 Alright, well I'm going to go ahead and begin. I want to thank you all for coming and to first off wish you a happy Darwin Day. An annual international holiday celebrating the release of on the origin of species. And there are celebrations both real world and internet every year. And what I decided to do. I think back in about 2015, I thought, you know, every year I'm going to do an annual heroes of evolution talk. And what I try and do is pick a prominent researcher dead or alive that made a major contribution in particular to evolutionary theory, but also as much as possible to the general layman's understanding of evolution as well. And so this year, I was very pleased to see that Svante Pablo was awarded the Nobel Prize in physiology or medicine. And so he is someone who's been on my mind for a long time. In fact, when I was in graduate school, getting my PhD in lecture genetics and cell biology, the news of stuff he was doing was always popping up. And I was always thinking that is really cool work he would be basically extracting the DNA of ancient organisms and it would always make the popular press. And so it was one of these things of a topic in science that ultimately I just think has a lot of great appeal. And then it's actually over time had a few interesting twists and turns, and it's something that has just become as the technology again it's important here that the technology of sequencing has really advanced, and he's been at the center of that that it's become a really interesting good story for everyone. So again, compared to a lot of my science circle talks, this one will be a little bit more light on data, a little bit more emphasis on the impacts. And I'm also not going to cover all Svante Pablo's publication and research history, just basically focus more on the stuff that led to the Nobel Prize is more specifically relevant for for understanding evolution. So he's Swedish citizen. Now interestingly, his mother was a chemist, and his father was a biochemist, and he himself was actually a Nobel Prize winner so he's one of I think about seven pairs of people where a parent and a child ended up winning a Nobel Prize not necessarily the same one. As a European molecular biology postdoctoral fellow, he moved to the United States in 18 sorry 1987, going out to again another one of their prominent research institutions Berkeley. And that he joined a lab that was interested in the genomes of extinct animals so again one of the, you know for runners in that type of field. His career advanced. Yeah, we'll talk a little bit about some of those publications during that time, his early years, and he in 1997 became the founding director of the Department of genetics at the Max Planck Institute for evolutionary anthropology in Leipzig, Germany. So again, this term, you know evolutionary anthropology is really in certain ways, a relatively young field. And then what his particular subset of that is what's known as paleobiology or paleogenetics, or even molecular anthropology is really just a new field that he was one of the prominent founders of. In 2007, he was considered one of the 100 most influential people in the world. Now a part of that of course is because of the research he was doing in paleobiology. But I think it's also important to recognize that from his early six research successes he joined many of these high throughput sequencing companies. And these high throughput sequencing companies were really coming to prominence in lots of areas lots of fields of medicine, genetics, genomes. And so that was a part of I think the influence there not just a paleobiology but the fact that he was helping enable this important. And again, useful in many ways, technology. And in last year, awarded the Nobel Prize in Physiology and Medicine, quote, for his discoveries concerning the genomes of extinct hominins and human evolution. And why these discoveries are important. And I'll come to this at the end, but I'm telling you the end of the last page of the book up front here is that by having comparative genomics. We've learned from comparing human to chimpanzee human to ape, even human to, you know, macaque, bush baby genomes that there's important things we can learn about how genes influence our biology. And this sometimes can come down to very important medical conditions, or even just baseline physiology. And so the fact that Zontepabo was so involved and the premier person at finding our closest extinct relative again we're talking about in the old days comparing genomes where we know there's a common ancestor and both exist at the same time. But very rarely, well, I would say it's unprecedented at this point to have a close cousin, where the, the cousin species was extinct and so the, but the fact that we can bring so close that common ancestor to that comparative analysis, and that means actually really useful in a lot of cases and we'll talk about some of that but I really think this is really the beginning of a lot of those comparisons. And so we'll see a little bit more of it as people even beyond Zontepabo work on it. Alright, so let's get into it. You know, the main concerning thing is ancient DNA. And, you know, the old school ways of looking at archaeology anthropology was digging up bones, comparing bones, and that was a lot of times what you're left with. Now, there's a lot that's come along the way where we can do, you know, electron microscope scanning to learn more about certain tissues and other stuff, but those can only lead to so much insight. Now, of course, in human comparisons, you can compare other archaeological finds are not biological, but in terms of really understanding genomics, this, this is the main point. And there's a challenge here, right? Because what you see here is a person in old timey dyes, their body is preserved enough that we can actually understand that there's a body there in modern day times. And what's left behind is their tissue, including DNA. Now, I want to make a quick note here. A lot of the early paleogenetics attempts were to look at mitochondrial DNA, because you have many more copies of that available in your archaeological sample. You have that tissue, and for every one, sorry, for every like two copies of the genome DNA, you might have hundreds of copies of the mitochondrial DNA. So that's always a first part. Now, there's a limitation to that, which is mitochondria are only inherited from mother to child, never from the father. And but what happens over time, and just, you know, anytime you think about anything you even leave in the ground for about a year, you know, what do you see happen to it, it degrades, it gets infiltrated by bacteria that are using it for food, all sorts of things happen to degrade it, including, you know, just oxidative chemistry damage from being in the environment. And so that chemical modification, those chemical modifications and all this contamination of other biological organisms was always one of the big challenges. And I think that this is, while there was this early attempt to do some relatively basic straightforward applying molecular biology to see if you could sample and capture some of this DNA. What we've learned from Slantepabo's career is that over