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

Introduction

0:00I am back with David Reich, who is a professor of ancient DNA at Harvard. How do you describe what it is that you study? I'm a geneticist, and I work on human history and how ancient people relate to each other and people living today. Great. And so we did an interview, was it two years ago at this point? Which ended up being one of the most popular interviews I've ever done. I think people just found it really compelling that there's so much about human history we don't know and are just learning about now as a result of the kinds of techniques that your lab is using.

New Preprint

0:34And you have a new preprint that's very exciting, and I wanted to talk to you about it. So let's begin. Can you give me a little bit of context on what we're talking about today? Well, the dream was that when this field started, this ancient DNA field started, more than 16 or 17 years ago, that we were going to 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.

1:08So 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.

Field Success

1:32And 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-grandparents and so on.

Ancestor Representation

2:03And 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 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 want to see how that changes over a time, a single person gives you only one sample or maybe two samples.

Large Sample Sizes

2:43The 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 can do something with the data to see how frequency changes over time.

3:13And can I ask you a question? I'll be asking a lot of negative 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 our history over the last tens of thousands of years to understand what's biologically significant 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 low place to a high place, then there's pressure on the population to adapt to these new stresses, these new needs.

3:57And the way you're going to detect that is you're going to 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 percent unless you have a very, very big sample size.

4:27And 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 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 Akbari, who 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.

4:59And 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.

5:29So 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.

6:01You can say, what are the most different mutations in terms of frequency between Europeans and East Asians? And there's almost no genetic changes that are 100% different in frequency between Europeans and East Asians. So Europeans and East Asians descend from a common ancestral population 40,000 or 50,000 years ago that came out of Africa and the Middle East. This population had a set of gene frequencies, genetic frequencies, and these variants bopped around randomly, a process known as genetic drift, or perhaps under selection in one direction or another. And the time that's passed since 40,000 or 50,000 years ago is sufficiently small on an evolutionary timescale that there's just not much genetic differentiation on average between these two groups, Europeans and East Asians.

6:42However, if there's been natural selection, for example, to help people in one place 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 40,000 or 50,000 years is a lot of time. It's maybe 1,500 or 2,000 generations. And so that might be enough time, easily, to see 100% different in frequency. And yet you don't see any more compared to what you'd expect by chance.

7:12So 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 different adaptive set point that's more favorable for the conditions that population is living in.

7:49So we were able to partition how much of the changes in frequencies of all the mutations that we're seeing in the DNA, we're looking at about 10 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 in population structure causing fluctuations in frequency. And as a result, it's super hard to actually detect the signals of natural selection, adaptive natural selection, because they're a tiny fraction of the total frequency change.

8:25The 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. Can I ask a clarifying question here? So why are we discounting population admixture or replacement as selection? Because if you think about it at a group level, if one population replaces another population, isn't that selection? Then, I remember from the last episode, you were explaining how there's been huge changes in what kinds of people are in a specific area.

8:57One population came in and kind of replaced the previous one, and then a new population came in and replaced the previous one. And to the extent that the genetics are relevant to why that population replaced the other one, why should that not count towards what we understand to be selection over the last 10,000 years? It could count 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.

9:27And 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.

10:02And during these times, you can actually see the mutation slowly blowing in one direction as a result. 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. And in each of those little experiments of nature, we can ask, does this mutation slightly increase in frequency?

10:35Does that same mutation slightly increase in frequency? And if all the arrows point in the same direction, we win. And they're telling us that natural selection is occurring. So, for example, 4,500 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.

11:10And 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?

Natural Selection Explanation

11:21Okay, in this next section, David explains the nitty-gritty of the methodology of this paper. It's honestly a bit technical, and I wanted you to get a sense of the results first. So I've moved that section to the end. If you want to understand the methodology, just stick around for the full episode. Okay, you found these locations that seem to be under selection. Oh, another clarifying question. So you have, you say, 3,800 locations which you're 50% confident have been under selection in the last 10,000 years. 7,200, which where we're 50% confident.

11:53Oh, 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. Ah, I see. So 3,600, which don't know which ones. Got it, got it, got it. So 3,600 of them are real. Okay, and does that also mean that outside of those 7,200, you're confident the other locations in the genome 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.

12:25In fact, multiple analyses we do suggest that the genome is vibrating with natural selection, 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 and being 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.

12:59So 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 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 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,

13:35do they have an unusual number of genetic selection signals? And what we found is there was a vast enrichment by about a four- or five-fold for immune traits. That is, there was a super concentration of selected signals in immune traits, whereas also we saw a strong enrichment for metabolic traits, things that might impact your obesity or fat traits or type 2 diabetes, and really almost no detectable enrichment, as far as we could tell, for behavioral traits or for psychiatric traits.

