Svante Pääbo: The Future of Ancient DNA - Schrödinger at 75: The Future of Biology

[Music] our final speaker this session is dr. sponte Pavo Pavo was the first scientist to successfully sequence the genome of Neanderthals he also discovered the previously unknown hominin group Dennis Evans recently Paabo and colleagues found evidence of a first-generation child with mixed Neanderthal and Dennis event origins providing evidence of interbreeding in humans of different subspecies pabu is the director of the department of genetics at the Max Planck Institute for evolutionary anthropology and Leipsic germany today he will share his insights on the future of ancient DNA please welcome span to Papa [Applause] okay so thank you very much it's very exciting to be here I was then asked to talk about the future of ancient DNA which sounds like an oxymoron to me so I sort of allowed myself to add one word at least in a title and what I actually then wanted to do is to base this on work that has gone on in our lab over the past 15 20 years on extinct forms of humans but what I will be discussing and doing sort of some cautious extrapolations into the future will apply to any other organism such as mammoths that you might be interested in from which you can retrieve DNA but we have done this sort of obsession with Neanderthals to the left is the reconstructed skeleton of a noun the tall to the right of the present-day human and as you know Neanderthals they evolved in Western Eurasia and Europe to Central Asia around four hundred thousand years ago and live there till until approximately 40,000 years ago when they become extinct in conjunction with that modern humans appear on the scene and what may then ask why should we be so interested in the under toes I think there are two reasons for that for me one is that they are the closest relative of all present in humans evolutionary relatives so if we want to define ourselves genetically and biologically as a group it's really them we should compare ourselves to in the first instance and another question may be how Crescent a people are related to Neanderthals but to then do that you need to retrieve DNA from the remains of Neanderthals and that's something that we worked on in the meantime almost 30 years in our lab and there are issues with that first of all butter is very little DNA surviving in bones of ancient remains often hundred thousand a million fold less than impressed with you it's degraded two very short pieces it's chemically modified and it exists in a large excess of bacterial and microbial DNA that colonized this remains over tens of thousands of years and as a consequence of that contemporary traces of DNA from present-day people humans say if you study Neanderthals that will not at all affect your experiment if you strata fresh DNA may totally overwhelm your experiments when you started this tiny amounts of DNA in old bones so in the meantime waste overcome that has been worked out part of it involves sort of being really paranoid about cleanliness working in special laboratories wearing funny clothes etc and also methods with which you extract the DNA efficiently and cleanly and transform it into forms where you can then do DNA sequencing and other analysis so in the meantime then we have several Neanderthal genomes from different places in Europe we can study we also have some very good near natal genomes from three different sites in the mean time so these are than genomes where we have gone over the last few years to have some fragments covering a part of the chromosome here to having in average every site covered 30 or 50 times over but I should stress that that is for the approximately two-thirds of the genome where we can map these short fragments there are still repetitive parts of the genome where we don't know the exact arrangement of DNA sequences and probably never will for this extinct species so we can then relate these Neanderthals to each other the oldest one is in order hundred and twenty thousand years youngest ones forty to fifty thousand years ago and one discovery that then came out of comparing his Ananta genomes or present-day people was that for many of us today we carry fragments of Neanderthal DNA in our chromosomes for one chromosome here indicated in red and you carry between 1 & 2 percent of the genome from Neanderthals if your genetic roots are in Europe or Asia or anywhere outside sub-saharan Africa actually and just as an example of that for example a particular variant here at associated with high levels of LDL cholesterol it's it's then on the big piece of DNA of a hundred and thirty thousand base pairs that is almost identical to the undertale' genome and it's really the size of this that then proves that this comes over from Neanderthals quite recently it hasn't had time to get smaller due to recombination in each generation so it couldn't come from back here from the common ancestor so since everyone outside Africa carry these traces of Neanderthal DNA also in parts of the world where Neanderthals have never been the model that explains this is then that when modern humans came out of Africa they probably met Neanderthals quite early on perhaps in the Middle East and if this humans mixed when the undertones they could carry with them this Neanderthal component but to say outer parts of the world when younger Tasos and not existed and these sort of remnants of Neanderthal DNA in the genomes of many of us today have consequences as you will see here different people is lying is a different individual tend to carry different fragments of the Neanderthal genome and they turn out to often be associated with things that can affect today just two examples for example one variant here of a unit is quite frequent in Asia up to 20 25 percent of Asians carry it it clearly comes from Neanderthals this is the value in the under-told variant here these individuals in Asia are closely related to that for this gene which encodes a liquid transporter that's associated with risk to get type 2 diabetes type of diabetes to get at old age yes two weeks ago there was another paper that appeared that showed that a progesterone receptor variant that exists particular in Europe and Western Eurasia comes from the under tall's and that's associated with an increased risk of preterm births and there are many many such cases now for diseases and sometimes protection against the diseases when the under-told variants influence the risk so say hyper correlation many skin diseases even things as depression and so on but what has made all this