David Reich – Why the Bronze Age was an inflection point in human evolution

and I work on human history and how people, relate, ancient people relate to each other and people living today. Great.

more than sixteen or seventeen years ago, that we were gonna learn a lot about biology, learn about how people's biology changed over time by getting DNA out of ancient human remains and tracking changes over time. And that dream has really not been realized, since the beginning of this field. So while the field's been a big success with regard to learning about human history, it's resulted in, surprising findings about human migrations, people not being descended from the people who lived in the same place hundreds or thousands or tens of thousands of years before and mixture being common in human history, sex bias processes being common in human history, and things that were not expected from archaeology.

And so the field's been a big success from that perspective. But what's not been successful is learning about, biology and biological change. And one big reason for that has been that the sample sizes have been too small.

So when you have a single person's DNA, it provides a tremendous amount of information about history. And that's because when you look at one person's DNA, it's not a single person. It's many people.

It's your two parents. It's your four grandparents. It's your eight great grandparents and 16 great great great grandparents and so on.

And going back in time, thousands, tens of thousands, even hundreds of thousands of ancestors going back in time contributed to people today. So when you look at the DNA of a single person's genome or a Neanderthal genome, you have effectively tens of thousands of ancestors all represented in your data, and you can ex you can position that individual exquisitely with respect to other people from whom you have data. But when you are interested in how a particular genetic variant that affects something like your skin pigmentation or affects your ability to digest cow's milk into adulthood or affects a behavioral trait, when you wanna see how that changes over a time, a single person gives you only one sample or maybe two samples, the one that is in their mother and the one that's in their father.

And so to get a high resolution picture of how the frequency changes over time, you need to have very big sample sizes of truly very large numbers of people, and we just didn't have that until the last few years. So what motivates this study that we're, I think, talking about today and the work that hopefully another number of groups will be doing in the coming years is the fact that we now finally have those numbers, and we could do something with the data to see how frequency changes over time. And can can I ask you a question?

I'll be asking a lot of naive questions through the next few hours. But why are frequency changes especially interesting? So what we're interested in is using the experiment of nature that's occurred, in in our history over the last tens of thousands of years to understand what's biologically, significant, in our in our DNA.

And if there has been a change in environment that a population has experienced, for example, people have shifted to agriculture or begun living close to domesticated animals or moved to a new environment from a cold place to a warm place or a a low place to a high place, then there's pressure on the population to adapt to these new stresses, these new these new needs. And the way you're gonna detect that is you're gonna see that the frequency of a genetic variant that, for example, might allow you to live at higher altitude, for example, or that might sort of nudge you to have a different behavioral pattern that might be advantageous in the new situation. That genetic variant might push systematically in some direction in a way that is enough that you can detect it.

Now it's very hard to detect slight shifts in frequency by a few percent or a 10 unless you have a very, very big sample size. And so what we're looking for are those changes in frequency that are too extreme to be due to chance, and that will tell us that there have been pushes in the against the biology as a result of the changes in environment that people have experienced. Interesting.

Okay. So what did you guys find? So seven years ago, Ali Akbarri, who is a, at the time was a postdoctoral scientist in my laboratory and a few years later became a permanent staff scientist in my laboratory, set out to use the data that we were producing to learn about biological change over time.

And I think the reason he was interested in our laboratory rather than other places was that a focus of our laboratory has been generating truly large amounts of data from ancient humans. We've been really trying to industrialize the process, make it very inexpensive, make it high quality, and generate large numbers of samples, with lots of good data for this purpose. So there's been this large amount of data that we've generated, and it made it possible to conceive again of asking the question about whether there's been frequency changes over time.

So the mainstream view in human evolution in the last several decades has been that natural selection has been pretty quiescent over the last several hundred thousands of years of human history. And there's several lines of evidence that have been deployed to document this. One is that if you compare diverse populations from different continents around the world, for example, Europeans and East Asians, and you look at mutations that differ in frequency between these groups, all mutations differ a little bit in frequency, sometimes a lot, you can say, are the most different mutations in terms of frequency between Europeans and East Asians?

And there's almost no genetic changes that are a 100% different in frequency between Europeans and East Asians. So Europeans and East Asians descend from a common ancestral population forty or fifty thousand years ago that came out of Africa and The Middle East. This population had a set of gene frequencies, genetic frequencies, and these variants popped around, randomly, a process known as genetic drift, or perhaps under selection in one direction or another.

And the time that's passed since forty or fifty thousand years ago is sufficiently small on an evolutionary time scale that there's just not much genetic differentiation on average between these two groups, Europeans and East Asians. But, however, if there has been natural selection, for example, to help people in one place digest digest alcohol better or, for example, digest milk better or do something else better, what you might expect is that there would be some mutation that would have rocketed up to very high frequency. And forty or fifty thousand years is a lot of time.

It's maybe fifteen hundred or two thousand generations. And so that might be enough time easily to see a 100% different in frequency. And yet you don't see any more compared to what you'd expect by chance.

So this made it seem that just selection has been quiescent. Maybe a few hundred thousand years ago, the ancestral human population got to some kind of optimum. And after that, there hasn't been much genetic change in one way or the other.

And there's been small amounts of natural selection, or there's been selection to remove bad mutations that are constantly raining down on the genome, but not what we call directional selection, which is newly arising mutations or mutations being pushed in a systematic direction to help the population get to a a different adaptive set point that's that's that's more favorable for the conditions that population is living in. So we were able to partition how much of the changes in frequencies of, of, of all the mutations that we're seeing in the DNA, we're looking at about ten ten million positions that vary, is due to directional selection adaptation versus other factors, especially genetic drift. And 98% of it is other factors, especially genetic drift.

So it's overwhelmingly migrations and population structure causing fluctuations in frequency. And as a result, it's super hard to actually detect the signals of natural selection in adaptive natural selection because they're a tiny fraction of the total frequency change. The vast majority of it are these migrations and mixtures.

Nevertheless, there's so much natural selection as our study thinks has shown that, in fact, it's been rampant in the genome.

and may count and probably should count in some respects. But it could also be that this population replacement is due to some cultural phenomenon, technology held by one of these groups, not others. And maybe there's some genetic mutations that are contributing to this.

Who knows? It's possible. But what you're seeing is a whole genome shift.

And so what we're looking to see is whether there's one place in the DNA that is driving the change in a way that's different from the rest of the genome. And, really, from a statistical point of view, what happens at these times of migration is there's just huge fluctuations in frequencies. And these are extremely uninformative times for looking and detecting natural selection.

The best moments to detect natural selection is when migrations and population admixtures are not happening for a few hundred years. And during these times, you can actually see the mutations slowly blowing in one direction as a result. Yeah.

Really, the way we think about the history of Europe and The Middle East and the way we think about it for the purpose of this study is as an archipelago of little populations in space and time, each of which are pretty isolated from each other. So a little population in Britain isolated for a few hundred years, a little population in Hungary isolated for a few hundred years between big events of migration and mixture. In each of those little experiments of nature, we can ask, does this mutation slightly increase in frequency?

Does that same mutation slightly increase in frequency? If all the arrows point in the same direction, we win, and they're telling us that natural selection is occurring. So for example, four thousand five hundred years ago in Europe, almost all mutations go through huge frequency changes.

And that's not because of natural selection. It's because of the steppe migration from the steppe north of the Black And Caspian Sea. 40%, 50%, 80% of the DNA becomes Yamnaya from steppe pastoralists.

And their frequencies of mutations were different, not because of selection necessarily, but just because they had evolved in different places for thousands and tens of thousands of years. And then if you look at the descendant populations, there's huge changes in frequency. And it's very what you need to do is see, oh, is natural selection explaining a shift more than you would expect by chance?

which where where we're 50% confident. Oh, sorry. So I think we're getting about 7,200 positions in the DNA that have 50% confidence of being real.

Yeah. So only half of those are real. I see.

I see. So 36 which don't know which ones. Got Yeah.

Yeah. So 3,600 of them are real. Okay.

locations that you know are not under selection? No. Okay.

So if you look at the 25% probability cutoff, there will be tens of thousands, and there will be many real ones there too. In fact, multiple analyses we do suggest that the genome is vibrating with natural selection. Mhmm.

And, there's all sorts of weaker effects that are there that would be picked up in larger studies even than we've done, and that, in fact, almost every position in the DNA is, correlated to a position that can be dragged in one way or the other by natural selection. Instead of being quiescent, natural selection is everywhere. Even though it's only 2% of the frequency change, it's tugging the positions in one direction or the other everywhere.

So we analyzed these positions that we had identified, these hundreds of positions, the ones we were super confident about. And we looked to see whether they were randomly distributed in the DNA or whether they had patterns. And what we did is we looked at maybe a 100 or so traits where there had been genome wide association studies for all sorts of different traits, like ones associated with immunity or autoimmunity or behavior or metabolism and, basically other, other things.

And for each of these, we could ask, are the genetic variations that are known to affect these traits from genome wide association studies? Do they have an unusual number of genetic selection signals? And what we found is there was a vast enrichment by about a four or fivefold for immune traits.

That is there was a super concentration of selected, signals in immune traits.

so it might seem from the, results of that analysis that, in fact, immune traits are highly selected and that there's been no selection for behavior in the last eighteen thousand years in this part of the world. But in fact, that's a wrong conclusion, and in fact, we have evidence that that's a wrong conclusion. And in fact, there's clear evidence of selection also on behavioral traits.

And the, reason we think we see, and we have evidence that this is so, much weaker signals for behavioral traits is that behavioral traits, we know from other studies, medical studies, are underpinned by much larger numbers of genes than immune traits, which are underpinned by relatively small numbers of genes of strong effect. Behavioral traits are shaped genetically by very large number of gains of weak effect, and we just don't have the statistical power to detect these very weak signals there. So when we do an analysis where we look at our very strong signals of selection, that collection of very strong results is very effectively querying the immune traits but is not very effectively querying the behavioral traits.