14:08And just to make sure I understand, this is not to say that behavioral traits or psychiatric traits or cognitive traits are not under selection. It's just that the individual sites where such traits are controlled are not especially likely to be among the locations that you've identified as under selection. Yeah, that's exactly right. 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 18,000 years in this part of the world.

14:40But 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 genes of weak effect.

15:16And 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 –

15:50we'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 natural selection seems to have been quiescent over a timescale of hundreds of thousands or many tens of thousands of years. There's a reason that you don't see 100% different in frequency variants 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

16:23over 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.

16:57And we could compare the last 5,000 years of our time period, what's called the Bronze Age and further onward, to the previous 5,000 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.

17:27So we're in a period of intensified selection. That's not implausible, because this is 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, 11,000 or 12,000 years ago. The people who invented farming exploded into Europe after 8,500 years ago and spread across Europe and expanded rapidly. In the Bronze Age, there was an intensification of how people lived

18:00with 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 ideally adapted position.

18:31That 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 10,000 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.

19:02Interesting. Okay, so it might be helpful to... In the paper, you have many examples of this intensification of selection around the Bronze Age. And so feel free to navigate it yourself, but it might be helpful to go through some of these examples. So we look... One of the things we do in this work is we look carefully at many, many of these positions in the DNA. We actually have an internet browser that you could look at called the Aegis Browser that Ali and a colleague of his, who's a co-author of our paper, built that allows you to query each of these 10 million positions

19:35and see the trajectories at each position and the evidence for selection. And one of the things that we see is that while for the most part, 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 5,000 to 2,000 years ago, which is the Bronze Age and the Iron Age, a period of rapid population growth and rapid movement to intensive use of many technologies

20:12that were not used that way before. So an example of this is the TIC2 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 this major risk factor for tuberculosis, this variant rockets up in frequency from 8,000 or 6,000 years ago to maybe 9% or 10% in this part of the world. And then it rockets down in frequency in the last 3,000 years. In both cases, there's very clear evidence of natural selection.

20:44In 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 2,000 or 3,000 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 opposite direction. That's speculative. Oh, interesting. And the thing it was protecting against was probably another disease?

21:18Maybe. Prepping for this episode required a full lit review. I needed to understand why other methods had failed to find evidence of natural selection over the last 10,000 years. What exactly did Reich and Agbari do differently? Honestly, this was quite subtle. Because the most important points were distributed across a bunch of different papers. And it was frustrating to talk to LLMs about it because they kept getting confused. One of them would fail to understand an important crux. And so I switched over to a different model. And that one would get tripped up on the very next point.

21:48I ended up using Cursor to kick off a handful of models at the same time and compare the results after. I could have one model critique the response of another. This was super useful because while I'm not a geneticist, I do have enough taste to be able to say, Hey, this answer makes sense. These ones don't. I also had Cursor turn this work into a flashcard so I could retain what I learned. Cursor started as a programming tool, but I found it really great for this kind of research. There's no other interface where I can get answers from a bunch of independent LLMs all while reading the relevant paper on the same screen.

22:19Go to cursor.com slash Thwarkash to try it out. One of the big takeaways for me from the paper was just that something weird happened in the Bronze Age. And that, as you said, across trait after trait, the selection intensifies during the Bronze Age. And this makes sense for some things. For example, why do we see lactase persistence where adults can process milk? Why is that intensified during this period? Oh, well, it makes sense. This is the time when we start using cattle, not just for the meat,

22:53but then also for milk and wool and other secondary products. So it makes sense. Because this is why lactose persistence would matter more. But then there's other things which seem like they should have been relevant since the dawn of agriculture. I forget the exact name of the allele, but was it FADS1? Yeah. Which helps convert plant fatty acids into long-chain fatty acids that your body needs. And that's also relevant when you move from a diet of meat as a hunter-gatherer to a diet of cereals.

23:24But that is also one I think you found was under a special selection, or especially high selection, during the, you know, 5,000, 3,000 years ago. Yeah, so what's going on? Why is the Bronze Age so special across all these different traits that you're observing? Right. So FADS1-2, this variant, is sort of a vegetarian-slash-meat-eating adaptation. And already in work prior to this, actually, Ian Matheson, who was a former colleague who worked with me in 2015,

23:57identified 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 A, B, 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, you know, other apes. And so these mutations, some of them have been going back and forth and fluctuating over time in different time periods.

24:29But we're talking about changes in the Bronze Age. So this TIC2 variant for tuberculosis risk, multiple sclerosis risk variant inflected and increased in frequency before the Bronze Age, and then 2,000 or 3,000 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 pathogenic iron buildup that causes problems in Europe, that, too, has reversed around this period.

25:05In 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 10,000 years. You can see it in our data. The period of strongest depigmentation is between about 4,000 to 2,000 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.

25:38And it's surprising on first principles. You might think, before you walked into this genetic data, that the big change is going to be starting to grow plants and maybe farm animals. And that happens in the Neolithic, you know, beginning 11,000 or 12,000 years ago and spreads into Europe after 8,500 years ago. But actually, the intensification happens like 5,000 years ago, 4,000 years 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.