long periods of time, sorry, over the development of the technology that you're actually developing specialized technology for this purpose. These are things that you, while they might be related to modern applications of developing sequencing and DNA capture technology, there are lots of examples where it's specifically developed for trying to capture this type of DNA. I think that's something where we should recognize those contributions, although I am not going to get heavily into those details because that's not typically how I want to do a Darwin Day type of talking. Okay, so what is Slantepabo's early interest? And again, there's a lot of biographical information, so I can't necessarily say much about what really spurred us on was actually being very interested in Egyptian mummies. And so one of his early publications was actually the ability to capture from a preserved mummy a stretch of DNA. Now, what was interesting is that the thought being given certain preservation practices and also desertification. Again, one thing that's nice is if you have a very dry climate, then the amount of microbes that can contaminate your sample become less because there's just they don't have enough water to live and metabolize. On the other hand, you could imagine that preservation practices would also completely ruin the DNA. And I think that's probably ultimately what happened to the most well preserved ones. And so among 23 mummies, they were able to capture one stretch of DNA. They were able to clone it and get some degree of sequencing off of it and able to just show that it was possible. So this was, again, when he steps forward, it's very interesting 1985, but in many ways using kind of classic DNA technologies known at the time. But it's the type of information that again the review and I have this in the notes, the work cited note card and that's all available on the web. People are very excited about being able to look at ancient DNA to understand the migration, the alleles, the patterns of disease that you might see in ancient DNA and also do that comparison to modern day DNA. For example, sickle cell anemia understanding is actually has helped people understand migration patterns in ancient Africa. Okay, so, but the exciting stuff the stuff that was making the news during my graduate day times of my postdoc times was this looking at ancient mammoths and sloths again nothing tends to capture the imagination of the general press as mammoths and sloths for whatever reason. Right. They're planning on reintroducing mammoths based on genomic DNA from this company called colossal biosciences just announced this year. And so the challenge though was this basic idea like I mentioned that that chemistry can mess up DNA that even if you have something that's not contaminated. Does the basic chemistry still work. And so the thought was an anything older than 10,000 years old, you basically was could not amplify because it was too chemically damaged. But the thinking of this paper was, well, if we can find some well preserved mammals that were in the permafrost that maybe those extremely cold stable temperatures would allow amplification, given the techniques at the time. And in fact, that's what they showed they were able to amplify nuclear DNA sequences so they didn't have to rely only a mitochondria they were able to amplify nuclear DNA sequences. And basically sequence and compare them. Well, no, so just just a touch on the colossal biosciences ideas that they do want to reintroduce mammoths to the wild, primarily in I think Siberia, because they think it can actually help with reestablishing the ecology and basically the carbon cycle in a much better way that actually their arguments is that they can help with climate change by reintroducing the woolly mammoths. We can I can show you my thoughts on that later about whether that will be successful. Well, let's talk about it at the end, but I it's a good conversation, we can talk about it then. And so I just want to give an example of from this paper, the types of information they're able to get out from just amplifying this genomic DNA. And so here's one of the genes I mentioned, the a to a b gene. And what you're looking at in this picture is you have the Asian elephant and consensus sequence. But notice it's only about 68 base pairs long right it's only 68 base pairs not that long. But when you look down the dots in every row below the top represent being the same sequence, the same nucleotide, but when there's a new letter introduced as saying oh it's differing from that consensus sequence at the top. And so what's really interesting here is that they were able this time to capture enough nuclear DNA. And if they were lucky about where they were finding that they could capture information that was useful for developing phylogeny, resolving ancestral relationships between different animals. And that's what was was interesting and useful about it. And then ultimately, but also other groups did more so than the font a pop up group was that once you had good primers to an amplifiable amount of DNA for something, you could then also try to understand the archaic distribution of those animals within the habitats. And so you could understand maybe migration patterns or, you know, even population levels in some cases. Now, moving on to 2003. Also looking again at trying to resolve relationships of the sloth. And what they were able to show in this case is again the ability to find the advanced here was with new techniques, able to recover single copy DNA gen genomic DNA. And that also was from a warm air climate. And so this idea that they that you have to be limited to permafrost type of samples with good preservation was apparently no longer true. And so basically this opened up new avenues new ways in which people could broadly apply this across various climates and can various ancient climates as well. And what you're seeing here in the figure is just this example of where, in terms of looking at the ancient Shasta ground sloth, they were able to phylogenetically place it as being more closely related to the three totes loss as compared to the two totes loss, which of course was an argument that had led to many bar fights among paleobiologists little known fact. Okay, so let me talk a little bit more about putting this all together to really understand ancient organisms. Oh, so actually, yeah, so I didn't even mention that one part that what a coprolite is just a reminder that is preserved fecal matter specifically. And so, again, it's one of these things that people thought for a long time might be very hard to capture DNA from that because that's an extract that has a lot of biological microorganism activity going on in it. But if it's preserved well enough, then it actually does seem to work. And actually, the other thing that's really interesting of course about it is that if you were to think about the availability of sampling ancient DNA, then corpora lights end up representing what 100 times the body mass of an actual fossilized animal that you could capture that information from corpora lights, the availability of samples are is astronomically larger. And then you also can get insight from the diet that