It may still be the case, and I guess it is, that immune traits are the most selected category, but it is not at all the case. And in fact, we can prove it's not the case that behavioral traits are not selected. So we think there's two reasons why natural selection has, we've been able to prove, really, that there's two reasons why, how to reconcile the previous observations with our new observations.

Remember, the previous observation is that is that natural selection seems to have been quiescent over a timescale of hundreds of thousands or many tens of thousands of years. Reason? That you don't see a 100% different in frequency variance across Europeans and East Asians.

So now we're seeing hundreds of positions that are rocketing up in frequency with selection rates 1% or more in a lot of cases. So 1% or more selection rates will mean that there'll be a rapid doubling over periods of dozens of generations. And so over 1,500, 2,000 generations like you see separating Europeans and East Asians, shouldn't you see many genetic variants that are 100% different in frequency across populations?

So we were able to show that this is explained by at least two factors. So one of them is that we actually, in this part of the world, Europe and The Middle East, are in a period of accelerated natural selection. And one way to see this is to look at this enrichment pattern that we're observing where immune traits are unusually associated with these selection signals.

And we could compare the last five thousand years of our of our time period, what's called the Bronze Age and further onward, to the previous five thousand years. And what we see is that this intensification of selection around immune traits, similarly, the intensification around metabolic traits, has accelerated over this time period. So it's not like natural selection has been at the same rate over all places and times.

In fact, it's increasing over the time period we're analyzing. And so, plausibly, the whole time period has increased compared to previous periods. So we're in a period of intensified selection.

That's not implausible because this is a a population that went through a huge shock in terms of the way people live and the culture. So this is a population that almost everybody we're analyzing are farmers or food producers in one way or another. Farming was invented for the first time anywhere in the world in The Middle East eleven thousand or twelve thousand years ago.

The people who invented farming exploded into Europe after eighty five hundred years ago and spread across Europe and expanded rapidly. In the Bronze Age, there was an intensification of how people lived with much higher population densities, people living more and more next to their animals and getting their diseases and exchanging their diseases with them and with each other. And so this is a period of rapid, rapid change in terms of how people are living resulting in different biological needs of this population.

So it's not surprising perhaps that in the context of these dramatic changes, the biology of the population might be not in the I ideally adapted position. That is that there might be what some people call an evolutionary mismatch where you take a genetic variation that's evolved in hunter gatherers and put it into farmers or pastoralists, and it's not exactly right. And so what you're seeing is the DNA of this population, which is descended from hunter gatherers only ten thousand years ago, reacting to the shock of having been moved into an agricultural and bronze age and high population density and urban environment.

And a hypothesis is that what we're seeing is the adaptation that occurs as a result of that. Interesting. Okay.

So we look one of the things we do in this work is we look carefully at many, many of these positions in the in in the DNA. We've actually have an Internet browser that you could look at called the Aegis browser that Ali and a colleague of his, who's a coauthor of our paper, built, that allows you to query these each of these 10,000,000 positions and see the trajectories at each at each position and the evidence for selection. And one of the things that we see is that while for the most part, the the signals of natural selection we detect are consistent with being constant natural selection over time, in a handful of them, we're able to see that there's been a reversal or a radical change in natural selection.

And very often, that occurs in the period between five thousand to two thousand years ago, which is the Bronze Age and the, Iron Age, a period of rapid population growth and rapid movement to, intensive use of of, of, of many technologies that were not used that way before. So an example of this is the TYK2, genetic variant that is a major risk factor for severe tuberculosis, which is the major infectious disease, the most important infectious disease killer in the world today. And if you look at the this major risk factor for tuberculosis, this variant rockets up in frequency from eight or six thousand years ago to maybe nine or ten percent in this part of the world.

Then it rockets down in frequency in the last three thousand years. In both cases, there's very clear evidence of natural selection, in the first case to increase in frequency, and then in the next case to decrease in frequency. And a possible reason for this is maybe the spread of tuberculosis, maybe becomes endemic in the population two or three thousand years ago that's potentially consistent with, pathogen, sequence data and other lines of evidence.

And maybe this variant was protecting against something before then, but then tuberculosis became, significant after that point, and it was so bad that it pushed in the up opposite direction. That's speculative. Oh, interesting.

And the thing it was protecting against was probably another disease? Maybe.

And already in work prior to this, actually, Ian Matheson, who, who was a former, colleague who worked with me in 2015, identified this as a very strongly selected variant. And it's actually been ancient. You see copies in archaic humans too.

One of the findings of our paper is the ABO blood system. You know, you get your blood type. It's AB and O.

The B variant has increased up to 10% at the expense of A. But previous work has shown that A and B were both already present in the ancestor of humans and gibbons. Mhmm.

You know, other other other apes. And so these mutations, some of them have been going back and forth and fluctuating over time, in different time periods. But we're talking about changes in the bronze age.

So this TYK2 variant for, tuberculosis risk, multiple sclerosis risk variant inflected and increased in frequency before the Bronze Age and then two or three thousand years ago reversed at that period. And there's differences in Northern Europe where this process is super strong, very strong positive selection, very strong negative selection. And then in Southern Europe, only a little bit and not even very strong negative selection.

For hemochromatosis, which is iron pathogenic iron buildup that causes problems, in Europe, that too has reversed around this period. In some of the complex traits that maybe we'll talk about later, these traits too have periods of intensification of natural selection. For example, depigmentation, which is the, Europeans have depigmented, gotten lighter skin over the last ten thousand years.

You can see it in our data. The period of strongest depigmentation is between about four thousand to two thousand years ago. And then after that, it's much less.

And so this seems to be a very impactful, eventful, important period where a lot of the processes that we are seeing become very powerful. And it's surprising on first principles. You might think before you walked into this genetic data that the big change is gonna be starting to grow plants Yeah.

And maybe farm animals. And that happens in the Neolithic, beginning 10 or 11 or 12,000 years ago and spreads into Europe after eight thousand five hundred years ago. But, actually, the intensification happens 5,000 ago, 4,000 ago.

And so it's really interesting, this observation of that being a key point, that being an inflection point, tells us something about when humans, at least in this part of the world, were wrenched into a way of living that was so different from how the hunter gatherer ancestors lived that the organism had to adapt very strongly. And that maybe the degree of that wrenching process moving into the Bronze Age was qualitatively greater than the degree of the wrenching process that happened from the initial transition to growing plants. So which is surprising because our cartoon picture is that the big transition is farming.

But the genetic data, the biological readout is saying our genome is reacting much more strongly to this these events that happened five thousand years ago.

Africans in Africa than being trans migrated to the, to the new world and then living under slavery. That that may be the case. It also may be the case that that period is just too short to see much effect.

So what you're looking in for in the Batya et al paper, where we looked at about 30,000 African Americans and look to see whether there is instead of the average percentage of maybe around 80% West African ancestry in some places in the DNA, more than 80% in some places in the DNA, less than 80% significantly, as you would expect, if there was natural selection from some genetic variant for your from Europeans or from Africans, we didn't see any place in the DNA that was significantly different from what you'd expect by chance. Mhmm. And so, one possible explanation for that is just that there's only a handful of generations, maybe five, over which the natural selection would operate.

And so maybe if the selection was 2% a generation, you would still only see maybe a 10% compounded effect. And there's just not enough time to detect it. But the bronze age is not 300.

It's 3,000. It's the power of compound interest. And you have enough time to begin to see a strong effect.

But this really, really, really does seem to be a very impactful time in terms of human history, and you can see it in our complex traits. So for example, if you look at pigmentation, for example, which is the, strongest signal of selection for a complex trait in, our dataset. So you look at genetic mutations that are known to affect pigmentations.

You add up their effect across all of the DNA, so there's dozens or hundreds of them. And you look to see in what time are the natural selection strongest, and the time period is really, two thousand to four thousand years ago. And for some of these other traits as well, you see, again, the time period over which the selection is strongest, is two thousand four thousand years ago.

So, for example, if you look at, genetic variants that affect, measures of cognitive performance, for example, such as performance on intelligence tests, in, people in white British people today. So this is, of course, a very strange trait to measure in the past because there were no intelligence tests and there was no school. But it is a predictor today, and you could look at how it's changed in the past.

And we see very strong natural selection for this combination of genetic variants that predicts people's performance on IQ tests and also is highly correlated to the predictor that predicts the number of years of school or the household wealth of people. All crazy traits in the past because there was no wealth in the past. There was no school in the past.

But if you look at the predictors today, there is a strong, there is a strong movement in a systematic direction, a large effect about a standard deviation on the scale of modern variation. Then we can do this trick of looking to see whether there's periods of time when this natural selection has occurred more intensely or less intensely. What we do is we drag a two thousand year window through our data, and we repeat our whole analysis not on eighteen thousand years, but just on a short two thousand year window.

And we can measure the strength of selection in each of these two thousand year windows. And what you see when you look at intelligence is you see that this maxes out in the Bronze Age between 5,000, 4,000, 3,000, 2,000 ago. And the impact in the last two thousand years is almost nothing.

There's no evidence of natural selection at all. You might think your bias coming into this, my bias perhaps, if there's any signal of natural selection on this trade at all, might be that it would be unusually strong in the last two thousand years. Maybe this is a time of industrialization.

Maybe this is a time of greater need for this particular trait.

over a ten thousand year period Got it. Within a population that is held constant in terms of its ancestry. Got it.

Because what's actually we're doing is we're looking in our dataset at a kind of heterogeneous group of people. There's, you know, Southern Europeans and Northern Europeans and hunter gatherers and farmers. And at different times in the past, those groups are more or less represented.

Yeah. So the whole strength of the methodology Eliak Barri developed is it corrects for that, changing ancestry over time. And as I mentioned before, really what's being asked here is we've divided up our whole dataset into an archipelago of little populations in different places in space and time.