26:19And 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 these events that happened 5,000 years ago. So, you did some work with Bhatia and many other colleagues in 2014.

26:51You were looking at 20,000 or 30,000 African-American genomes today. And you were saying, look, there's some percentage, 80% West African DNA and then 20% European DNA. And can we look at their genomes today? And do we see that their allele frequencies are much different than what you just expect from this admixture? And you find, correct me if I'm wrong, but you found that they weren't. That is to say that over 200, 300 years of extremely intense environment change, you know, going from, you know, chattel slavery and, yeah, completely new environment.

27:29There's no effect of natural selection. And so, we see episodes like this where we don't see natural selection, but then the Bronze Age apparently must have had an even stronger effect, where the change in environment is even stronger than what we see from Africans in Africa, then being migrated to the new world and then living under slavery. 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 for in the Bhatia et al. paper, where we looked at about 30,000 African-Americans and looked 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 from Europeans or from Africans.

28:21We didn't see any place in the DNA that was significantly different from what you would expect by chance. 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 years, it's 3,000 years. It's the power of compound interest, and you have enough time to begin to see a strong effect.

28:52But 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 data set. 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 is the natural selection strongest.

29:25And the time period is really 2,000 to 4,000 years ago. And for some of these other traits as well, you see, again, the time period over which the selection is strongest is 2,000, 4,000 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.

30:00But 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 movement in a systematic direction, a large effect about a standard deviation on the scale of modern variation.

30:32And 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 2,000-year window through our data, and we repeat our whole analysis not on 18,000 years but just on a short 2,000-year window. And we can measure the strength of selection in each of these 2,000-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 years ago. And the impact in the last 2,000 years is almost nothing.

31:04There'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 trait at all, might be that it would be unusually strong in the last 2,000 years. Maybe this is a time of industrialization. Maybe this is a time of greater need for this particular trait. But in fact, there's no evidence of natural selection at all in the last 2,000 years. But there's very strong evidence in between 2,000 and 4,000 years ago where instead of a one standard deviation strength of selection, it's a two standard deviation strength sort of averaged over this time period.

31:37And the standard deviation here is how much the polygenic score for the trait itself moves? How much the polygenic score trait moves over a 10,000-year period within a population that is held constant in terms of its ancestry? Because what's actually we're doing is we're looking in our data set at a kind of heterogeneous group of people. There's Southern Europeans and Northern Europeans and hunter-gatherers and farmers. And at different times in the past, those groups are more or less represented.

32:09So the whole strength of the methodology Ali Akbari 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 data set 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 Italy from 2,000 years ago to 1,500 years ago.

32:43And 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. And what we're doing here is we're measuring the strength of selection at each point in time after correcting for the big population changes that have occurred. Okay, so the effect here is huge then because if you're saying one standard deviation, a standard deviation above the median would be somebody in the 85th percentile.

33:15So you're saying that the effect of selection has been so strong that compared to 10,000 years ago versus now, you know, the median has gone to the 85th percentile. And that's just like a huge effect over the last 10,000 years on something like intelligence or the thing that predicts household income or whatever. So these seem like, especially given that this is only 2% of the change in yellow frequencies and then like the 98% is coming from migration.

33:45So then it's sort of stupendous to think about like, well, what is the impact of migration then? If this alone can explain or is driving a standard deviation change in these kinds of qualities, at least among the kind of variation we see in the world. 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 tests 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.

34:20So that's hugely different. And then you see a huge jump from them to the hunters, to the farmers who are like at the mean, at zero, and that's migration. So what you're seeing is those two groups had different set points for those traits. And then the step past story lists have a lower set value of this. 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. But what our test is telling you is in addition to those fluctuations due to migration, is there a consistent effect of natural selection blowing the trait in the same direction over all places at times?

35:00And that's what we're detecting. So there's this person who has a collective intelligence hypothesis, which is this idea that the selection for intelligence has actually been in the opposite direction, that as society has developed, there's been more specialization. If there's more specialization, each person only needs to understand a smaller and smaller part of the world. And therefore, actually, the ancients were much smarter than us, and we've sort of evolved out in intelligence.

35:31And your results seem to point in the opposite direction, that although there's not been a selection in the last 2,000 years, as society has gotten more complicated, at least when society began, there was more need for the kind of thing that predicts intelligence today. And the reason that's surprising is if you think about hunter-gatherers, yeah, reading your colleague Joseph Hendricks' book, the amount of information that they needed to hold on to and assess everything from how to process food to how to build shelters, fire, et cetera, compared to my world where I got to know how to set up mics and ask questions.

36:09It's just like, it seems like the demands on intelligence should have been way higher in the ancestral environment. And so it's very surprising that the beginnings of civilization increase the selection on intelligence. Right. So, you know, this is the power of data, right? Like, you know, 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.