you had not just what the animal did, what the animal was phylogenetically but also what it ate. And so those are again all things that became very exciting as people. Well, you can actually recover plant DNA sumo, you can recover plant DNA from from corpora lights, other animal DNA, but then a lot of times it's the thing about it that the challenge is it's much more contaminated by microbial DNA. But in some cases you can actually learn about the microbiome that an organism had so lots of interesting stuff. So what I've mentioned so far are generally small amounts of DNA that they were starting to be able to capture whole mitochondrial DNA sequences so you actually had the entire genome of the mitochondria for many animals. But when it comes to trying to understand again that nuclear DNA that tells you the most information about what's going on within a species that was problematic. And the reason why and what I'll show here is how these were standardly put together with the technology. And that is if you had captured some DNA, what you do is put what's called a primer on it, and then you're captured DNA you have a template, and you basically add all the DNA synthesis enzymes and chemistry you need to extend that DNA. And then what you see on the right hand side you see an example in the old days at this time of basically a radiograph where you put in what are called chain terminators, so that you get a radiometric reading at every length at which you're substituting in a chain terminating C for a regular C, and then a chain terminating T for a regular T, and you get this population of modules but the key thing here. And this is what's important to recognize is you need a pretty large population of DNA to work with to have that work very well. And a lot of times ancient DNA, you just had very short segments because the chemical modifications and damage already in your template your original template already basically created chain terminators. And then assembling a genome. What I have shown here is like your standard old genome assembly technique is that as you get lots and lots of single reads. Just little short horizontal bars. In order to assemble that to a genome you need overlapping sequences, and then you understand what the overlaps are between those chunks. And then you create bigger chunks and hopefully you can keep going until you create chunks as big as the chromosomes themselves. And one of the challenges for ancient DNA is very hard to get enough of these overlapping chunks, because they were so chemically degraded or you know, not representing the best regions very well that you just could not assemble them to make larger scaffolds and contigs and all these things. So, one of the big technology revolutions was what are known as high throughput sequencing. This in many ways relied upon a relatively different strategy, which was, instead of trying to assemble, I'll come to that question in a second. And instead of trying to create multiple long reads using your standard technology, that what these machines do is use some very specialized types of chemistry to just only make short reads. On the machine on the left, it's reads size, which is only 500 base pairs. On the machine on the right, only 150 base pair reads. However, the copy number you'll notice is 500 million or 95 billion, which ends up being enough overlapping short DNA sequences that you can assemble genomes relatively easily. So, the barragon does bring up a good point, and I want to touch upon this, that this is really great for mitochondrial genomes, because you have short reads. The DNA itself is not very complicated. It's very easy to find these overlaps, even among short reads. Now, the problem that comes up is something barragon mentions as tandem repeats, but there are also other types of repeats known as repetitive elements. For me, you know, talks I've given, I've talked about repetitive elements in genomes before, those really do complicate a lot of these analyses. So, again, important to recognize that it's not an end-all solution to all this, but it can be a very powerful way to understand all of the unique coding parts of genomes by taking this very separate strategy of sequences as much as you can, and then do basically computational analyses later to clean it up. And that's what's shown here in the next slide. Again, these last couple slides I've basically stolen directly off of, I should say, fair use borrowed off of the Nobel Prize lecture website, which again is also a citation. Flante Pabbo's talk is very accessible if you want to watch it independently. But here's this very fresh strategy that now this new technology could enable, which is, even if you have a relatively small amount to DNA, maybe not very many copies of it, maybe it's highly degraded. What you can do is, if you're trying to assemble those blue segments, is you just sequence everything, right? While you try and do as much as you can to reduce contamination, what you can do is just sequence billions upon billions of copies of DNA, and then use computers to recognize where the blue, again, your target genome sequences compared to all this other stuff you're getting. And what the red might represent, for example, would actually be human DNA, right? You're extracting these from sites, and then human DNA can be one of your contaminants. But because we know the human genome sequence, even though it might be similar to the antithal sequence, we can positively identify it in many cases as being human. And then actually there are other chemical tricks you can use to sort out old versus young DNA as well. So this is kind of a good pausing point, because I'm going to get into all the genome stuff in just a minute. But anybody have any questions about paleobiology or how the techniques on this work? While you're collecting your thoughts, I'll mention that. I think one of the challenges for reviving the woolly mammoth based on sequence DNA will be they're going to try and recover and use CRISPR to basically modify elephant genomes to be more like the woolly mammoth. The problem is, unless you understand all the repetitive elements that I think have very important transcriptional regulation controls, they've been modified to do that. What's going to happen is you might have all the genes in place, but you're not going to have all the regulatory control of all those in place. So I don't think it's as easy as they say it's going to be. Okay, Phil's amazed. If Phil's amazed, then I think we can move on. Alright, so let's talk about publication history with hominin genomes. That 2008 was the publication of the mitochondrial genome of Neanderthal. And this came from an individual. This is important to recognize that the geography of this individual was from Croatia. So again, Eastern Europe. They were able to, again, put together 8,000 base pairs of sequence, but they used it from five gigabases of sequencing DNA. And so that's the important thing to recognize that, again, that technology enables this type of thing. Sorry, those are 8,000 different sequence reads. The actual nucleotide sequence is 16,000. And so, you know, they put it together, they showed the conclusion that was really interesting, and this was