And we're asking in each place in space and time, a little pocket of people in Britain from 4,000 years ago to 3,500 years ago, a little pocket of people in Hungary, a little pocket of people in in Italy from 2,000 years ago to 1,500 ago. And each of these places, where the ancestry is relatively similar without being too disrupted in that short period by, migrations, we watch to see if the genetic changes blow in the same direction. Yeah.

a standard deviation change in these kinds of qualities, at least among the kind of variation we see in the world today. One thing you can see in the data is the migration impact is huge. So for example, if you look at the trajectory for, you know, measures of cognitive performance like, scores on intelligence test in white British people today, but you look at the predictor of that in people in ancient times, the estimate for the hunter gatherers of Europe is like three standard deviations below the modern mean.

Right. So that's hugely different. Yeah.

And then you see a huge jump from them to the hunter to the farmers who are, like, at the mean, at zero, and that's migration. Yeah. So what you're seeing is those two groups had different set points for those traits.

Yeah. And then the step path store list have a lower set value of this. Mhmm.

And so you see huge fluctuations in the predictor of this trait over time. That doesn't prove selection. What that is just telling you is migration.

the selection on intelligence? Right. So, you know, this is the power of data.

Right? Like, you know, the I think, Joe, if you asked him, prior to this work, what the hunter gatherer selection would be and where their set point for, you know, this particular trait would have been, you know, I think he probably wouldn't have made a very strong prediction, but he would have said, well, maybe you would have expected it to have a high predicted value of this trait because these people were really having to do a lot of things and figure a lot of stuff out maybe. And that maybe once you have more complex societies, there'll be more of a collective brain, and maybe there'll be selection against this trait.

And in in fact, it's sort of the opposite in some ways. So it's the power of data. It's not what you expect.

And, you know, after looking at this data, it's actually the value of data to try to make sense of all these things. You know, it's very interesting. Like, the genetic predictor of intelligence, there's lots of kind of things that are confusing about it.

So it's actually worth talking about it. Or the genetic predictor of years of schooling, which is highly correlated to it and is measured even better. So if you look at the genetic predictor of years of schooling, there's another amazing study from 2017 from a group in Iceland, that looked at this measure over the last hundred years in Iceland.

And it looked at older people and it looked at younger people, people born more recently in Iceland. And there's an estimated point one standard deviation decrease in genetic predictor of intelligence in Iceland just within one century, is an absolutely huge effect over a short period. And this is selection against years of schooling.

If I said intelligence, didn't mean to. It's selection against, the numb genetic predictors of numbers of years of school. And so one possible interpretation of this, sort of hand wavy, is that actually what's being measured here is not selection for years of schooling or for actually real intelligence, but for another trait altogether that's correlated to both of them.

For example, the predictor of numbers of years of schooling is very, very strongly correlated to the age at which women have their first kid. And if you control for that for numbers of years of schooling, all of the signal of, years of schooling goes away. So maybe what you're measuring is women's decision about when to have children.

And, you know, if you have children earlier, you don't go to school as much. If you have children later, you go to school more. Maybe it's some kind of measurement of delaying gratification or putting things off or planning.

The same trait is correlated to body mass index, to obesity, or to, walking pace. So is this really, like, intelligence as we think about it, or is it something else that manifests itself differently in different times, in the past? Yeah.

And how how should we think about this? What like, what is the actual thing that's changing in the genome? Yeah.

Well, I think that there's two things going on that you need to think about. So One of them is that years of schooling is connected to so many other things genetically. If you look at the genetic predictor of years of schooling, this trait has been measured in millions of people now.

Actually correlated to really, really surprising things. It's correlated to the age at which women have their first kid. It's correlated to people's obesity.

It's correlated to people's walking pace. It's correlated to people's household wealth. It's correlated to a variety of other traits that seem quite different from it.

So if you think you're actually measuring years of, genetic prediction of intelligence or years of or or actual, you know, studiousness or something like that, you should think again because there's many things that it's correlated to. There seems to be some kind of general trait that maybe you could think of as executive function or maybe propensity to defer gratification or something, or I may just waving my hands that is under selection, and it pushes all these traits in the same direction, one way or the other. And in different times in the past, it's it's it's advantageous or disadvantageous.

But when we found this signal of, years of schooling, being increased, the the genetic propensity to go to school for more years, as it manifests itself in people, in white British people today, when we found the signal, we were sort of incredulous. Like, how could this be? Maybe this is a problem.

So we did a few tests to try to figure out whether this was real. And one of the tests we did is we looked for a study where this measurement of the numbers of years of school was done not in Europeans but was done in Chinese people in China. And we looked at variants that had the effect size of many variants as they affected the number of years of school in China, and we saw whether they had a relationship, a correlation, to the trajectory of those same genetic variants in Europeans over the last ten thousand years.

So these are two parts of the world where the populations have been essentially completely disconnected. And there's no way by chance that the trajectory in Europeans over the last ten thousand years will have anything to do with the number of years, the effect on the years of schooling in China today. But there's actually a huge statistical correlation, a five or six standard deviation correlation between the effect size of variance, a number of years of school in China today, and the trajectory in Europe.

Just as strong, actually, as the effect size of variance in Europeans to years of school to to the trajectory in Europeans. So we just could not see a way this could happen by chance. And once we saw that, we really felt quite convinced that this was a real signal and that really somehow there has been natural selection to increase the genetic changes that today manifest themselves as more years of school predicting more years of schooling.

Alright.

I think that that's a great question. And, like, as we talked about before, the the the the human adept selection is very effective. You it can move the mean value of traits within hundreds or thousands of years in one direction or the other if that's adaptive in a particular environment.

And so you might wonder, isn't intelligence good, you know, in all contexts and places and time? And I think that there's a number of ways to think about that. First of all, I think we are speaking from the point of view of a society which intensely values this particular trait, you know, ability to score well on, IQ tests or things like them or to go to school for a long time or whatever it is.

And I think this is unprecedented in human history that we live in a time like this. Like, if you look at the, you know, Hebrew and Christian bible and you look at how much intelligence is valued, it's basically not at all. Wait.

But that when when the Bible is being written, especially the Old Testament, is exactly when selection for intelligence is the highest point Yeah. It's apparently ever been. Yeah.

Exactly. But, like, there's it's about strength or courage or religiosity or right. Those are the values.

Right? Or if you read Homer, or the other texts of other religions, it's not intelligence. It's it's beauty.

It's, like, other other things. And so this value system, which has a hyper focus on, you know, you know, smarts is not obviously a trait trait value that's been common in the past. You might think that in certain communities, like, you know, some communities are not, there might be valuation of things that are more proximate to, you know, years of schooling.

But really broadly, it's not been a high value in the population.

have this trait maxed out. So so I'm being very speculative. Yeah.

And let me give you two examples about how about what this about in my head, how I'm thinking about this, and not that I'm a particularly good authority on these things. But as I mentioned, a lot of these traits, which are quite disparate, are highly correlated to each other. Yeah.

Obesity, years of schooling, walking pace, you know, performance and IQ test, household wealth, all these crazy traits all seem to be governed to a substantial extent by a shared combination of genetic variants. And let's just think about what this might mean. So in Iceland, in the last hundred years, there's been selection against this combination of variants.

And one possible interpretation is it's basically selection for two ways of investing in your children, having many kids and not investing a lot in them or having few kids and investing more in them. Right? So if you invest in deferring deferring having kids but becoming, you know, having more wealth, having more resources, and putting more into each kid, you're gonna have a lower fertility and you're gonna have fewer kids.

And that's gonna result in lower fertility, but those kids might survive more and do better in society. Alternatively, you can just have as many kids as you can and invest less in them. They might have individually less good outcomes, but in a time of plenty, which is potentially Iceland in this twentieth century, it might make sense to have more kids and invest less in them.

And so there's a toggle between having more kids and investing less in them and having more kids and investing in less in one's life, and having fewer kids and investing more in excelling in various ways or something like this. And so you can imagine that actually at different times and in different places, in in ecology, there's resource there's different ways. Like, mammals often invest a lot in with a pregnancy and a small number of children, whereas fish will spawn huge numbers of offspring into, you know, the the the river, the great majority of whom will be eaten, but that is an effective way to produce offspring in certain conditions.

So there'll be a toggle depending on the environmental conditions back and forth between investing in large numbers of offspring with fewer and less investment or smaller numbers of offspring with more investment, and maybe we're just seeing that move back and forth over different places and times. Similarly, for schizophrenia and bipolar disease, how could this ever be advantageous? But maybe what we're seeing with these diseases is a kind of readout of some kind of spectrum of traits that actually in some context might be advantageous.

Maybe being anxious or being imaginative or being neurotic might be helpful in a shamanistic tradition, you know, in a religious tradition which values people who can have visions, or values people who can be creative. And maybe these are subclinical versions of schizophrenia or bipolar disease that in certain times may be advantageous and in other times may be disadvantageous. Maybe you're just seeing selection from different types of creativity or other thinking that can be valuable in different contexts.

I'm waving my hands here, but my sense is that these complex traits have not pushed in one direction because there's advantage there are spectrums where there's advantages to both ends of the spectrum, and there's multidimensional, you know, impacts of these different traits.

gods or whatever were real people that you're communicating with. And his claim is that ancient texts seem to show people behaving in this way. Or You're being asked to believe in visions.

Yeah. Exactly. You know?

And even today, I think, you know, there's valuation in some religious communities and, you know, communicating with God and having visions and having supernatural communions. Yeah. And so, I just don't know.

Yeah. But I think it's super interesting to imagine to to to ask the question why certain traits are not always advantageous. For schizophrenia and bipolar disease, there is a sense in which most of the mutations are disadvantageous.

Why is that? So this is, what you see is a reduction in the combination of genetic mutations that make you at risk for obesity, body mass index. And similarly and very correlated to it, higher fat mass, higher waist to hip ratio, higher type two diabetes risk.

And so there is clear selection by about a standard deviation on the scale of modern variation for these traits reducing about 10,000 over the last ten thousand years, in this part of the world. So what can be going on there? Why was there not selection for this combination of traits before?