36:50And 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 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.

37:23So 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 0.1 standard deviation decrease in genetic predictor of intelligence in Iceland just within one century. It's an absolutely huge effect over a short period. And this is selection against years of schooling.

37:53If I said intelligence, I didn't mean to. It's selection against the 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. So, 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.

38:29So 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?

39:00Yeah. Okay, so obviously a trait like years of schooling was not itself a meaningful thing in the past. And the underlying things for it seem to have been under strong selection. So whatever in the genome predicts years of schooling seems to have been under strong selection. And how should we think about this? 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.

39:34So if you look at the genetic predictor of years of schooling, this trait has been measured in millions of people now. It's 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 actual studiousness or something like that,

40:08you 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'm 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 advantageous or disadvantageous. But when we found this signal of years of schooling being increased, the genetic propensity to go to school for more years as it manifests itself in people, in white British people today,

40:47when 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 10,000 years.

41:20So 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 10,000 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 variants, a number of years of school in China today, and the trajectory in Europe, just as strong actually as the effect size of variants in Europeans to the trajectory in Europeans.

41:55So 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 predicting more years of schooling. Okay, just to make sure I understood, you're saying you're looking at this ancient DNA in Europe and you're saying, well, it seems to predict years of schooling for modern people in Europe, or at least a selection on that ancient DNA seems to predict more years of schooling in modern Europe.

42:34And then you also find, well, it also predicts how the same variants predict more years of schooling for Chinese people in China. Yeah. And so this is not just some weird artifact from the way these GWAS were done in Europe. This seems to have, these parts of the genome seem to robustly predict the kind of thing that actually leads to more years of schooling, at least in people today. Correct. Jane Street is pretty secretive, but they did learn about one internal mechanism, which illustrates how high trust and weird their culture is.

43:07Researchers aren't given compute allocations. Instead, Jane Streeters use an internal currency called Hive Bucks to bid for compute in real-time auctions. Everybody can spend as many Hive Bucks as they want, but your Hive Buck bid is meant to represent the real dollar value of the experiment that you want to run. Now, notably during the auction, anybody can change anybody else's bid. And after the auction, people can even kill each other's jobs. People just trust each other to do this in a way that benefits the whole firm. As a result, Jane Street's allocations reflect a near real-time consensus on the highest priority uses of compute.

43:38As Axel, one of their ML engineers, put it. I think Jane Street's pretty bottom-up in terms of we have lots of different researchers who are all training their own models, sequence models, all sorts of other weird and wonderful things. By the way, with their new compute deal, they've just added a $6 billion Hive Buck stimulus to their internal economy. Jane Street is hiring researchers, engineers, and interns. Go to jainestreet.com slash thorkash to learn more. Okay, so stepping back, I want to understand, I think there's this question about, what does this tell us about what actually changed in our environments over the last 18,000 years?

44:14And we talked a little about what happened after the Bronze Age. I want to understand, it's surprising to me, we're talking about this during the collective intelligence part of the conversation, but it's surprising to me that things like intelligence or lack of schizophrenia or so forth, things just seem kind of robustly good. We're not maxed out before the Bronze Age. And in fact, there were so much, the diversity among different populations was so big that you have the European hunter-gatherers having three standard deviations, less predicted value for what they would score on intelligence tests if it existed.

45:00But they were existing in the real world, in a place where intelligence matters. And so how can it be that this was not a, you just look at the human body or any animal, it's just like, evolution has been acting on it so strongly to make it functional, the things it needs to do. And this one thing, which seems like so relevant, especially to what human hunter-gatherers needed to do, is not under, doesn't seem to have been under that strong selection in the Mesolithic or Paleolithic or those eras?

45:30I think that that's a great question. And like, as we talked about before, the human selection is very effective. 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 in 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.

46:11And 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 when the Bible is being written, especially the Old Testament, is exactly when selection for intelligence is the highest point it's apparently ever been. Yeah, exactly. But like, 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 beauty, it's like other things.

46:46And so this value system, which has a hyper-focus on, you know, smarts, is not obviously a trait value that's been common in the past. You might think that in certain communities, like, you know, some communities or 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. But obviously, the thing we're referring to is not, or the thing we care about is not direct performance in an IQ test, especially in the past. I think the thing I'm trying to understand better is this, is intelligence more broadly?

47:20And maybe just that IQ test intelligence is not that correlated with, here is a new world environment, and go figure out how to process food there and make shelter and everything else. All the things which, you know, your colleagues like Joseph Henninger talked about, like, how modern people underestimate the difficulty of doing this kind of thing with a small band of people. Anyway, this is a, like, maybe that's not IQ test intelligence, and that's why we don't see that strong a selection effect on this thing.

47:50But just intuitively, it seems like, regardless of the value system, it just seems very valuable to have this trait maxed out. So I'm being very speculative. And let me give you two examples about how, about what this is, 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. 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.