big news at the time, was that the mitochondrial DNA did not match anything in modern humans. And I remember there being, I think there was even a whole NOVA special about this type of stuff. But if you look at this phylogenetics down here in the lower left hand side, that little red dot is, they're saying the split of Neanderthal from modern humans. And so there's no cross-contamination, no representation of Neanderthals. And so the conclusion, and then the right hand picture is just showing this in a more graphical sense, that where is this overlap? And because the red does not overlap the black, then humans and Neanderthals, the conclusion was they were ancestry related, but never interbred. At least based on the mitochondrial inheritance pattern, right? So they're saying they did not interbreed. Which of course then made 2010 an interesting year when they sequenced up the human draft, the genome of the Neanderthal. Well, yes, Sumo, you're pointing something very interesting out, is that when they published the whole draft sequence, and again, I only have access to the abstract for this paper, so I can only recapitulate what's there, is that when they compared that Neanderthal genome to present day humans, they identified a number of regions that may have been affected by positive selection. Genes involved in the types of things you might expect, things that might be different in metabolism or cognition. And the conclusion was that we share a lot of genetic variants, which means we must have interbred at some degree of overlapping time. And one thing that they could do by doing this comparison, and you'll see this come up in the maps, I'll show you multiple times, is that the Neanderthal interbreeding with ancient Homo sapiens only occurred really outside of Africa. That however the human migration patterns worked, they left the interbreed with Neanderthals in a relatively wide amount of space, but that Neanderthals never went to Africa. There's lots of arguments to say that Neanderthals were particularly cold adapted, but that really the gene flow back in Africa was zero, non-existent for Neanderthals. And I'll talk a little bit more about this positive selection. Positive selection is a term meaning that the amount of that gene, that particular allele of it, increased in the population probably because of some useful selective purpose that was existing at the time. Okay, so the other fun surprise in this whole story was that when they were randomly sequencing a sample, again a small little bit of a finger bone, and this was in Dinosava Cave, which is in the Altai Mountains in southern Siberia, they looked at the DNA and said, well, this is not human, but you know what turns out this is also not Neanderthal. And so from that they said, hey, there's another branch of human evolution of hominids, exactly Phil. They just came along, weren't expecting it. And so what this is showing here, and there's a little bit of a graphic representation of this, is that their estimates for what happened in the branching was that about a million years ago Neanderthal and humans had a common ancestor and then branched. And then within that branch, that is what led to Dinosavans and Neanderthals. And so that's the relationship between all those. And so, and then the branch point between Neanderthals and Dinosavans was more like, I think, 600,000 years ago based on that. But the other thing too is that really made the representation, given the dating and the time of these sample remains, that it probably meant all three branches existed at the same time between 30,000 to 50,000 years ago. So that became this question too of, well now that we have this Dinosavans mitochondria, can we get the Dinosavans genomic DNA, and just like what's in the Neanderthal draft sequence, see a signature of that in modern day humans? And bearing on again, that brings up an interesting question which has not been answered, right? So the absence of human DNA in Neanderthal mitochondria, or I think what you're actually meaning is that the lack of Neanderthal DNA signatures in human mitochondria, maybe the only way this worked was Neanderthal men interbreeding with human women. And so, I've not really seen anybody give a good answer to that and we can speculate a little bit at the end, but let me just push that conversation off to the end. So what they showed in this paper, in terms of looking for the existence of Dinosavans DNA signatures in human genomes, was that, and then also having the genomic DNA, they gave them a better resolution of these divergence times, is that human diverge from Neanderthals and Dinosavans more like 800,000 years ago, and then Dinosavan Neanderthals, they had a common ancestor that diverged about 600,000 years ago. Now what's interesting is that the signature of Dinosavans relatively limited in human populations, but there's a relatively high percentage of it in Melanesians. And so this map here is showing an extraction from their paper that if you think about Micronesia, Polynesia, the islands, the larger islands right above Australia, but not Australia itself, you see a pretty good signature of the Dinosavan DNAs. But remember also, the likely crossbreeding of this probably actually occurred back in Siberia, and so something happened there that then later human migrations led to this. All the way in, we don't know all of the geographical location of all the Dinosavans either. Right, so Aurora points out something too, which is, and this is a number I wanted to just gloss over, but I think it's important to recognize, is that within human populations, if you take probably all the humans, sequence all their DNA, and asked how much of the Neanderthal genome is covered, is represented, they think we can recover about 40% of the Neanderthal DNA within the genome within the existing human population. However, the fixation of Neanderthal DNA into humans is mostly concentrated in ancient European populations, and it's typically anywhere between 1.6 to 3.5%, or something like those numbers. So almost all of this, again if you go to 23andMe, and we'll come back to 23andMe again later, they will tell you how much Neanderthal DNA you individually personally have, and again, which part of the Neanderthal genome might be very different. But we'll talk about, from an evolutionary point of view, which regions that might be likely to be. Okay, so once, so in the all-time mountains, they also were able to capture a much better purified genome from the Neanderthal. So this is known as a more high-quality genome sequence, and they wanted to make some other inferences about it. Berrigan, just remind me about that question a little bit later. And so, when they took this high-quality sequence, they make the estimate that, again, the particular proportion of amount of DNA that you have, again, now that you could resolve a lot of the smaller differences in nucleotide alleles, and really map this a little bit better, is that in general, the amount of Neanderthal drive DNA in people outside of Africa is anywhere between 1.5 to 2.1%, although that would be much depth a little bit higher within the ancestral European populations. And then they also could do a better comparison of Neanderthal