There's a long standing idea known as the thrifty genes hypothesis. The idea is that, that once you have hunter gatherer populations that move into a farming environment where there's plentiful food, there is no longer a need, to the same extent to be able to build up body fat to sort of survive in times of stress because there's more constant stores of food. And so as a result, there will be no, there will be natural selection against body fat, which can be, once you move into an agricultural environment and to periods of food plenty.

And so maybe what you're seeing is that this group of people in Europe and The Middle East over the last ten thousand years has moved into a a period of relatively more stable food where building up stores of fat are not as advantageous, and there's been selection against this combination of traits. Europeans actually are relatively better protected genetically against type two diabetes than some other populations around the world, like African Americans and native Americans that have perhaps not been as exposed to agriculture for as much time. So you may be seeing the effect of more exposure to more stable food accessibility.

it's at least more stable than what the hunter gatherers had. I think there's a timescale issue. You're absolutely right.

So I think, as I understand, and I'm no anthropologist. No. But my understanding is that when there's a hunt in some of these, in in in traditional societies or communities that hunt, people will often gorge themselves and eat a huge amount and build up a sort of temporary store of fat and then go with multiple days without eating meat sometimes until the next hunt.

And so there is this sort of boom bust, access to high value nutrition, that is not true to the same extent in farming communities. On the flip side of this, these long these famines are, I think, something that occurs more commonly in agricultural societies, but the time scale and the tempo of them is very different from the hunting tempo. So maybe there's a famine every three years.

And indeed, if you look at the bones of farmers, at least in some communities, there's more stress in them, maybe due to a famine every three years or a famine every five years. But selection might not be acting on that three year time period. Your fat store, from, you know, the latest hunt is not gonna carry you through to the famine three years later.

And so survival of famines is a different thing than building up body fat for, being able to, survive two weeks later.

over the last ten, twenty, hundred thousand years. Does that mean that there's more room at the top for this trait? I think there's more room at the top for a lot of these traits.

Yeah. I think that you can move height very extremely in one direction much more than it is today. You can move any of these traits very much more extreme in the other traits.

There's probably very strong negatives to doing that. You're probably sacrificing other things. And I think that there's trade offs probably.

But, I think it's highly likely that if natural selection was pushed pushed any of these traits, in, more in one direction than it is, the mean would move.

a rich question. And I think that the human population has with complex traits a tremendous amount of variation. So, within the human population, there's a huge amount of variation that affects height.

There's a huge amount of variation that affects body mass index. If you take all these mutations and all set them to the high height variant, a person will be extremely tall, like as tall as a tall building. Yeah.

You know, if you of course, which will never happen. But if you take all these variants that affect schizophrenia risk, they will and you point them all in the same direction, there will be extreme risk or extreme protection, for schizophrenia. So for complex traits, one's underpinned by many mutations, all the variation already exists to move the population to a different adaptive set point that's optimal in the environment which it's in.

So if you push the in a population into a new environment within hundreds or thousands of years, the population can rapidly move to a new adaptive set point. There are some unusual traits like ability to digest cow's milk or protection against sickle cell anemia that require a single very important mutation that may not yet exist in the population. And then you have to wait for the mutation to occur in some people.

And when the populations are relatively small, only 10,000 people, you might have to wait dozens or hundreds of generations for that mutation to arise. But when the populations are large, there's not mutation limiting anymore. Every mutation that can occur does occur.

There's 8,000,000,000 people in the world. There are maybe 30 new mutations every generation. So that's like, what is it?

It's like two forty billion new point mutations every generation. There's only 3,000,000,000 DNA bases in the genome. So every mutation that can occur does occur about a 100 times every generation, and we're not mutation limited anymore.

And so it's not like you have to that the mutations can arise again. They do arise again.

visible to selection. I think that's not likely to be true, but it's extremely interesting thing to think about. So I think already when population sizes are on the order of a million so or so, every mutation that can occur does occur within a few generations.

And so that's well before the Bronze Age if you take the population even of a place like Europe, but also also of of of other places, or maybe it's the dawn of the Bronze Age or the farming period. So the the question you ask is maybe when the population is small, natural selection doesn't work effectively. Yeah.

So a common thing that people think about with natural selection, and that is true, is that in small populations, selection doesn't work effectively. And that's because mutations bop around in frequency from generation to generation a lot in a small population just randomly. So if you have a population of size 1,000, populations mutations will bop around by a frequency of one over a thousand every generation.

And if the selection coefficient is less than that, it will be drowned in the random bopping around of frequencies due to genetic drift. But that is already for a population of 1000.1% selection coefficient is very weak.

We're talking about 1% effects, and that's much very strong. It will work very well even in a population of a size a thousand or 10,000. If you are talking about mutations of the type that will start rising in some only in large populations but not small populations, those are selection coefficients that are on the scale of one over 10,000 or one over a 100,000, and those ones will take 10,000 or a 100,000 generations to rise in frequency, which is hundreds of thousands or millions of years.

So that's not gonna do anything over the time scale we're talking about. There's just a time scale issue. I understand.

So we're talking about strong measurable selection coefficients on the order of half a percent or more in this study, and all of those are gonna work in small populations or large populations.

not population size. Correct. Okay.

Interesting. It's very interesting. And it's actually not widely understood.

Yeah. Okay.

ago or so or maybe hundred hundred thousand to 50,000 ago, there's a quickening of the pace of change in culture. So people you see the first extensive rep representational art and like bead necklaces and drawings on the wall and so on and so forth, and also a rapid increasing pace of innovation, the types of tools that people use. And so the thought might be that there was gonna be have been some kind of genetic switch, a kind of, important genetic change that, was occurred in the population and that swept to high frequency that everybody suddenly had, soon had, and that made it possible for do these thing to do these things, maybe some genes that allowed people to have rep complex language, representational language, for example.

And so one thing that we did in 2016 in this paper by Shat Malik and colleagues, is we looked across the DNA for places that might be expected to look like this, that where all people living today or nearly all people living today share a common ancestor, maybe a 100,000 or 200,000 years ago. And we looked really hard and right across all the DNA we could look at, we couldn't find anything more than four or 500 more recent than four or 500,000 years ago. This is like a crazy result because, it looks like there's no key selective sweeps that have occurred in this period that is ancestral to everyone living today.

We talked before about no selective sweeps between Europeans and East Asians, but there don't even seem to be any selective sweeps between like, shared between all humans in this really important period when a lot of, evidence in the material culture record appears. And so it could be that there's biological adaptation in this period, but it's polygenic.

this is the population that's ancestral to West Africans, to most East Africans, to all non Africans. And there's a couple of populations in Africa that have substantial ancestry that comes from more divergent groups. For example, Khoisan, from Southern Africa or Central African rainforest hunter gatherers have substantial fractions of their ancestry from groups that diverged maybe 200,000 ago from the other lineages.

But all of these groups today are able to do go to college, do everything everybody else does. And so there is, like, no evidence that there is any key mutation lacking in some groups that are not present in the others.

comes from a very small population. I think a lot of us in human genetics think that the, our population contains within it the clay that's needed to make almost any trait. Mhmm.

And that depending on environmental conditions or selection conditions, the mean value of these traits will move in different directions. There's an empirical question, a real question about how much selection there's been, in different human populations over time. One of the things this new work that we're involved in is doing is showing that at least in the last eighteen thousand years, ten thousand years, five thousand years in this part of the world, there actually has been significant movement, at least for a handful of important traits.

We looked at more than 500 traits. About a 100 of them, complex traits showed significant movement in a systematic direction, over this time period. So it really does seem that there is a response, to the environments people are living in that has occurred over this period and is potentially stronger than in previous periods.

And, you know, these people are distributed into different parts of the world, The Americas, you know, fifteen thousand years ago or whatever it is, you know, New Guinea, forty thousand years ago, East Asia, you know, Europe, you know, West Africa. No farming develops, before, you know, 12 or 11 thousand years ago. It only develops in the last, you know, twelve thousand years, the period known as the Holocene, which is sort of the end of the ice age.

And if you talk to climate scientists, and archaeologists, you know, I keep asking people this question every time I meet someone who's an expert in this. It's like, how can this be that farming develops in all these places? Are we really living in such an unusual time?

And people tell me, indeed, we're living in an un very unusual time on a scale of 2,000,000. That is 12,000 ago, we switched into this period of not just warmth, but climate stability. That and that actually this is true and sort of hard to believe that we're living in special such a special time.

But if you look at, for example, data from bottoms of ponds where you can measure the fluctuations of temperatures using isotopic signatures, apparently, we're in a period where it's just fluctuating a lot less year to year and see and ten years to ten years and hundred years to hundred years, and it's just a period of relative stability that we are miraculously living in. And that when this period of relatively stability happens, you somehow it follows that multiple groups independently turn to agriculture even though the genetic complement, you know, all of whom have the same genetic complement that arises 50,000, a 100,000, 200,000, 300,000 years ago. It's kind of a crazy observation that people just accept, but it's, like, unbelievable.

they're modern 300,000 years ago? I don't know. Like, I'm thinking about this all the time right now.

This is actually, like, actively what I'm thinking about right now. And, like, you know, there's a big transformation in terms of the culture of humans 300, 400,000 ago, this invention of level, technology, the ability to make stone tools out of cores. Yeah.

The middle stone age revolution or the middle paleolithic revolution, depending on whether what you call it in Africa or Eurasia. And this is a revolution, a new way of making stone tools that's shared by Neanderthals and by modern humans, but is not shared in East Or South Asia. And it's a big change, and it it involves a cognitive change presumably in order to make this sort of technology.

And then there's a further change to the upper paleolithic later stone age, maybe, a 100 to 50,000 years ago, when there's the second transition where the new type of tool making, but not as revolutionary as the earlier one. So when the cognitive leap happens is unclear. The diversification of the lineages leading to people living today, like Khoisan Southern Africas and rainforest hunter gatherers, and that all occurs more on the timescale of three hundred thousand or two hundred thousand years.