progress and possible is improved methods to retrieve tiny amounts of degraded old DNA from small amounts of material so today we often work with 40 50 milligrams of bone powder and a sort of striking example of that is this little bone it's a fragment of the last balance on a finger that was found by russian archaeologists in 2008 at the site in southern Siberia at the nest of a cave and we were able to see it was a quite a good quality you know from this finger and was very surprised than to find that it was not a modern human was not a Neanderthal but something else that way far back to common ancestor shared with Neanderthals that's about four times deeper back in time than any split between to present a popular patience among humans so this was cleared for some new group of extinct hominins that we then called Dennis Simmons after this site in Russia and still today this group of individuals is only known from this little fragment and three teeth that has been found been found in this cave so it's a group of hominids that we really only know from their genome sequence and not from any fossils that one has found yet we think that they've been quite widespread in the past in Asia because all over Asia people carry small amounts of the nispom DNA in the genome and people in the Pacific say Papua New Guinea people have up to five percenters as you know from these decibels so we then think that when they were Neanderthals in Western Europe and modern humans appeared there were these Denisovans probably around a large pot or Asia so this is an part of it trend where you can now retrieve DNA not just from being nice bones but from very tiny bones and also from other types of material so for example from coprolites sword old poop that you find that archeological excavations dental calculus for example and what's particularly interesting at the moment for us from ice cores and from sediments in the permafrost particularly so we focus very much on that lately looking at archaeological sediments from archaeological excavations using tiny amounts and trying to retrieve DNA from them and that is an often possible for example in this site where these Denisovans were found what can then show that deep down there are the National remains DNA in the sediments and the under-told DNA this once again the under thoughts and so on reconstructing the history of who has lived in this cave and if you want to do this on a large scale you of course need to process hundreds if not thousands of soil samples and that now becoming possible in terms of that DNA extraction and the production of these libraries immortalized form so this DNA that you can study and the capture of this part of the genome you're interested in have all been automated you can do it with robots such as this lab robot here and go into cave and actually study hundreds and hundreds of seven samples through the stratigraphy and for example reconstruct and very well what animals have lived at different times in this cave and you can also do with them for how many in DNA and find for example Neanderthals these samples here and the measurements and these samples further down and so far this has only been done on mitochondrial DNA which is a tiny part of the genome that exists in many copies per cell so it's particularly easy to retrieve but the big picture of course if you want to reconstruct the history of individuals it's a nuclear genome so very recently with that focused on that trying to make DNA probes to fish out interesting parts of the nuclear genome from these sediments and the challenging part with that is that there is much more animal DNA there so you need to then do probes to fish out this excludes all relevant animals allows you to focus only on hominins here and that turns out to be possible if it's not a target part of the genome where say humans that you need when other hominids are unique in having some substitution where they differ from everyone else will preferentially fish out this and you will also recognize that you have right DNA molecules so you can then for example distinguish very well modern humans from Neanderthals from bone DNA go into archaeological sites take sediments and see that in one of these sites were clearly modern humans that live in the for other sites over Neanderthals so I think as a first extrapolation into the future then for the next decade or two I think this will become common practice presumably in archaeology you may just drill coerce at archaeological sites or maybe even across the landscape and isolate DNA from different depths down in the stratigraphy so you will have truly molecular archeology if you like not limited to looking for bones or artifacts anymore so you can have this course and you can add different power points in this core sort of then fish out at the moment a bit over a million sites in the genome and if you then take only one DNA fragment representing every such site you're interested in you have sort of a statistical population sample about what that population looked at genetically you will then be able to sort of use that to sort of reconstruct population history across time and the beginning of that sort of exists but by studying those as you may know if you now go across time and look in Europe for most of this work has been done on certain type areas from which you had DNA genomes retrieved from bones you can go out begin to go across time and follow population changes across time and that's then something that will presumably become much more common with a sedimentary may in the future I believe the other area that I then want to stress here is that when we now have the genomes for example Neanderthals our closest relatives we can then because on genetic changes that happen here recently in human history I have to be separated from the others and we are particularly interested in that of course because it might be sort of the genetic background of functions unique to modern humans that hi there and that may be interesting because when modern humans of course comes technological change that happens very fast counseling's as figurative art that really depicts things and a tremendous increase in population size and population start colonizing all habitable part of the planet influencing in the end the whole biosphere as you heard in the last talk so what one can now do then when one has is good genomes from my closest relatives is to focus on the things that changed there and became present in all people today no matter where we live and make a catalogue of those things and to me the