48:24And 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 having kids, but becoming, you know, having more wealth, having more resources, and putting more into each kid, you're going to have a lower fertility and you're going to have fewer kids.

48:55And that's going to 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 the 20th 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 less in one's life, and having fewer kids and investing more in excelling in various ways, or something like this.

49:28And so you can imagine that actually, at different times and in different places, in ecology, there's resource, there's different ways, like mammals often invest a lot with a pregnancy and a small number of children, whereas fish will spawn huge numbers of offspring into, you know, 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,

49:59or 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 contexts, 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,

50:32or 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 are spectrums where there's advantages to both ends of the spectrum,

51:03and there's multidimensional impacts of these different traits. Julian Jaynes has this famous theory in the origins of consciousness in the bicameral mind that I'm butchering this, but fundamentally, the way I understand it is that up until Homer, basically everybody was schizophrenic in the sense that people genuinely thought that 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.

51:36You're being asked to believe in visions. Yeah, exactly. And even today, I think there's valuation in some religious communities, and communicating with God, and having visions, and having supernatural communions. And so, I just don't know. Yeah. But I think it's super interesting 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. We can see that from the patterns of variation, where the variants that are risk factors tend to be low frequency,

52:07and they tend to be small effects. So, another trait of fine underselection is the trend away from body fat. Yes. Since the agricultural evolution. Why is that? So, this is what you see as 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 2 diabetes risk. And so, there is clear selection by about a standard deviation on the scale of modern variation

52:38for these traits, reducing over the last 10,000 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 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 survive in times of stress because there's more constant stores

53:09of food. And so, as a result, 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 10,000 years has moved into 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 2 diabetes than some

53:43other 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. This is also another way in which the data goes against a common story. And the common story is that hunter-gatherers actually had much more stable diets because they were more varied. And so, they weren't reliant on a single cereal or a single crop for their calories.

54:13And if, you know, if one game went away, they had other things that they could scout for, they could move locations more easily because they weren't tied down to the land. And so, they were more food stable. But in fact, if there's been selection against storage of body fat, that suggests that as unstable and as common as famines might have been in agricultural societies, 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 it, I'm no anthropologist, but my understanding is that when there's a hunt

54:48in some of these 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.

55:19But the timescale 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 the latest hunt is not going to 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

55:52survive two weeks later. A kind of random question I have is, if you were mentioning, look, as compared to these other things which matter much more for fitness and the ancestral environment, the immune system, especially after the Bronze Age, all these other things have mattered more than intelligence. And so, they've been under much more selective pressure than intelligence. Right. That makes you wonder whether there's much more room at the top for intelligence. As in, if humans had been selected, especially for intelligence, they could have been much smarter. And the reason that's relevant is we're currently building AI systems, which are trying to make

56:26as smart as possible. And in fact, the only goal of the training process is intelligence. We don't have to worry about also, at the same time, making their immune systems powerful. We have lots of energy to spend on it, right? And at the same time, making sure they're not schizophrenic. I guess we kind of have to worry about that. But if intelligence has not been the dominant trait under selection for humans over the last 10, 20, 100,000 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. I think that you can move height very extremely in one direction, much more than it is today.

56:59You 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 any of these traits in more in one direction than it is, the mean would move. So all of this evolution since out of Africa is acting on alleles that already existed in the pool of human variants from that first group, which we were talking about last time,

57:31on the order of 10,000 people that exploded out of Africa. And is it surprising that across all these different traits from cognitive profiles to resistance to different kinds of diseases to height to whatever, that that one pool of people contained so much latent variation that they could supply enough stretchiness to accommodate

58:08all of these different traits that you're studying now? That's a rich question. And I think that the human population has within it for 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, of course, which will never happen. But if you take all these variants that affect schizophrenia risk, and you point them all in the same

58:43direction, there will be extreme risk or extreme protection for schizophrenia. So for complex traits, ones 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 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

59:15anemia 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 billion people in the world. There are maybe 30 new mutations every generation. So that's like, what is it?

59:46It's like 240 billion new point mutations every generation. There's only 3 billion DNA bases in the genome. So every mutation that can occur does occur about 100 times every generation. And we're not mutation limited anymore. And so it's not like you have to, the mutations can arise again. They do arise again. But when the population is only 10,000, you have to wait dozens or hundreds of generations sometimes for the new mutation to occur. And so how likely is it that the thing that changes the Bronze Age is just that the human population was big enough? So in 3,000 BC, you go to, I think, a population of 50 million-ish people.