to denosevins, and what they found was something a little bit better. They found certain signatures in human leukocyte antigen region, and the CRISP gene cluster chromosome 6, both of which are involved in immunity and sperm function. And so, this interesting little inference about immunity is interesting, because we will see in repeated fashions that perhaps one of the best values that you can get by having interbreeding with a more distant population are things that are affecting, and you can see these signatures because you have very strong selection from pathogens. Again, pathogens are the things that sweep across populations and can lead to very strong selective pressures. And I think the best example that people always talk about with this is the Black Death, I also know it as bubonic plague in Europe, where in its first pass it killed two thirds of the population, and then every subsequent epidemic, a small number of people passed away from it because there were genes that enhanced people's immunity to it, those were the survivors. And that's evolution, that's how evolution works. Okay, so here's a little bit of a map that they put together, which is again showing the branch points, not necessarily in time, but giving some degree of the branch points of these different hominins, and showing you in these orange arrows where there seem to be specific gene flows from introgression crossbreeding. And so you'll see some of the Neanderthal genome pass into De Noseva, but that more was only limited to Siberia that weren't the European Neanderthal populations, whereas the European Neanderthal populations clearly branched into the Homo sapiens, although at a point after the migration out of Africa. And then you can also see some other De Nosevan integration into very specific subpopulations of human populations, that as I mentioned seem to be representative of Pacific islands. And then what's also interesting here is that there's enough signature from the DNA that we look at the genomes and compare them, there seem to be these islands and haplotypes of yet another unknown hominin that has interbred with De Nosevans. And so there are no archaeological samples that represent that actual genome, but by comparing having enough DNA information you can say, hey, there's something extra in here that's not a part of these species. Okay, so while I think it's really important to recognize the power of these understand paleobiology, and to understand human migrations, understand this, that's not going to win you a Nobel Prize in medicine and physiology. And what's really I think the last part of the story is that the power of having these genomes and looking at these signatures has led to advances in understanding the medical pathological conditions of humans as compared to Neanderthals. So here's the first example. This is just an interesting one about a nerve receptor protein. And that nerve receptor protein is different between the Neanderthals and humans. And they did a couple things to characterize this is that one, if you look at a sample of British people, that where you have both their genomics, their allele and also some sort of other sampling data, you can ask them, you know, things about their lifestyle, and they say they experience more pain than others. And then also you can do physiology, you can basically take this back to the lab and compare the expression of physiology these with molecular chemical assays and compare the difference. And that's what they found is that the this nerve receptor shows reduced inactivation meaning it's sending more and more of a signal back to the brain. And so because the suspicion they have is that this is a pain receptor. And so their argument is, perhaps Neanderthals are more sensitive to pain than humans. Again, we don't know. But that's, but this is the type of analysis that then when you have this comparative genomics, and you have sample size data, and you can do some molecular biology on it, you can make these inferences. Another great example is the progesterone receptor. And so progesterone is important for preparing the urine lining for egg implantation and maintaining the early stages of pregnancies, as well as, again, it's involved in the menstrual cycle as well. Again, if you, does anybody know of any particular drug that might relate to progesterone offhand? What they showed is that these are different between Neanderthals and humans. And that given what we know about modern day progesterone is that this can have a consequence for carrying pregnancies to turn. And so I want to just focus a little bit on the map here for a second, what these pie pieces are showing that the orange slice represents more representation of it within that population. Again, you'll see in Africa, very small, in Europe, a lot higher, but then you'll also see it in the western world populations and within Asia as well. And Aurora points out, I think a useful thing to recognize is that genes that actually help you with directly with fertility and the amount of children you can have ends up being a very powerful thing in terms of human evolution in terms of a what's called a positive selective factor. And so in following up on this, you know, they look at that particular polymorphism, and they again use a comparison to the UK Biobank when they can identify different patients and given different descriptions of what their pathologies or why they went to the hospital, is they found a so-called negative association between the Neanderthal allele and hemorrhage in early pregnancy. And so what, and then also reporting less or fewer miscarriages within that population, if you're a carrier of the allele. And so, and then also looking at just overall census data, you can see that those individuals carrying the Neanderthal allele had significantly more sisters, although interestingly not an increased number of brothers. And so these, again, somewhat indirect logic and reasoning, and again inferring from excellent data is that these may reduce the frequency of miscarriage. Although this is in a sense competing against the fact that the lower progesterone levels and receptor levels might mean that fewer pregnancies implant well in the first place. So you might have a somewhat lower fertility in terms of implantation, but it seems like the net effect is that the trier is done, is that you do have a net impact that's positive for fertility. And also, and I think this is where the sister information comes in, is that remember one of the causes, one of the major causes of death for women is, you know, death during childbirth. And so the fact that you have adult sisters that are more prevalent from the statistical data may indicate that, in fact, less miscarriages, less issues with pregnancy. So here's something that you may have heard the news and I have to apologize yet again for bringing COVID back into the conversation. I know lots of people are sick. I'm tired of hearing about COVID. But this was an interesting set of data that came from an analysis by 23andMe. So 23andMe is a company that has a huge amount of biological genetic information about people. And they basically sent out a survey to their subscribers, people who set samples again