the father's chromosome which is the father's mother stitched to the father's father in a single chromosome so this happens this process happens more or less in a random place along the chromosome in every generation so if one is to trace one's ancestry back in time there is in fact a different ancestry at every place in the genome every place in your genome traces back a different path through your ancestors so if you are to ask for example where did I say there's a gene here for a very wide nose like I have so this wide nose gene is here maybe I got this from my father who got it if it's in this yellow region from his father who got it from his mother if the female is on bottom here well where in my genome is that gene from my father's mother it's not there I didn't get anything in my genome there from my father's mother my father's mother is missing in my ancestry for that gene maybe some other gene I did get something from my father's mother so this makes reconstructing ancestry very very difficult it also means that if you compare any two people who are alive today and ask where and when in the past did they have a common ancestor who was that individual who gave DNA to the two people who were comparing now there is always a person who was that common ancestor but as you move across the genome from place to place that person who had the DNA that would eventually be inherited in the two people you're comparing now that will be a different person who may have lived in a completely different part of the world hundreds of thousands of years different in time so these genealogies go back in time sometimes very shallow sometimes very very deep that's just the reality of the population genetics within humans or any sexually reproducing diploid species okay so with this in mind we can ask how long ago in the past on average do two humans have a common ancestor to random place in the genome and this turns out to be for humans something like 450,000 years ago in the past okay so it's 450,000 years ago plus or minus about 450,000 years ago which is funny but it's also true this is a Poisson process the mean and the variance are the same so it really could be much much more recent it is much more recent in some places and much much deeper in other places and we can say now with Neanderthal genome the average coalescent between a human and a Neanderthal was something over 800 and years ago in the past okay but we know from various lines of evidence that the population split that would lead to humans on one hand and Neanderthals on the other hand from this ancestral population that the Chris stringer might call Homo heidelbergensis something like this this common ancestor population it wasn't a single individual it was a population that had its own genetic variation and something like 300 thousand years ago this variation would be split off into one population that would become us and into another population that would become Neanderthals so what this means is these random genealogies that go back in time they often predate the population split that would lead to humans and Neanderthals so the variation that's alive today within us was already alive in that common ancestor population and was alive within the and earth all's up until the time that they went extinct so one implication of this is that there are many places in the genome where you may have a common ancestor with a Neanderthal more recently than you have a common ancestor with another human in fact we think this is true for about eighty-five percent of the genome that Neanderthals fall within the variation and through about eighty-five percent of the genome okay so that means that we share variation with Neanderthals for a seemingly uninteresting reason that they fall within our gene trees we're that closely related to them that we might share I might have an a where a Neanderthal has an a because that mutation happened in a common ancestor and someone else doesn't have an A because their common ancestor was longer go in the past didn't have that mutation somewhere else in the genome maybe they're more closely related to a Neanderthal than me okay so this is the backdrop against which we must compare human diversity to understand how we are different from Neanderthals so this process being random sometimes I'm more closely related to a Neanderthal than you sometimes you more than me it is random and the the the expectation is that if this completely random process is going on then over the entire genome I will be more closely related to an and Ertel than you exactly as often as you are more closely related to a Neanderthal than me as long as they are a clean out group to all humans we're all dis the equally distantly related to Neanderthals so to test this hypothesis we sequence a genome of five individuals from around the world - from Africa 3 from outside of Africa from the places shown there one can ask along the genome locally along the genome how different are the three Neanderthals and orange and yellow here or the five humans that we sequence to the reference human genome just one instance of the human genome and this difference and the units here are as a percentage of the way back to chimpanzee this difference has a distribution because of that random coalescent process sometimes two people are very different and the you get a segment that's way out here sometimes they're very similar but on average the Neanderthals are more distant to the reference human than any human is to the reference human but that summary turns out hides a