1:00:20The population is big enough that, and the gene flow between different areas is high enough, such that things which don't have an overwhelming selection coefficient, which aren't overwhelmingly favored by evolution, are finally visible to selection. I think that's not likely to be true, but it's an extremely interesting thing to think about. So I think already when population sizes are on the order of a million 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

1:00:52Europe, but also of other places, or maybe it's at the dawn of the Bronze Age or the farming period. So the question you ask is, maybe when the population is small, natural selection doesn't work effectively. 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 a size of 1,000, mutations will

1:01:25bop around by a frequency of 1 over 1,000 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 1,000, 0.1% selection coefficient is very weak. We're talking about 1% effects, and that's very strong. It will work very well even in a population of a size 1,000 or 10,000. If you are talking about mutations of the type that will start rising only in large populations but not small populations, those are selection coefficients that are on the

1:01:58scale of 1 over 10,000 or 1 over 100,000. And those ones will take 10,000 or 100,000 generations to rise in frequency, which is hundreds of thousands or millions of years. So that's not going to do anything over the timescale we're talking about. There's just a timescale issue. 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 going to work in small populations or large populations. It's not going to be affected by the population size. Interesting. But you're saying more generally, once you hit a given threshold of population, the dominant factor is time span, not population size.

1:02:33Correct. Correct. Okay. Interesting. It's very interesting. And it's actually not widely understood. Yeah. Okay. So speaking of data contradicting what you might have otherwise assumed, one of the papers you sent me beforehand, Malik 2016, found that there are not fixed differences between modern and archaic humans 50,000 years ago. And of course, we know this is the period in which the so-called cognitive revolution happened and modernies started and people are making art or

1:03:04whatever. Does this suggest that nothing biological change to make modern humans modern and the thing that happened with some cultural change? How do we understand what this data tells us? Right. 50,000 years ago or so, or maybe 100,000 to 50,000 years ago, there's a quickening of the pace of change in culture. So people, you see the first extensive representational art and like

1:03:35bead 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 going to 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 and that everybody suddenly had, soon had, and that made it possible for do these things, to do these things, maybe some genes that allowed people to have complex language, representational language, for example. And so one thing that we did in 2016

1:04:10in 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 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 keen selective sweeps that have occurred in this period that is ancestral to everyone living

1:04:44today. 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. There's lots of mutations that all shift in the same direction to help the population to move to a new set point, but there's no key biological change that rises to high frequency in this time. And this group, 50,000 years ago, they are the

1:05:20ancestors of everybody out of Africa or also some Africans? So this is 100 to 50,000 years ago, and 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 years ago from

1:05:53the other lineages. But all of these groups today are able to 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. So the differences we see between different groups of people, especially if this group of people, 50 to 100,000 years ago, had a very small population size. I think last time we were discussing on the order of 10,000 people? Yeah. So basically, everybody in the world, or almost everybody in the world,

1:06:25or the variance we see between different humans today was latent in this group, which sort of seems... And I get your point that, well, if you just stack up different things across the genome, then stacking them up really has a big effect. But it's interesting that, like, we have so many different groups in the world today, and all that diversity comes from a very small population size. A lot of us in human genetics think that our population contains within it the clay that's

1:07:01needed to make almost any trait, 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 18,000 years, 10,000 years, 5,000 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 100 of

1:07:35them, complex traits, showed significant movement in 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. Crusoe has an amazing MLInfo team that keeps finding clever ways to squeeze more performance out of their hardware. For example, tokenization has become a real bottleneck for Argentic workloads. Argentic prompts are often extremely long. They tend to have high KV cache rate rates, which shrinks the GPU's

1:08:06pre-fill work. This means that the tokenization step, which is traditionally sequential, is a much larger fraction of time-to-first token. To solve this, Crusoe built Fast Tokens, an open-source Rust-based tokenizer which paralyzes things in order to take advantage of all the cores on modern CPUs. Crusoe had to get creative here because the naive approach doesn't work. For example, for pre-tokenization, you can't just split your text into chunks and run regex because you'd end up with issues whenever a word straddled the split. Crusoe solved this by giving each thread an authority zone plus the ability to

1:08:38read one kilobyte past its own edges. This one kilobyte buffer guarantees that you won't misprocess a token and the authority zone guarantees that you won't end up with duplicates. No cross-thread coordination required. Crusoe combined this optimization with a handful of other smart tweaks in order to get up to 40% faster time-to-first token on real production workloads. To learn more, go to crusoe.ai slash Thorkesh. We were talking earlier of how there's no fixed differences between humans 50,000 years ago and humans today. So if there's no genetic basis for

1:09:11the kind of thing that allowed humans to have more symbolic representation, have farming, etc., I think I asked you this question last time we talked, but especially with this context, why no farming before the Ice Age? Genetically, we were there. That is such an interesting question. Genetically, we're there. The common ancestral population has all of the ingredients for farming 50,000 years ago. These people are distributed into different parts of the world. The Americas, 15,000 years ago or whatever it is. New Guinea, 40,000 years ago.