after the fact and said how bad was your COVID. So what the graph on the left represents are signatures of correlations between severe COVID, not necessarily the prevalence of COVID or having COVID, but actually having severe COVID specifically, and a potential allele signature. And so you notice there's a very big spike on chromosome three. And the right hand image shows the set of genes that are in within that signature area. And what's being represented there in the red are the genetic variants that are correlated to the risk variant, and those risk alleles match this one particular Neanderthal genome. And that black bar at the top, that black bar, that's basically a haplotype, again, a whole stretch of DNA that is from Neanderthal. So what did we learn about that? So again, here's the signature seems to be correlated to Neanderthal of having the Neanderthal DNA makes you more susceptible to severe COVID. And then here's the geographical distribution of this, and you'll see, again, low in Africa, a decent signature in Europe, but interestingly, a pretty high prevalence of this gene in that, you know, Middle Asia region around India. And so the interesting follow up to this, and I think this is really important, is that that DNA segment may also relate to the expression of something known as CCR five. And when a follow up paper, again, slantepabo didn't publish this, but the person who published the COVID-19 paper with him published this by himself, showed that these individuals with this particular gene segment that is susceptible to severe COVID is actually protective against HIV infection. And so this is one reason why it may be a relatively prevalent gene in certain populations is that it was protective and a survival advantage in places where HIV was also prevalent. And so this is the, as slantepabo put it in his talk, the double edged sword sometimes with evolution. Now there's another variant that came out that seemed to connect with Neanderthal genome to less severe COVID. And again, I don't know a lot about the biology this one in particular. But what they showed is that a set of genes that are involved that encode work known as oligo, so oligo adenylate synthetases. And these are things that are involved in immune responses, as well as being involved in double stranded RNA. So again, double stranded RNA is something that comes from your right invading viruses. So the fact that there does seem to be this prevalence and you can see a worldwide distribution of this, there may be some positive selection. In particular, a places that have gone through other types of maybe even specifically coronavirus infections, where this was a survival advantage for them in the past, and then you've retained some of the survival advantage with a new infection to new COVID-19. Well, yeah, just to point out that again, there are two things that go on when you think about these pies is that in both cases in Africa, if you don't have the Neanderthal genes there, you can't have a positive or negative selection for them. But then when the Neanderthal genes are there and available to go through evolutionary forces, you can see different amounts of them coming back and forth. But again, that actual selection, those actual increases or decreases in percentages will reflect the living history of those individuals and the pathogens they face in this case over time. So that's kind of why you see some similarities, but then also there are going to be some differences between two. So for example, if you look back at the previous one, you know, the amount of stuff happening in the North American population seems to be a little bit less, whereas you have a lot more of it here in this particular one. So anyway, last couple. Another example looking at metabolism differences is that one thing we don't we have genes to protect us from oxidative stress, because oxidative stress is something very damaging to the molecules in the cells. And one thing that we that you could look at is the fixed the fact that the fact that there's something that was fixation, which means that at some point in time all humans had the fixed version of the gene 100%. In other words, fixed means 100%. And it wasn't until later that in Brady interbreeding with the air falls they got introgress back into humans. And again, when they look at the prevalence of it. They see a relatively larger signature in Indian Sri Lankan Puerto Ricans bangledeshes, but a lot of other world genomes don't show this illegal. Again, when you actually look at what these genes are involved with are involved in immune mechanisms, or other types of chronic diseases like inflammatory bowel diseases. So what the images show here in this case is again, while some chemical assays, you did not see very much of a difference between those particular enzymes between humans versus nanofall. But that in other cases, when this case looking at NADPH oxidation, a super oxide production, you can see the difference between the gray, the modern human version of the protein, the enzyme versus the brownish nanofall version. So again, coming back to doing molecular assays to actually compare the biochemistry of these enzymes and how they're different. Okay, so yeah, or you're asking a question about, you know, what do we consider modern human. I mean, in this case, you have a very specific consensus sequence where you can make the argument that the enzyme you're looking at is a modern human version. Now, when you talk about current North American populations, I believe and again, I would have to go through the materials and methods. Typically, that just means you're geographically locating these people and saying the North American. That's not trying to represent the old, you know, either cross ocean or cross Alaska Ice Age bridge to say North Americans are specifically derived from those right now. Sorry, that's what I was just answering that it's typically that's just going to be based on the geography of who is here is going to be based on geography, not any sort of racial inferences. Although again, there are ways that you can refine the data if you want to, but typically with these types of large global maps, they're not doing that that would take extra time and money is just geographic. This person was here. Another example gene is again coming back to metabolism is cytochrome P 450. And it's getting encoded by the gene notice C Y P to C nine. It's actually pretty highly polymorphic gene and present a humans, but this is an important time we know about a lot because if you certain people have this variance can actually get overdosed on things like warfarin, which is a, you know, blood thinning reagents and phenatoid, which ended up being direct to the end time. So if you are, if you have a mutation this the dosage of DNA you can get site dosage of a drug you can get can actually kill you, even though, you know, the vast majority of the population, that's not problematic. And so related to C Y P to C nine is also C Y P to C eight, which encodes and codes another cytochrome gene and important also for metabolism as some other pharmacological agents. And what's actually interesting is that there are certain alleles again the asterisk to an asterisk