lot of very important interesting details so in an analysis devised by Nick Patterson and David Reich this very simple comparison we can ask this question are any two people that we compare equally dissimilar to a Neanderthal so if we find a place all the places in fact genome-wide where the West African and the French guy have a genetic difference maybe this guy the West African has a T and the French guy has a G what does the Neanderthal have if Neanderthals are a cleanout group it should be 50/50 sometimes matching the West African and sometimes matching the French guy the the observation was that when one compares two Africans the result is statistically indistinguishable from 50-50 furthermore if you compare two of the non-africans the result is also statistically indistinguishable from 50/50 but any comparison between an African and a non African showed excess allele matching of the non African to the Neanderthal and this then is a summary of this these guys are basically the same in increased neanderthal allele matching and these guys are the same but any comparison across them shows excess here so from this we devised the the parsimonious model that when humans migrated out of africa maybe 70 or 80 thousand years ago and first came into the Neanderthal territory there was an episode of admixture and this group of individuals would then colonize the rest of Eurasia and bring 1 to 4 percent of this Neanderthal ancestry with them so that was the interesting story and kind of how things stood for a few months until a bone from this cave was discovered with remarkably well-preserved DNA there was some technological improvements that removed this base damage at the end so that from the Denisova compared to the Vindhya in the end earth all's we get really really clean data and could do a lot more with it it looks very similar to the Vindi in terms of divergence if you make a tree the denisa bow sits in a really weird place it's a sister group to the Neanderthals and out-group to humans but it's genetically more distinct from Neanderthals than any two human are today and there's this really really odd signal of increased allele matching from individuals in Papua New Guinea this has been investigated more and this signal seems to locate east of the Wallace Line its present in Australians and people from this region and largely absent from mainland Asia technology keeps getting better this guy Matthias Meier had the imagination to think that DNA might actually be single-stranded from these bones and devised a method of pulling down single-stranded DNA not just double-stranded DNA and was able to increase the yield from this Denis of a bone many many times over and get DNA genome from the Denisova of about 30 full-coverage this allows one to pretty much wring out all the errors every base you get to see on average 30 times and now instead of having an excess branch leading to the archaic group you have a shorter branch which is in fact what one would anticipate if this individual has been dead for long enough the evolution that continues through every generation these accumulation of mutations the clock stopped on this individual and he's missing we estimate somewhere between 74 and 80 thousand years of molecular evolution which presents a new way to date bones just from the missing DNA sequence mutation within it I'm running out of time but I just want to finish up with this one last thing as I mentioned you have two copies of the genome the one that mother and father gave and every place in the genome tells a different evolutionary story a different tmrc a this means that within the genome of a single individual one can answer lots of questions about the whole of human evolutionary history and in fact you can look at the local density of heterozygous sites places where your mom was different from your dad and infer how long ago their common ancestor was across the genome and make these plots in a very creative use of genetic data that say through the past how big was the population size that led to various individuals here including the Denisova and one outcome of this was that the Denice event sample seemed to indicate that not only did they eventually go extinct but their effective population size the amount of diversity that they were carrying had been low for a long long time so this population the population size of whatever group this individual belonged to was low and likely struggling for quite some time up until the point when they eventually disappeared so I will just end with some questions there are a lot of great answers from you know ancient DNA but they propose new questions and one of them that is really a hot open question is this one episode of admixture that we have here with a rather rude method asking how much allele matching is there does that hide details that might be interesting might there have been subsequent episodes of admixture in the long time that humans coexisted with Neanderthals who were these Denice events we have a single pinkie bone and a molar we know very little about them morphologically we don't know their range we know that their DNA winds up in people who live very very far away from the cave where this bone was found and finally were there other archaic that were involved in ancient admixture events thank you

Channel: University of California Television (UCTV)

Views: 101,996

Rating: 4.8031173 out of 5

Keywords: Richard Green, Ed Green, Neanderthal, Denisovan, evolution

Id: o25ANiRAMvM

Length: 24min 32sec (1472 seconds)

Published: Thu Aug 01 2013