And all of these people are capable of, you know, going to college and doing everything. And so, you know, it's not obvious that all the toolkit, the cognitive toolkit, the behavioral toolkit, the genetic abilities were not all in place two or three hundred thousand years ago and that even Neanderthals had them. Right?

So it's not obvious that this was not the case. Yeah. And so, like, I just don't know.

You sort of distribute these people to send it from this diversification that happens 200, three hundred thousand years ago to different parts of the world. And then, bing, you know, after 12,000 ago, you start having agriculture popping up in different places. It's kind of an outstanding mystery Right.

Of human history. And, you know, I I find it unbelievable that we live in a play in a time period that climatologically is so unique on a scale of two million years. But my colleagues tell me it's true.

know, serials in the old world and so forth and just in a very different environments makes it surprising that it was very, very surprising. And I think we accept it, but it's just, like, a crazy observation Right. That most normal people don't realize.

Yeah. You know, the thing that basically everybody accepts is that the common ancestral population of almost everybody in the world, except for rainforest hunter gatherers and Khoisan is like around 70,000 And everybody accepts that these people all have in place the cognitive behavioral intellectual ingredients that are necessary for the farming revolution and state building state societies. Because when these descendants of these people get distributed to West Africa, to East Africa, to The Americas, to Europe, to South Asia, to East Asia, to New Guinea and so on, their descendants all do this.

Yeah. Like independently or semi independently or completely independently or demonstrably completely independently in all these different parts of the world. So the cognitive resources for doing this must have all been in place, but it's a very long fuse.

Like it delays for forty thousand years for seventy, you know, sixty thousand years in all these different places after the common ancestral population splits up and then, you know, ignites into, like, agriculture and all these other things after that point. It's kind of a crazy claim. Know?

And then you could argue about whether the actual fuse is three hundred thousand years, you know, from when Neanderthals separate and from when different lineages of extant modern humans separate, and that's also plausible. So it's kind of a crazy sort of set of things that we're being asked to believe.

I I think we would see their archaeology. And, like, you know, the extraordinary developments in The Americas, which are entirely stone age. You you would see them today if if they had gone completely vanished.

Oh, yeah. I mean, there's, like you know, you you know, we we should go for a trip to Teotihuacan in Mexico. Oh, yeah.

Course. Of It's, like, like, so impressive. Yeah.

Like, you know, when I went there when I was 20, you know, it's just like it's totally as impressive as as ancient Egypt. Yeah. You know, it's, like, huge.

It's massive. It's without metal. And it's, it's even more impressive because it's not only without metal, but it's without animals and without wheels, which is crazy.

Like, the the the the Marvel is just, like Right. Hauled without wheels. Right.

Like, take any person who has, like, an old Willworld superiority and, like, take them to these places, and they will not have it anymore. It's just extraordinary what's in these places.

you know, just had the same biological, you know, cultural shared toolkit from then, but there's just a a fuse, a long fuse delay until all this stuff happens. Interesting. It's kind of like an amazing thing, and we don't question it.

I think that I'm I mean, I'm I'm perplexed. I don't know if we talked about it before, but, like, I remain very, very confused about the relationships between archaic and modern humans. We have genome sequences now from archaic humans who lived in Europe and the West Eurasia and Central Eurasia, the Neanderthals.

We have archaic sequences from these enigmatic Denisovans who we now have, a skeleton for, since we last talked. There's now a skull from a Denisovan that's been shown to be a Denisovan. And we have data from lots of modern humans.

And there's really big mysteries about the relationships amongst these groups. So genetically the Denisovans and the, Neanderthals are sisters. They descend from a common ancestral population five or 600,000 years ago.

And that group's descends a couple 100,000 years before, seven or 800,000 years ago from the common ancestors of modern humans. And so genetically, the whole genome data says that Neanderthals and Denisovans are archaic humans from a common ancestral archaic population. But there are so many things shared between Neanderthals and modern humans that don't seem to be shared between with East Asians.

They both share, Middle Stone Age tone stone tools, level one technology, this cognitively unique type of way of making stone tools that wasn't used in East Asia. They both have the same mitochondrial DNA and Y chromosome sequence. So the Y chromosome sequence of Neanderthals, the mitochondrial DNA of Neanderthals is actually modern human that came through interbreeding Mhmm.

Two or three hundred thousand years ago and then shot up to a 100% frequency. And then Neanderthals and modern humans are both the product of mixture events that happened between archaic and modern humans three hundred or two hundred thousand years ago, demonstrably through patterns of variation in ancient and modern DNA. And so it feels that there's something shared between Neanderthals and modern humans that's not shared with Denisovans even though the vote of the whole genome says that Denisovans and Neanderthals are related.

So one wonders whether there's something connecting kind of, Neanderthals and modern humans that's different from Denisovans even though genome wide Denisovans and Neanderthals cluster. So I'm thinking about that all the time now.

modern humans into Neanderthals, but it's supposed to be only 5%. Yeah. So I'm interested in that that that 5% is actually a sign of something much more impactful.

That is that somehow Neanderthals are in some sense deeply modern in some ways. And even though they get swamped by archaic genes, that somehow they actually have more of a modern impact than one would think and that the Middle Stone Age and, you know, Middle Paleolithic revolution that they share with modern humans is actually more fundamentally a part of who they are in some sense than we think. Interesting.

I sorry. When was this interbreeding event? 300,000 to 200,000 ago.

divergence to all the archaic humans, including Dinesovans, is within human variation. Okay. So but Wait.

What? Yes. So the average time to the common ancestor of any two human genes is one or two million years ago.

So like, if you look at any a bit of your DNA that you get from your mother and a bit of your that same bit of your DNA on the same chromosome copy of chromosome three you get from your mother and the copy of chromosome three you get from your father, typical time they share common ancestor is one or two million years ago. That's before the split from Neanderthals and Denisovans. So there's many places in your DNA where you're more closely related to a Neanderthal on your mother's side than you are to your father.

This is it's the same reason that, like, if you have, like, a sister, you know, you're, in some places in your DNA, more closely related to her than you are to me because you share a parent. Yeah. But in other places, you are more closely related to me than you are to your sister because you happen not to share the same DNA from your parents.

ago, seven hundred thousand years ago, a million years ago. And Some of us descend from some of those ancestors, and others of us descend from other of those ancestors. Neanderthals split from our lineage really close in time on human evolutionary timescale such that in some places in our DNA, we're more closely related to Neanderthals than to each other.

Interesting.

I think that's the main thing that I'm thinking about a lot these days.

is the possibility that it's maybe we're not thinking right in the right way about the relationship between archaic and modern humans. So the standard model is one like this, where, Denisovans, these archaic humans that were found from ancient DNA and Neanderthals descend from a common ancestral populations five or six hundred thousand years ago. And that these two separate earlier, 700 to 800,000 years ago from the ancestors of modern humans, people like us.

So that's the big result of a lot of studies since 2010. But there's also evidence of, interbreeding events, that happened maybe 200 to 300,000 years ago. And that actually resulted in, modern humans, contributing DNA to the ancestors of Neanderthals.

So this is maybe 5% of the DNA of Neanderthals comes from this interbreeding event and a lot of studies have shown this. I'm very interested in this because, actually from the archaeological record, Neanderthals and modern humans look actually quite similar to each other, much more similar to each other than a lot of them do to Denisovans, these archaic humans in East Asia. So a lot of the history, people have thought that Neanderthals are our sister.

In two but in 2010, the sequencing of the Denisovan genome made it very clear that on average, Denisovans are closer to Neanderthals than to modern humans. So this was like a very confusing result. And most people now think that Neanderthals and Denisovans are like descend from a common ancestral population separated earlier from the ancestors of modern humans.

So, I'm interested in the possibility that actually the right way to think about Neanderthals is actually as somehow culturally modern humans. And, even though that genetically, they're mostly Denisovans. And the model I'm thinking about is motivated by this archaeological phenomenon known as the Middle Stone Age revolution.

So if this is Africa and this is, I don't know, Europe, we know that the, new way of making stone tools, with, these cores that were very carefully, mined far away from the locations they were used made out of high quality stone like flint, start being used three or four hundred thousand years ago, first in the Caucasus, places like Georgia today or East Africa. This way of making stone tools, which is quite revolutionary and is known in Europe as the Middle Paleolithic and Africa as the Middle Stone Age, is associated with much more widespread use of fire and also moving stone around at much further distances than before. I'm interested in the idea that this is something that's shared between modern humans and Neanderthals.

There's somehow some shared cultural feature that's absent in East Asia, And that might have a relationship in the genetic data and is somehow related to this 5% DNA. So the idea I'm interested in is the possibility that there is a population here that invents the Middle Stone Age and the Middle Paleolithic, sometimes called Le Velwa technology, and that people from this population expand into Europe. And they mix with the local archaic humans who are there.

And that is what this 5% interbreeding event is. It happens two hundred to three hundred thousand years ago. And it produces a group that as it expands across this landscape in Europe, mostly picks up the local DNA and becomes mostly archaic genetically, but retains its modern human culture, the way of making stone tools and some of its traditions.

And so one of the things that's super interesting about this is that if you actually look at the genetics, the whole genome, the Neanderthals and Denisovans cluster. But if you look at the mitochondrial DNA, which people get from their moms and they get from their moms, Neanderthals and modern humans cluster. So if you look at the mitochondrial DNA, Denisovans and modern humans share an ancestor well more than 700,000 or 800,000 years as you expect from the history.

And if you look at the Y chromosome that you get from your dad, Denisovans and modern humans share ancestor more than 700 or 800,000 years ago, which is, consistent with this history. But if you look at the Neanderthal mitochondrial DNA, it's only 300 to 450,000 years. If you look at the Y chromosome, it's only 300 to 450,000 years.