fascinating thing is that that's not a tremendously long list of things it's an order of 30,000 changes in our genome I think it very interesting direction in the next decade or two is to focus on those changes from a functional perspective to try to find out if you like what made human history possible in terms of the biological background and that is work it's just sort of in the very infancy as to give you feeling for that how one might go about that let's focus on the most simple changes of those 30,000 or 96 changes to change amino acids in proteins they affect only 87 genes and if we just look on one of them that we started studying this adsl that encodes an enzyme involved in purine biosynthesis so the synthesis of two of the nucleotides in DNA and many other functions in the body this change is the change look interesting because it's close to the active site of the enzyme so what I can then do what we are done is to engineer this change in human stem cells back to the ancestral state and you can then compare the metabolism of these wild-type normal cells that we all carry in our bodies with these ancestral Isis ancestral eyes for this function and you can then look in the metabolism downstream of the two reactions catalyzed by this enzyme and you will find that the human cells the concentration in the cells of all the metabolites downstream or lower than in the ancestral state cells so this change then obviously happened at least a large extent after we separated from the undertoads you can look at other genes here a striking thing is actually there are three genes here that encode proteins that are all involved in the spindle so that's a molecular machinery at cell division that pulls the chromosomes apart to the daughter cells it seemed very surprising that such as of a concern basic mechanism might have changed very recent in human history but we have some indications of perhaps what might be going on and that comes from other work that goes on in our department where we study brain development comparing humans to Apes so that's an work for you use stem cells from humans and apes you can make those stem cells make this brain organoid so these are 1/2 millimeter big little doubles which mimic sort of the early stages in brain development and you can compare that then between chimpanzees and humans and overall is very very similar but there are some subtle changes that you can actually find so if you look in the epithelium here there are stem cells top of epithelium which is down on this picture that divide and make eventually neurons in the cerebral cortex so if you now look at time-lapse images here of chromosomes during cell divisions in humans and chimpanzees you will see the chromosomes lining up here and then being pulled apart during cell division here for the chimpanzee and you will notice that that happens a bit later for the humans so this face when the chromosomes are lined up before being pulled apart is a longer in humans and in Apes and it's specific it seems to this stem cells during neuronal development so obviously that makes these three genes particularly interesting so what you then want to do is to go and engineer these changes into human stem cells back to the Sesto state and make this brain organoids also engineer less into the mouse the modern human changes into the mouse and study brain development to then find out if this happened back here or if it happened or you're back there so this is then the area of okay were sort of working on doing this with another sort of investigate the metabolism as we indicated the same division then aspects of how cells established neurons establish connections to each other and other areas you could think about and obviously what will happen in the future I think is that one will get more extinct forms of humans not just Neanderthals and the Missis one will have other forms here so it will become possible then to study not only time change it's not only see what's happened here since the separate from Neanderthals but going back in the things that happen there and there and know what's happened even further back there she was time when this changes happened in the past something that will also happen is and it's already beginning to happen instead we had many Neanderthal genomes so we'll also be able to see what was fixed among all named the topsail change that happened here and define the under trance as a group and we can similar cross test those in stem cells and in model organisms so to sort of them and up I think that what what can then do we sort of recreate phenotypes of extinct organisms perhaps metabolic pathways perhaps organelles in model system that we already heard hinted at in the last talk and what we also heard hinted at is that there are people who are more visionary who go around and suggest that you should even bring species back even Neanderthals back and that's of course something that we will not be doing but to end them I think the sort of things that I think will happen over the next 10 years or so is that we will have a truly molecular archeology where one will then be liberated from being limited to just finding bones and artifacts one will be able to sort of isolate DNA at archaeological sites just from sediments and perhaps also across the landscape one will be able to do truly population genetics over time because one will have many many genomes from many many places from many different time periods hopefully systematically over the area an area you will be able to not just use models to see what happened in populations in the past but you will actually be able to observe if you know I can read real-time genetic variants spreading in a population and coming fixed in species and finally what would be really interesting is to reconstruct past traits and that will then be done in model systems of different sorts cellular model system organism model systems and there are cost many many people that have been involved in this more than I can mention I'll just show the faces of the current group leaders in the department that all have been involved or involved in some aspects or what I've been talking about there are also groups that we collaborate we will cause particularly young holder and his group on on brain development in a mouse and field character which on the metabolic metabolic analysis and with that I don't thank you for your attention [Applause] [Music]

Channel: Trinity College Dublin

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Length: 25min 36sec (1536 seconds)

Published: Tue Nov 20 2018