1:09:45East Asia, Europe, West Africa. No farming develops before 12,000 or 11,000 years ago. It only develops in the last 12,000 years, the period known as the Holocene, which is sort of the end of the Ice Age. If you talk to climate scientists and archaeologists, 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? People tell me, indeed,

1:10:16we're living in a very unusual time on a scale of 2 million years. That is, 12,000 years ago, we switched into this period of not just warmth, but climate stability. Actually, this is true. It's sort of hard to believe that we're living in such a special time. If you look at, for example, data from the 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 10 years to 10 years and 100 years to 100 years. It's just a period of relative stability that we

1:10:50are miraculously living in. When this period of relative stability happens, somehow it follows that multiple groups independently turn to agriculture, even though the genetic complement, all of whom have the same genetic complement that arises 50,000, 100,000, 200,000, 300,000 years ago. It's kind of a crazy observation that people just accept, but it's like unbelievables. Oh, so you increased the range there. You said 100,000, 200,000, 300,000 years ago. Based on

1:11:22the genetic differences between modern people and people from even 300,000 years ago, you think basically they're modern 300,000 years ago? I don't know. I'm thinking about this all the time right now. This is actually actively what I'm thinking about right now. There's a big transformation in terms of the culture of humans 300,000, 400,000 years ago, this invention of level of technology, the ability to make stone tools out of cores, the Middle Stone Age revolution or the Middle

1:11:52Paleolithic revolution, depending on what you call it in Africa or Eurasia. 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. It's a big change, and it involves a cognitive change presumably in order to make this sort of technology. Then there's a further change to the Upper Paleolithic later Stone Age, maybe 100,000 to 50,000 years ago, when there's this second transition with a new type of tool making, but not as revolutionary as the earlier one. When the cognitive leap happens is unclear.

1:12:28The diversification of the lineages leading to people living today, like Khoisan Southern Africa's and rainforest hunter-gatherers, that all occurs more on the timescale of 300,000 or 200,000 years. All of these people are capable of going to college and doing everything. It's not obvious that all the toolkit, the cognitive toolkit, the behavioral toolkit, the genetic abilities were not all in place two or 300,000 years ago, and that even Neanderthals had them. It's not obvious that this

1:12:59was not the case. I just don't know. You distribute these people descended from this diversification that happens 200,000, 300,000 years ago to different parts of the world, and then, bing, after 12,000 years ago, you start having agriculture popping up in different places. It's kind of an outstanding mystery of human history. I find it unbelievable that we live in a time period that climate orologically is so unique on a scale of 2 million years, but my colleagues tell me it's true.

1:13:31The climate thing seems surprising given there were so many different environments in which agriculture was independently developed. Now, I understand that across environments, the variants could have gone down. If it only had happened in one place at one time, I could have bought that explanation, but the fact that they're making maize in the new world and they've got cereals in the old world and so forth and just in very different environments makes it surprising. It's very, very surprising, and I think we accept it, but it's just a crazy observation that most

1:14:06normal people don't realize. 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 around 70,000 years ago. Everybody accepts that these people all have in place the cognitive, behavioral, intellectual ingredients that are necessary for the farming revolution and 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,

1:14:39their descendants all do this independently or semi-independently or completely independently or demonstrably completely independently in all these different parts of the world. The cognitive resources for doing this must have all been in place, but it's a very long fuse. It delays for 40,000 years, for 60,000 years in all these different places after the common ancestral population splits up and then ignites into agriculture and all these other things after that point. It's kind of a crazy claim. And then you could argue about whether the actual fuse is

1:15:11300,000 years 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. Is it possible that agriculture existed, but you didn't have modern metallurgy or whatever it was that allowed populations to explode starting in 5,000 BC with the Bronze Age? Because like population-wise, it doesn't seem like, you know, 10,000 BC to 5,000 BC, the early Neolithic, much is

1:15:43happening. It's as possible that they had farming, but they didn't have copper, they didn't have tin, which you needed to go to, I guess, the Middle East for, to develop a civilization that could make use of bronze at a large scale. And so they just disappeared from the historical record? I think we would see their archaeology and like, you know, the extraordinary developments in the Americas, which are entirely Stone Age. You would see them today if they had gone completely vanished. Oh yeah. I mean, there's like, you know, you, you, you know, we, we should go for a trip to Teotihuacan

1:16:17in Mexico. And it's like, like so impressive. 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. You know, it's like huge, it's massive. It's without metal. And it's, um, 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. Right. Like take any person who has like an old world superiority and like, take them to these places and they will not have it anymore. It's just extraordinary what's in these

1:16:49places. And these are people who separated 20,000 years ago, at least from the ancestors of East Asians and 40,000 years ago from the ancestors of West Eurasians. And, you know, just had the same biological, you know, uh, cultural shared toolkit from then, but there's just a, a fuse, a long fuse delay until all this stuff happens. It's kind of like an amazing thing. And we don't question it. What are other questions you have that, um, people, uh, yeah, you're, you're either