three represent alleles versions of these genes, and they tend to co segregate. And what they actually found by with the high resolution nanosol genome is that these alleles are both co inherited from nanosol. So again this is like one of these examples of a haplotype where that whole chromosome segment of two genes that are near each other ended up being inherited, and then has maintained that haplotype through multiple generations of humans. So in this case, I just mean drugs that are known and actually prescribed to people in modern day. So warfarin is something that's commonly prescribed for people who had a heart attack, for example. Again, I don't have on the slide but like the C Y P to C nine asterisk to allele is about 14% of the European population, at least in one copy. That's his prevalence not necessarily where it's almost like us. And again, the reason sumo this is important. And it's not like xenobiotics in general what it is is the biochemistry of what these enzymes do is specifically recognizing these and breaking them down so again drugs work in different ways sometimes you actually have a drug where the active version of what you imbibe. But there are actually other examples of drugs where the active version of it is what the liver metabolizes in a way, but in all cases whatever pharmacological dose you have that always is degrading over time as you clear the drug from your body so many cases, you're just pissing it out. This appears because it dissolves it's a solute and then you you get rid of it that way, but there are lots of drugs where the dosing information is very relevant to how quickly the body specifically degrades it as well. And so in these cases, these are drugs where, you know, you think you're giving you're giving them a normal dose because you're expecting it to get cleared out so so go take, you know, 200 milligrams every eight hours. It's based on its removals rate. And so if that removal rate is different because the enzyme metabolizing it is defective, then over time you're do you're overdosing somebody based on those, what's called pharma kinetics. So let me give a quick summary of these genes that, you know, the nerve receptor is one that shows differences between the intervals and humans that may be relevant. I'm not sure that and people reporting symptoms related to it, progesterone receptor against something related to pregnancy that very clear signature this. I give a CCR five which I put in here indirectly because it's an expression of the allele that they looked at. Again, enhances COVID susceptibility. So it's maybe prevalent because it helps with HIV resistance. And then OAS one through three, again, involved in viral defenses and the fact that Neanderthal one maybe seems to be given a signature that makes it better and enhanced against COVID 19. They actually showed in that paper to that it helped against MERS and maybe even COVID one. And so a little bit of, again, more in depth study was interesting there. Again, and this was the power of looking at these various biobanks, as well as, you know, registries of people's symptoms and diseases and things they went to the hospital for is you again see a signature for things related to diseases related to that. But it's not as clean cut as say sickle cell anemia. And then these last two, maybe things related to drug metabolism. Now, if you go through some of the pop those publication history beyond what he talked about in his Nobel Prize talk. There are a couple other interesting genes that that they've done comparative genomics with including Fox P two, which involved is maybe in language and speech development. There's 18 a and killing one, which are involved in chromosome separation metaphase growth, which along with novel one may reflect differences in how brains develop. And so that's actually one of these big questions that you have is what really distinguishes Neanderthals versus humans could be their use of language, their use of tools. Could there be things having to do with their brain development, where Neanderthals specifically cold adapted that's why you don't see them in the north and lesser climbs all these types of things are the types of questions that are very interesting. So here's a slide that I put it in here and maybe you can review it later. I just want to make one quick point is that really. This is from a review of looking at ancient DNA analysis and the various different landmark things that occurred during that period of time. And you'll see that really he starts it at 1984 when the first arcade DNA sequences were captured. And then things that progress both in the wet lab, as well as what's known as the dry lab, another way for saying computational analysis and whatnot. And I do sometimes wonder that maybe there's still another Nobel Prize for chemistry in the works first Fonte Pablo, given how much he was involved in both ends of the companies involved in sequencing. The genomic sequencing and other aspects of these types of techniques. But this is kind of history. And that paper is a nice review of the history of modern techniques if you want to get more in depth into the technology. Now, like I mentioned, Fonte Pablo relatively quiet person, he's never been as far as I know he's never been parodied on the Simpsons. I couldn't find anything about South Park with him being in that. And so, you know, I'm a little disappointed because I wanted to show something cute funny, but he did write a biography and autobiography. The NFL man of search loss genomes were talked to me about his life. And he has been, for example, in prominent documentaries been so much interviewed. Although the, the, if you look on YouTube and look for interviews with Fonte Pablo, he's all over the place and he's represented in a lot of modern media. Anyway, so for these reasons, for the power and the investments and the knowledge and discoveries he's made in the history of analyzing archaic DNA, but then also in the ability to do comparative genetics, really get involved in the biochemistry and understanding those differences between humans and other genes and those ended up being many cases relevant. And in the future, we expect them to be increasingly relevant to understanding human medicine and physiology. Fonte Pablo is my 2023 hero of evolution. So with that, I will be happy to take any questions or clarify things and any comments that you guys might have so thank you for your attendance and coming today. Yeah, not. I'm glad I could talk about again, he was someone that I just always whenever I saw publications come out when I was going through my professional development. But yeah, just a quick mention, Berrigan is hosting naked scientists in two minutes. So if you want to go listen to that podcast from nature from, from I think nature UK again, Ergon's not getting naked. So that's not what that's about. Yeah, so you bring up a really interesting point. And that is, you know, early on, there's a lot of bias, in terms of how people thought nanophalls and humans interacted and of course that bias came down to saying, oh, humans are just superior. So we out competed them. And we just basically beat them off and we didn't interact with them. We were just better. And