So what the current genetic work is asking us to believe is that even though this is only 5% of the whole genome, it reintroduces mitochondrial DNA in Y chromosomes, they jump up to 100% frequency. It's kind of a crazy claim because the probability of this occurring by chance is low, maybe five percent times five percent. So a very small number.

And so it's sort of what we actually all believe. But it's sort of a very sort of surprising event. And somehow it's accreted all the findings in the whole literature so that we make ourselves believe this.

But it seems sort of unlikely on first principles that somehow only five percent will introduce both the Y chromosome and mitochondrial DNA. And it really looks like this. So there's this amazing data from this site in Spain that's like 200 to 400,000 years old.

It's 300 to 400,000 years old at a site called Cima De Los Huesos. And they have a nuclear genome that looks Neanderthal like, most of the genome, but their mitochondrial DNA microchromosome is Denisovan like. So it really looks like there was a population related to modern humans that pushed into this Sima De Los Muayas like population, displaced its mitochondrial DNA in Y chromosome, but kept the rest of its genome.

So it really looked like something like this happened. So the idea that I'm sort of playing with, and probably it's wrong, who knows, but is that there's a landscape. This is maybe Europe.

And you can break it up into a 100 or so deems, areas, and modern humans get introduced at the bottom right corner in The Middle East or something, and they spread into Europe. And as this population spreads, there's a wavefront of expansion and they're interacting with the local archaic humans. And even if there's a small amount of interbreeding, the theory, from lots of studies simulations and lots of studies of all these different species like mammals and birds and so on shows that when there's even a little amount of interbreeding, as there's an invasion or a movement of expansion of one group into the territory occupied by the other, there's massive introgression of local genes.

There's, that That these pioneers at the wavefront, they'll sometimes interbreed with the local population. There are so many of them around that their DNA will get swamped by the local groups. By the time they make it to the other side, they're largely local.

And so maybe what we're seeing is that this is what's happened. You have a modern human population that's matrilineal, for example, where transmission of making stone tools this way is happening from your mother to the kid. And that's why they're retaining their mitochondrial DNA.

But by the time they get to the other end of Europe, they're mostly archaic. They're mostly local archaic. So you end up with a ninety five percent population replacement.

So this would explain why the mitochondrial DNA is shared between Neanderthals and modern humans. And it would also explain why the mixture proportion is only 5%. But the really interesting thing is that actually there's other evidence from studies of modern humans that actually modern humans are too also admixed.

And that the right way to think about this is that modern humans are a mixture of two groups, maybe like 1,500,000 years ago, and that they come together 200 to 300,000 years ago with like twenty percent two hundred to 300,000 years ago, with maybe 20% ancestry from this archaic African group and 80% ancestry from this early modern lineage, and that the same group then mixes with with Neanderthals and it's 5% modern here and 95% local here. And so you actually have this key population that makes the Middle Stone Age or Leva Watt technology, this one that appears here, And it expands in all directions into Europe here, into Africa here, two to three hundred thousand years ago, bringing this technology, bringing these new ideas, bringing perhaps some genetic adaptations. It expands into archaic humans in Europe.

It mixes with the local population. It gets 95% replaced, but still retains its cultural features and maybe some genetic features. And it expands in Africa too, and here it's not 95% replaced, it's only 20% replaced.

And probably the reason that happens is that this group is much, much more diverged. It's much more archaic. It's 1,500,000 years diverged rather than seven hundred eight hundred thousand years diverged.

And as a result, there's many more incompatibilities genetically and there's much more barriers to gene flow. But there's still a lot, maybe 20%. And we have evidence that this is a big mixture that happens.

And so what you're actually seeing is a modern human expansion both into Europe and into Africa. In one place as it forms Neanderthals, in one place as it forms the ancestors of everybody living today. But all of these groups are descended from this key sort of revolutionary event that happens here.

So we often talk about the revolutionary events fifty to a hundred thousand years ago, the more symbolic behavior and so on and so forth, that sort of first appear in Africa and The Middle East and spread beyond. But there's also this earlier event, and this event is sort of contemporaneous with the breakup of all the different groups also in Africa today, the Khoisan Southern Africans and the Central African Rainforest Hunter gatherers. So one wonders whether this is an equally important formative event.

And it also, if that's true, makes you think of Neanderthals as actually somehow our cousins, that they actually share our Y chromosome, they share our mitochondrial DNA, they share formation of this 200 or 300,000 year old event, their shared toolkit.

So they, the genetic data suggests this is analysis not of any ancient DNA, but only an analysis of modern DNA from different people, mostly in Africa but also non Africans. And multiple studies there's at least three, maybe four or five studies that I know about have looked at the patterns of variation in people today and say the data in modern people today, including in Africans, is not consistent with a homogeneous population. It looks like a population that split well more than a million years ago into multiple, at least two but maybe many groups, and then came together with an important coming together a few 100,000 years ago.

The papers have different models that they fit, but they all have this feature of more than a million years ago there's a split up, and then on the order of a few 100,000 years ago there's a coming together and a remixture event forming the ancestors of anatomically modern humans. And then this includes the Khoisan and whatever other Yes. Okay.

Great. All of these groups have this. Maybe it's in slightly different proportions.

So you ask, where are these people living? Who knows? In this scenario, the 80% is coming from the Caucasus or Northeast Africa, where this Middle Stone Age formed.

It's from this population that forms the Middle Stone Age. And they mix with local groups. And who knows where they are?

Southern Africa, Western Africa, Central Africa, Eastern Africa. We don't have any ancient DNA. But like, you know, this is a very rich environment.

People have been living there for like seven million years at least. And like, there would have been different groups of people everywhere. Probably it's not just two groups.

It's probably more groups. I think the important theme here is there's evidence of substructure that's well more than a million years ago. And this place would have been a landscape full of archaic humans that would have been differently, you know, related to these expanding people and would, and would have admixed with them when they came through.

Okay.

Well, spreads through genes too. If you look at Yamnaya in India, there's almost no Yamnaya ancestry in India.

mean, it's just diluted, diluted, diluted down. As modern as Yamnaya expanded into Central Asia, you know, like expands into Europe and it makes the corded ware. There's a 25% dilution.

It expands back across Central Asia. It goes through the Hindu Kush. You know, it gets into Northern South Asia.

It admixes more with local people by the time, you know, today, the most Yamnaya ancestry you see in India is 20% or 10. You know, most people have less than 10% or 5%. I see it's, you know, there's just been a lot of mixture on the way, but it is the tracer dye, right?

Like it tracks into European languages and important aspects of into European culture are coming through Yamnaya. So if you know where to look, that tracer dye is only 10%. It's only 5%.

It's only 2% in some groups, but it's the languages people speak and it's important cultural shared elements that connect them to people on the other side of the Indo European speaking world. So this 5%, you shouldn't sneeze at it. Right?

Like, that's tracing something important in this model.

So the reason I'm talking about these matrilineal or patrilineal expansions is I'm really troubled and have been troubled for, like, many years, actually fifteen years, but, like, especially in the last three or four years, by the fact that the mitochondrial DNA and Y chromosome cluster Neanderthals in modern humans, but the rest of the genome clusters Neanderthals and Denisovans. This is like a crazy result that is not seen in any other species where you see this pattern. So I'm very interested in patterns that would explain this.

If you invoke and assume that there was like a matrilineal or a patrilineal expansion, it could be either, where modern humans, when they were expanded across the landscape of Europe, retained their identity along one of the lines. Like if you incorporate a local, if it's, if it's matrilineal, when they incorporate a male from the local community, they're brought into the community and the kids are raised by based on the culture of the mothers or something. Or, or if it's a patrilineal expansion, they incorporate a female from the community.

It's incorporated sort of raised with the culture of the fathers. So if that happens, it guarantees one of these two parts of the genome to look like it does because it's a modern human expansion. If it's patrilineal, it will retain the Y chromosome.

If it's matrilineal, it will retain the mitochondrial DNA. So it will solve one of your two problems. But not both.

It won't solve the other So you need to solve the other one. So the other one you can solve either by natural selection or you can solve it by social selection. So, So by the way, patrilineality and matrilineality are the rule, not the exception in human communities.

Usually communities sort of follow, have continuity along the nail or the female line. And usually it's patrilineality. Sometimes it's matrilineality.

So you can also have phenomena like social selection. So, so it could be that once you have kids of someone who is from, the, whose father, for example, is from the outside community that those, the male, usually in most communities, females all reproduce. Like that's typical today.

Like usually women have kids if they can, but men in traditional societies are actually very variable in their reproductive success. A large fraction of men never have kids. Then there's a relatively smaller number.

There's a subset of men have many kids with many women. There's competition among men for kids. In this context where males are competing for access to females, then female mate choice begins to be an important process.

And, you have a phenomenon where, it could be the case that like the if you are your dad is an archaic male, then you're not going to be as successful in the competition for local females if your dad is a non archaic male. So some simple social phenomenon like that could explain the data. We actually see this in human society.

So for example, if I remember right, like in central African rainforest hunter gatherers, there's different treatment of boys and girls depending on whether their dad or mom is one group or the other.

So, it's a question. So there's multiple possible explanations, but it's much easier to explain that than both mitochondrial DNA and the Y chromosome. One possibility is that the mitochondrial DNA was less biologically fit.

Another possibility is that there's social discrimination against people based on whether their parents are archaic or not. Interesting. Which is, I think, not at all surprising in a human context.

What okay. So the Neanderthals It's the weakest link in this this argument. This argument's probably wrong, but I'm just telling you what I'm thinking about.

I think that this is not at all surprising given the context. So if think about this model, this is 700 or 800,000 years ago. This is 300,000 years ago, right?

So this is like 400,000 separated. You talked about the Batya paper with me earlier. Yeah.

That's two populations 70,000 separated. There's no biological incompatibilities between West Africans and Europeans. There's no natural selection against biological incompatibilities.