1:17:19are investigating right now or want to investigate these kinds of big picture questions of human history. 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 and the Neanderthals. We have archaic sequences from these enigmatic Denisovans who we now have, uh, a skeleton for, um, since we last talked, there's now a skull from a Denisovan

1:17:53that's been shown to be a Denisovan. Uh, and we have data from lots of modern humans. Uh, and there's really big mysteries about the relationships amongst these groups. So genetically the Denisovans and the, uh, Neanderthals are sisters. They descend from a common ancestral population five or 600,000 years ago. And that group descends a couple hundred thousand years before, uh, seven or 800,000 years ago from the common ancestors of modern humans. And so genetically,

1:18:24the 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. Uh, they both share, uh, middle stone age 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

1:18:55is actually modern human that came through interbreeding two or 300,000 years ago, and then shot up to a hundred percent frequency. And then Neanderthals and modern humans are both the product of mixture events that happened between archaic and modern humans 300 or 200,000 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

1:19:28connecting kind of, uh, 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. And then connecting them would be interbreeding events or being in the same place at the same time that we missed? There's a known interbreeding event from the lineage leading to, uh, modern humans into Neanderthals, but it's supposed to be only 5%. 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

1:20:03some ways. And even though they get swamped by archaic genes, that somehow they're 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 that we think. Interesting. Sorry, when was this interbreeding event? 300,000 to 200,000 years ago. And so the common ancestor between Neanderthals and most humans alive today is potentially more recent than the common ancestor between all humans alive today.

1:20:36Oh, for sure. Yeah. Which is crazy. Yeah. Well, you, not, not, the divergence to all the archaic humans, including Denisovins, is within human variation. 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, the same bit of your DNA on the same chromosome, the 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

1:21:07is 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. And I'm sure that there's a simple explanation, but how? 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. But in other places, you're more closely related to me than you are to your sister because you happen not to share the same DNA from your parents. It's a process. It's just that the DNA that we get from

1:21:41our common ancestral population was already quite variable. I see. 500,000 years ago, 700,000 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. And 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. What are the other big questions? I think that's the main thing that I'm thinking about a lot these days. You know, I think that

1:22:11I'm really continue to be very obsessed with questions about the spread of human populations around the world and trying to reconstruct that with ancient DNA. After the recording ended, David started spontaneously explaining a new theory he's working on about Neanderthal genetics on a whiteboard in the room, which I ended up capturing on my iPhone. Because it's a whiteboard, I think it might be helpful to switch over to a video platform like YouTube or Spotify. But if you can't, it's totally okay to listen on audio. The thing I'm thinking about a lot recently is the possibility that it's maybe we're not thinking in the right way about the relationship between

1:22:46archaic 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 600,000 years ago. And that these two separate earlier, maybe 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

1:23:23since 2010. But there's also evidence of interbreeding events that happened maybe 200,000 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

1:23:55of studies have shown this. And so I'm very interested in this because actually from the archaeological record, Neanderthals and modern humans sort of 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. But in 2010, the sequencing of the Denisovan genome made it very clear that on average, Denisovans are

1:24:26closer 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.

1:25:02So if this is Africa, and this is, I don't know, Europe,

1:25:13we 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. And that this way of making stone tools, which is quite revolutionary and is known in Europe as the Middle Paleolithic, and Africa is the Middle Stone Age, and 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

1:25:49idea that this is something that's shared between African, between modern humans and Neanderthals, and 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 level law 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%

1:26:22interbreeding event is. It happens two 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

1:26:56modern 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 an ancestor more than 700,000 or 800,000 years ago, which is consistent with this history. But if you look at the Neanderthal mitochondrial DNA, it's only three to four hundred fifty thousand years. If you look at the Y chromosome that's only three to four hundred fifty thousand years. So what the current genetic work is asking us to believe is that even though this is only five percent of the whole genome,

1:27:30it introduces mitochondrial DNA and Y chromosomes and they jump up to a hundred percent 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

1:28:05Spain that's like two to four hundred thousand years old. It's three to four hundred thousand years old at a site called Sema de los Huesos. And they have a nuclear genome that looks Neanderthal-like, most of the genome, but their mitochondrial DNA and Y chromosome is Denisovan-like. So it really looks like there was a population related to modern humans that pushed into this Sema de los Huesos-like population, displaced its mitochondrial DNA and 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, you know, probably it's wrong, who knows, but is that there's a landscape, this is maybe Europe,

1:28:40and you can break it up into a hundred or so deems, little 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 wave front 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 there is, when there's even a little amount of interbreeding as there's an invasion or

1:29:15a movement of expansion of one group into the territory occupied by the other, there's massive intergression of local genes. That these pioneers at the wave front, they'll sometimes interbreed with the local population. There's so many of them around that their DNA will get swamped by the local group. So 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 like a modern human population that's matrilineal, for example, where transmission of making stone tools this way is happening from your

1:29:49mother 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.