one of the rationales behind that was some early physiological data where people said the NFL's I think had shorter throats. And so maybe they couldn't enunciate as many things as well. So their language capacity was just not good. But I think, you know, with more time or research and even the genetics, we don't see those. We don't see signatures of obviously one being inferior to the other in the vast majority of us, although I will say that you know, when they did this organoid, if anybody saw this that came out, I think about two, maybe just last year, where they're trying to compare the NFL genes and the development of brain organoids again organoids are like a tissue like organ assembly little tissues you have in a petri dish. See a shot and tell thanks for hosting that because the human ones were a little bit more complex than the Neanderthal ones. And so there's some argument that maybe again when you think about all cognitive brain intellectual capacity. Maybe they're still as a signature that's different between those two. Yes, you're welcome Keisha. Thanks for coming. And I think it's I think it's unfair to say Neanderthal behavior, we think they were actually much more sophisticated than we were. Okay, so the term species, we have to be a little clear on what we mean by it is that we would still characterize them as separate species, because for the vast majority of their interactions that they had enough time again 800,000 years is enough time to be your own considered your own species. However, the barriers to interbreeding were not 100%. And so it's like the idea of a horse versus a donkey versus a mule. You still consider the horse and the donkey to be separate species because there's enough genetic separation to say that they are their own species. And I can't interbreed and make, you know, a still hybrid offspring that answer your question, I hope. But I think one thing that I'm. Yeah, so I kind of bypassed this because wasn't spontaneous work, but as far as we can tell, Neanderthals were red heads. And so we believe, although this is not this is not 100% the case that some of the redheadedness you have in humans probably came from Neanderthals. But I haven't looked up a lot of the paleogenetics of that particular gene, but that's one example I don't know about the blue green eyes being a Neanderthal thing that's prevalence in humans because of Neanderthal interbreeding. But again, it's not one of these ones where you when when you compare genes of Neanderthals versus humans. The ones that I gave examples of were in many cases clear examples where you could distinguish Neanderthal versus human but there are lots of examples of leels where because they're highly polymorphic and really subject to a lot of mutation pressures or selective pressures. Maybe we also don't have enough multiple read information from the genome it's really hard to exactly say where they came from. So I think that's important point to see them. Well, I think I have a second here folks. I want to go back to that business about sensitivity to work from being a different being associated with the Neanderthal gene. I mean, We're from didn't exist back then but Neanderthal, but the boyfriend is a current. And I wonder just, and, and based on what we're saying now with this in mind, does that indicate something about the Neanderthals environment or diet I mean c'morans are in like clover and stuff like that. And then c'morans. I know, or c'morans are also light sensitizers. You know, if you're too many c'morans can cause you to blister and all that sort of stuff in the sun more than anybody else. And I wonder if that's all interrelated with this part of the discussion or Neanderthals are redheaded and paleide, which also indicates a lack of regular moment which is protected against the sun. I mean I'm piling up a lot of stuff here but what I'm getting at is is what does this sensitivity to work from being related to the Neanderthal gene say about the Neanderthals. So soon you ask, yeah, this is that's really the big question that these always occur right and how much resolution can you get and really understanding it and you really need to know a lot about the specific light life history of an organism to come to good conclusions. And so we don't my answer is we don't know genetics genetics as a whole can only tell you so much about these signatures. And so, you know, but let me give you an example of like a type of analysis which is for the longest time, people did not understand why, why sickle cell anemia was so prevalent. Right. What was why do you why so many African Americans have sickle cell anemia. And then it wasn't until you could correlate that with resistance to malaria, which again, one reason you could do that is you could basically do a geographic overlay of sickle cell anemia to malaria prevalence and you could see the signature. And so, you know, that's still one of the big downsides of Neanderthals is we don't know everything about their habitats what they were exposed to, what diseases they encountered. Like you're saying maybe there was some pathogen, or maybe there was some drug in their foods in their potential food supply like a potential poison in their food supply, where having resist having a decreased ability to metabolize it was a survival advantage but we just don't know. But that's the type of thing where once you have the genetic signature something then this can get people to ask those questions and then maybe explore it further and come to an answer. Hope that answers your question. Yeah, so brings up the northern climate adapted aspects of of Neanderthals. You know, we don't, I have yet to see papers that explicitly describe the genes that do seem to correlate with that other than of course the fact that the vertical skin that does come back to the vitamin D conversation that some people wonder, and I don't know that I've looked through all the little haplotypes for this but you know being fair skinned is a big advantage in northern climates, where in the old days you needed UV light to make vitamin D and vitamin D is really important for like bone density and strength. And so Neanderthals may have a bunch of adaptations. In addition to maybe just being cold adapted but also to being low light adapted. And so the fact that maybe some of that got got reintroduced into humans has what allowed humans to really spread outside of Africa some people made this argument that without Neanderthals. Maybe humans couldn't spread as far as I did. Right, but I think the majority of the interactions of humans that 30,000 50,000 years ago, that that I think that's looking so late police is right is we typically consider that to be a pretty cold time that was really a little bit pre. The major ice age was 10,000 years ago but even preceding that 10,000 years ago, that was pretty cool. No, no, no, I know I know that cold adaptation of Northern climate are there. You used to be talking about cold but I wanted to bring it back to. Well something I knew more about and that was vitamin D. Great. Yeah, thanks. Thanks for all coming. Hope you all really enjoyed it. If there's anybody you think would be a great candidate for a hero of evolution. Let me know.