So we know with when Neanderthals and modern humans met and mixed, there were there were biological incompatibilities. That was at 700,000 ago. And so there's as populations become more apart, there begins to be biological incompatibilities rapidly developing probably as the square of the distance separation because you need pairs of interacting genes, and therefore it's the square of the separation.

So here, it would have been maybe only 400,000 years separated between this lineage and Interesting. This Here, it's like 1,200,000 years. It's a lot.

So these are at the edge of not being able to produce children. So this is quite different humans. These are actually three times closer than these.

And if you look at mixtures of humans today, there are mixtures in Southern Africa today are people who are half this distance. If you look at Khoisan and Bantu people mixing in Southern Africa like the Xhosa, which is the population of, for example, Nelson Mandela, this is groups that are separated by almost two hundred thousand years, which half of this, totally compatible. And so what you're seeing is this is a group that's actually completely permeable genetically or nearly completely permeable.

This one almost certainly has substantial biological incompatibilities because two hundred or three hundred thousand years later, see the interbreeding between Neanderthals and modern humans or between Denisovans and modern humans. There's clear evidence of incompatibility at that point. Interesting.

But this would be even bigger. So what you would expect to see is that as this group spread, they would be moving into a territory full of archaic humans and there would be some interbreeding, but the kids would be not very fit. Would die off.

There would be a lot of infertility. And so the barriers to gene flow or the of of and to interbreeding would be greater. So to me it's not at all surprising that as this group moves into Eurasia, here's Eurasian archaics, the ancestors of Denisovans.

These are only four hundred thousand years diverged from these people over here. And here's African Archaics. And these are like 1,200,000 years diverged.

So they just don't interbreed as much. And so you don't get as much gene flow. But the key thing is at the same time.

It's the same time. So it really feels like the signature of an explosion of people from one place interacting with people here, interacting with people here. It's the same of sort of cultural revolution or technological revolution impacting this place, impacting this place, and creating populations that are both impacted by this cultural revolution, which we know is the case because they share the same toolkit.

Some people argue that level wide technology is independently invented, sort of but, you know, it's very similar. And, this would be a way that it would have the same origin. Interesting.

And sort of so there's a cultural shared thread, this shared tool toolkit. There's a mitochondrial DNA and Y chromosome thread, which is and then there is a timing shared thread, which is they both form by mixture. Because otherwise, you'd have to believe that Neanderthals independently developed stone age Yes, which is not inconceivable.

But it's a little bit like believing that farming independently developed in multiple parts of the world. Right. But it did.

It did? Yeah. So as I said, this is probably wrong.

I'm trying to tell you that we don't really know the world we live And this is not obviously wrong. In fact, to me, this is much more plausible than the model we currently sort of write down. Like, you know, it's probably wrong, but it like, it's just much more plausible.

It explains many more things. It's no more complicated. Interesting.

Do you wanna recapitulate the thing you're saying about the, I love the analogy to the Ptolemy and the epicycles was quite interesting. Yeah. I mean, you know, like, I think that, you know, the model that we've put together collectively about the relationships between archaic and modern humans is sort of accreted over time.

There was this, you know, idea that modern humans are distinct and that Neanderthals and Denisovans are like sisters of each other. And then over time we developed and detected additional mixture events like this modern human into Neanderthal and then other ones I didn't even talk about, like super divergent lineage filling into Denisovans and like all this other stuff. And we still say, oh, the whole genome says Neanderthals and Denisovans are sisters, so that's the truth.

And we've like patched it all together and gotten it all to work. And oh, you look at the mitochondrial DNA in the Y chromosome, and they have this odd pattern, it's improbable. But we can get that to work if we invoke natural selection, you know, things like this.

So so you patch it all together. You make these. It's a little reminds one of, sort of what happened in the ancient worlds where, there was this idea that the, sun revolves around the earth.

But it doesn't quite explain the movements of the planets properly. And so in order to get the movements of the planets to work right, you know, the Ptolemian astronomers would have made up these, epicycles, these special, like, extra rotations and movements to make everything work about right. And it was such a convoluted model, then when Copernicus, and colleagues suggested instead that actually what's happening is everything's revolving around the sun, that simplified things and made things ever so much simpler.

What the situation that was happening is that as astronomical information accumulated, it kept being contradictory to the standard model, but it could be made to work by proposing another complication and another complication and another complication. But, you know, this is not, like, as, like, fantastic as, you know, proposing that everything revolves around the sun rather than the Earth. But it is much simpler, and actually it explains many, many things.

I mean, I don't know. It's just I think that I I don't know.

That's a great question. I think that we have to assume that there's a linkage between the cultural transformations in Africa and Eurasia at this time, and that's sort of not something that the community has really put together with the genetic data. I think that there's this thread in the genetics about substructure in Africans.

Then there's this whole world based on ancient DNA, and they've never been put together. Nobody's put together the now extensive work on modern human substructure with the now extensive work based on ancient DNA of archaic human relationships to modern humans. If you put them together, realize they line up in terms of their time of substructuring.

I don't know if that's improbable. It seems actually parsimonious to me.

you could not show people how to use Who knows? It could be that actually this was genetically driven. And we talked before about the time to the common ancestor of human genes.

There's nothing at 100,000 years or 150,000 years. But there's a lot at 400,000 or 500,000 So if that's what happens and you have a mutation that occurs in The Caucasus or somewhere in The Middle East or Northeast Africa and there's key genetic mutations that make people able to do this And then this population expands. When it moves into Europe, it's swamped by local genes, but there could be retention of those genes through selection as it expands.

So maybe what you're actually seeing is that actually there are genetic developments. Most of the discussion on this, I point, has been focused on the fifty thousand to one hundred thousand year event. And this is like anatomically modern human behavior.

But this is like a lot of my archaeologists think this is an equally, if not more profoundly significant event in many ways. And why is that not the event that we should be talking about?

interbreedings? I think that this is what we're talking about, which is like if you look at the genetic variation going back 300 or 400,000 years, then, there are do begin to be places where all modern humans share common ancestry 300 or 400,000 years ago. And that's another way of saying there begin to be fixed differences at that time depth.

So that is where you start seeing, evidence for possible fixed differences. What's basically happening if everybody shares a common ancestor 400,000, 500,000 ago is there's a single ancestor at that time. If you compared it to another population like these guys, they would descend from a different lineage.

Any mutation that occurred ancestral to that single ancestor would be a fixed difference. This is the time at which you can begin to see fixed differences.

group of Africans or breeding with the anatomists. Anatomically modern humans occur exactly here. It's the same moment.

This is when they occur. The people who have skeletal features like ours and Neanderthals appear exactly then. This is when it all happens.

So is this disconnect between anatomically modern humans in the skeletal record and between behaviorally modern humans, which is 50 to one hundred thousand years ago. But anatomically modern humans appear at this time, and actually recognizable Neanderthals appear roughly around this time too. Interesting.

Interesting.

to behavior My understanding is no. You know, there begins to be you know, they're busy making left of lost stone tools like Neanderthals for 200,000 and not more impressive than Neanderthals in any way. I understand.

And in any obvious way, as I understand. And then there begins to be in the archeological record, a quickening of sort of, you know, behavioral sort of traits, which could be not genetic at all, or it could be genetic. There's lots of arguments about this.

But people are obsessed with We were obsessed with intelligence earlier in our conversation, but people are obsessed with art and these things that seem important to us. But, like, who knows what's important? Yeah.

And yeah. Interesting.

The work that I've been involved in has consistently shown that I was wrong in my biases is coming into the work. And I've really been almost traumatized by this. Like, again and again, I've come into a project with some kind of guess about what the data was showing, and then the data doesn't show that.

So for example, when I got involved in the Neanderthal genome project helping to analyze data, looking at how archaic Neanderthals were related to modern humans, I was part of a group of scientists who had established that non Africans were a simple subset of African variation and that there was no evidence at all of Neanderthal interbreeding into the ancestors of modern humans or other archaic interbreeding. Different analyses that I and and very much more other people had done made it look like non African variation was just a subset, a small sample of that in Africa, and that could fully explain the data. And so that when I was involved in analyzing the Neanderthal DNA sequences, what happened was I found this very strong evidence of Neanderthals being more closely related to non Africans than to Africans.

It was very surprising, and I thought it must be a mistake. I thought it was I was quite incredulous. I thought it was unlikely to be true because other evidence that had been found before seemed to point in the other direction.

And so I spent several years trying to make these results go away, as did my colleagues, and we just couldn't make the results go away. They just kept getting stronger. And this experience working on natural selection was the same.

So what we had felt here was that what we were convinced of was that natural selection had been pretty quiescent in our species over the last several hundred thousand years. Therefore, if we look at patterns of variation in non African people today, or in any people today, we should see not a lot of selection going on. And, indeed, the first ancient DNA studies beginning in 2015 with this paper that we were involved in with Ian Matheson and colleagues, Indeed, these papers seem to show relatively small numbers of genetic positions associated with natural selection.

So in 2,015, we analyzed data from about 200 Europeans and Middle Easterners to try to understand frequency changes over time. And we compared those ancient people who were the sources of modern Europeans to people in Europe today, and we looked at frequency differences that were too extreme to be due to chance. And we were very excited to find 12 positions that we were convinced were highly different in frequency between Europeans today and what we would expect based on the history that that that we had we and others had identified was the history relating modern to ancient Europeans.

And so some of these were known, and some of these were not known. And this was very exciting. And we hoped that as the numbers of samples would increase and we would get higher resolution to be able to appreciate differences in frequencies over time, we hoped that this would make it possible to detect far more.

And what was quite disappointing over the subsequent decade is that that didn't happen. So for example, the largest study of that type in 2024 by a group in Copenhagen analyzed the data, much better data than we had in 2015, and found only 21 positions that were highly different in frequency across time. And while that was exciting, it was almost twice as many as we had found in 2015.

In a lot of ways, it was disappointing because the sample size and data quality had gone up so much, and yet this is all that was found. And so what that suggested is that we might be hitting an asymptote, and we might not be able to get beyond where we currently were, and that this approach to learning about biology sort of which would be was very promising in theory might actually not produce a high yield. That maybe, in fact, natural selection was quiescent.

And in fact, what the reason we're seeing so few changes is that actually there's not been a lot of adaptive directional selection. So that was the situation we found ourselves in until just a a few years ago when we carried out this study in our research group led by Ali Akbar. So so what we did is we, deployed a few, innovations or change, to try to improve our power to detect natural selection.

One of them is we just pumped a lot of data into the system. And so we increased the amount of data by about 14 fold. And the main thing that we do in this study is we report data in this study from about 10,000 individuals, with new data.

So this is like a very big increase in the amount of data in the literature. And, the total dataset size of ancient individuals distributed over the last eighteen thousand years is about 16,000 people. So this is a large dataset.

It's much larger than was previously possible. And when you have more data, you can estimate frequency changes with much more subtlety. And the data comes from only one part of the world, which is Europe and The Middle East.

It's not a more important part of the world than other places, but it's the place where maybe 70 or 80% of the data in the ancient DNA literature so far comes from due to historical reasons. And it provides us with a natural laboratory where we can see what happens over one place over time as environments change to the genome. It's really interesting to imagine doing this type of analysis in other parts of the world, and the comparative analyses are super important and interesting.

But this study right now is about this one place in the world where we have particularly fantastic data. The other thing we did is we developed an entirely new methodology that hadn't been used in this area before. And the methodology is based on a technique that had been developed for finding risk factors for disease in in medical studies.

And a simple way to explain it is we ask how to predict the genetic type a person has based on its pattern of relatedness to other people. So we'll have a dataset of about 16,000 ancient people and 22,000 people if we include the ancient and modern people. And then we look at how closely related each of these 22,000 people are to each other, and we predict the genetic type at each position in the DNA at 10,000,000 positions based on the pattern of relatedness to all of the other 22,000 people.

And then we ask if if natural selection blowing the frequency of the mutation in the same direction in all geographic places and at all times predicts the data a little bit better than just knowing the relatedness to all the other samples in the database. So we're simply asking the alternative hypothesis is that selection has been blowing in the same direction at all times, and we simply ask if that explains the data better. And that's a dumb assumption, because, of course, the truth is that natural selection is gonna have changed in frequency over time.

But we're just asking the simplest of questions whether assuming a constant rate of selection explains the data more than not doing so. And just to summarize to make sure I've understood, you're trying make a model that predicts allele frequency changes over time. Right.

And you have two different parts. Right.

when we analyzed the data this way, we looked at 10,000,000 positions in the DNA, that in in these 22,000 people, 16,000 of them were ancient. And we looked to see if there was more change in this consistent direction over time than you would expect by chance. And when we analyzed the data, we found many, many hundreds of places in the DNA that were changing too much, over time and too consistent a way to be explained by chance.

Now there's a bit of a statistical problem in figuring out how many there are because they're so densely packed that they're close to each other, and they're interfering with each other. But when you try to piece them out and say, let's look at let's count them only one in each place in the DNA and blank blank out the others, we find at least about 479 positions that are all independently pushing in the same way. Those positions are 99% confident that they're real.

By another criteria of more than 50% confident that they're real, we think that about 3,800 positions are all pushing in the same direction. So this is like a crazy number of results given that in our work previously and other people's work, there were at most a couple of dozen Mhmm. Discoveries coming from a single scan.

So when we got this result, we were very surprised. We were thought it must be wrong, and we spent the next couple of years trying to make the results go away, but they just got kept getting stronger. And so what we were trying to do is to look for some kind of independent type of evidence to tell us whether these positions were real.

And we stumbled on something really, powerful for this purpose that had not been used in this way before, and it relied on the fact that we had very large numbers of discoveries, like many hundreds of discoveries or even thousands. And so what we did is we took a completely independent dataset, which was the corpus of genome wide association studies. So these are studies that people have carried out in hundreds of thousands of people looking for whether particular genetic mutations are more common in people with high blood pressure with than with low blood pressure or something like this.

So we took the UK Biobank, which is about 500,000 people from Great Britain who have been measured for hundreds and hundreds of traits. The whole genomes of all these peoples have been sequenced. And for each of these traits, we could look whether each of these 10,000,000 positions are connected to this trait in some way in a convincing way.

So in 10,000,000 positions, about fifteen percent, about 1,500,000 positions in the DNA are predictive of at least one of these several 100 traits. So then we could ask a question. Is our natural selection signal, our statistic, is it related to whether a a mutation causes a high blood pressure or some other trait?

So we slid our statistic for natural selection from upward, you know, to a value of one, a value of two, a value of three, a value of four, a value of five. And as we did that, the enrichment for genetic mutations that affect traits got higher and higher.

This is the statistic we use to measure whether a mutation is changing over time significantly, in a nonzero way. Got it. So it's it it can be approximately thought of as a normally distributed statistic, a Gaussian statistic, which is the number of standard deviations, the statistical value is away from zero, where zero is the pass is no natural selection.

It's not exactly that, but it's close to that. And so if this statistic is above five, we see about a fivefold enrichment in mutations that affect a trait. Interesting.

And so instead of fifteen percent of the, mutations that are, the at random affecting the trait, it's like 60 or 70 that are are are affecting the trait when we slide our statistic upward. And this is providing completely independent evidence that these sites are real. And as you slide above five, there's no more enrichment.

So our interpretation of these results, and that we were able to validate and show that these interpretations made sense using computer simulations of our process, our interpretation of this result is that once you slide the statistic above five, essentially, all the signals of natural selection are real.

that have like some functional thing that we can measure. That's exactly right. And this is like a brilliant idea that Ali had.

And it's it's it really abandons the traditional approach of assigning statistical significance to mutations that cause, a trait because we're just using an external piece of information, the the correlation to traits, measured in a completely different way to read off the probability mutations are real. So we can ask how much enrichment for real signal is there given a particular selection statistic. And if it's halfway enriched to the plateau, the correct interpretation of that we're able to show is that fifty percent of the mutations are, are, are really selected.

If it's three quarters of the way toward the plateau, there's a three quarters probability that the mutation is real. If there's a 99% of the way to the plateau, there's a 99% probability that's real. So that gives us a calibrated estimate of the probability that a particular position is really under natural selection.

A a major concern here is that actually what we're seeing is not that these mutations are really under selection, but rather that both association to a disease and, our selection signal are due to some third thing that's causing both of them, which is a type of selection, which is not what we're after, not selection to adapt to new environments, but what's called background selection, selection against newly arising bad mutations that are removed from the population that tend to be concentrated in genes. Genes are also the parts of the genome that tend to be associated to traits. And so this common process is causing both the enrichment for trait signals and is also causing the enrichment for selection signals that we're observing.

That's the concern. We were super concerned about this. So what we did is we repeated this enrichment analysis in slices of the DNA that all were affected to the same extent by background selection, by this rain of slightly bad mutations, and we get exactly the same pattern.

We also repeated this experiment in just using mutations of the same frequencies because there's different statistical power to detect these signals at different frequencies. And we see the same pattern where above a value of the selection statistic of around five, we get this plateau.

I think that the, the the the big ones have been the huge drop in sequencing cost, which made it possible to generate ancient DNA in the first place. So the drop in cost has been a million fold, since the late two thousands, and another maybe one to two orders of magnitude from 2010 to today. Mhmm.

So that's one big change. Another change has been in solution enrichment. So it's been this way of taking a sample that has very small percentages of human DNA, but then suddenly creating a a a process that will mean that the great majority of the sequences that one's analyzing will be useful for analyses.

And so the approach that we used was we took the DNA samples that we had, most of which were very low percentages of human DNA, less than 10%, often less than 1%, which is such a low proportion that it's prohibitively expensive to sequence them and to just brute force sequencing them given the technology that we had available at the time. And so we took these samples and washed them over a artificially synthesized set of short DNA fragments that targeted positions of the DNA that we were interested in analyzing. So this is more than a million positions that are highly variable in people, and we picked many of these to be biologically interesting.

We had a whole set of known biological targets that affected traits in genome wide association studies, which is the way that people look to see if there's particular genetic variants in modern people that cause, that have particular impacts and phenotypes and traits. And so what we did is we, had this artificially synthesized set of, DNA fragments that we washed our ancient sample over, and it bound the parts of the DNA that we targeted. And the resulting sequence that we generated was very enriched for the parts of the genome that were informative about history.

And even though only 10% or 1% of the DNA was human, it ended up that a very large fraction was from the parts of the genome that we were interested in, and it became economically efficient to do it. And sorry. What was the other 99% of the DNA?

It's mostly microbial. So it's from bacteria and fungi that colonize a person's body after they die. Depending on how they die, there'll be more or less of these bacteria and fungi.

And so when you typically sequence DNA from a person, they'll just it'll just be full of of microbial sequence. Sometimes the microbial sequence is very interesting. So it might be pathogens that that that that a person died of.

So there's, for example, amazing amazing work, about, for ex different plagues of malaria and black death and hepatitis b and so on that have been obtained from the sequences of these pathogens in people's teeth and other parts of their body when they died. But we're focusing here on the human DNA. And, so what we did is we this changed the amount of data that was possible to produce from tens per year to hundreds per year, and then we further roboticized and industrialized the process so that there were many hundreds or even thousands per year.

So just in our laboratory, we've been generating genome scale data from, more than 5,000 individuals per year. I know this is true also of several other laboratories in the world now. And this huge jump in data, this sort of semi exponential or even super exponential jump in some cases, has made it possible to ask and answer questions.

So while the we're they were only on the order of 10 genome sequences from humans in 2010, there this year, it was passed more than 20,000 reported sequences. So there's several orders of magnitude increase. And the questions we were able to ask in 2014 are just not the same as the ones we can ask today.

Yeah. Awesome. Excellent.

David, thanks for your time. Thank you. Thank you, Durkash.