6. Behavioral Genetics I

[MUSIC PLAYING] Stanford University. [SIDE CONVERSATIONS] OK, let's get going. Let's see. First off, apologies for Friday. Sometimes, what seems like a flawless set of connecting flights on paper turn out not to be in reality. So hopefully, people made good use of the time. OK. We are ready for our next bucket, our next bucket, our third one in this series, just in time to convince you that we just keep jumping these. As soon as you get accustomed to one approach, here we are, yet another one, where we are going to trash everything that's come before us. OK. What have been the two broad approaches so far? The first one, the sociobiological/evolutionary psychology one-- behavior evolves exactly under the same sort of wind tunnel of selection as does the heart of a giraffe, blah, blah, that whole song and dance. Following certain rules, you could generate fairly structured predictions about social behavior. And then, the we-win version of using that is, here's what we predict. Here is the way we explain this complex system of social behavior, using these rules which assume certain degrees of heritability of behavior, following certain rules of evolution. And until you come up with a better explanation for how this goes on, we win. This is how behavior works. Then we shifted over to the molecular end. And what we saw was, on a certain sort of trendy level, molecular biology is the answer to the people who would sit around to the sociobiologists and say, show me the genes. Show me the genes for what you keep talking about inferentially. And what we saw was how evolutionary change works out in the DNA level. Very importantly, the common mechanisms for microevolutionary change and how that supports the picture of gradualism. And then seeing all of these relatively new, unexpected ways in which you are getting big time changes in DNA, all these amplifying effects of macroevolution, and suddenly support for punctuated equilibrium in two ways. The first one being, as soon as you get one, little, tiny mutation affecting transcription factors, affecting splicing enzymes, affecting entire networks, it is going to be real rare that you don't get a mutation that's a disaster. Stabilizing. Stasis, that's the long-term feature of the punctuated equilibrium. The equilibrium part and the punctuated seeing how, under circumstances of extreme selection, something that is come up with is wildly adaptive, wildly advantageous, quickly fixates in the society. And thus, we have step functions. OK. So what we do today-- and Wednesday is now shift to another field-- thinking about behavior in a genetic context, in a heritable context, this whole field of behavior genetics. And what you'll see is, depending on your stripe, either these are a bunch of really powerful approaches for being able to infer some sort of genetic components to behavior, often getting a whole lot of insight into what's going on, and in some cases, a more negative view, more critical one, the entire field is gibberish. And a way to summarize the view of it as being gibberish was this great cartoon I saw a while back. OK, two scientists are standing around the lab. And they've got their lab coats on, and their test tubes, and going about doing science stuff. And one of them is saying to the other one, you know how sometimes you're on the phone with someone, and you've been talking for a long time, and it seems like they decide they want to get off, but they don't want to say they want to get off, so they say, I probably shouldn't keep you any longer, even though you're not the one wanting to get off, because they're the one who wants to get off? Well, I think I found the gene for that. [LAUGHTER] And that winds up being one of the criticisms of the behavior genetics. Once again, this world of inferring genetic bases to behavior in often the most deterministic possible way and using techniques which are often complete nonsense. And what we'll see are the tools of behavior geneticists, and all the criticisms, and why this winds up being a very contentious field. OK. So this being another version of getting at, how do you know when a behavior has a genetic component. And we're immediately allowing ourselves to be a little more subtle here, not determined by genes, not determined purely by nature. All of that merely to have a genetic component, a genetic influence, how do you begin to do that? And this is a world where people, the scientists, don't sit around coming up with evolutionary models. They don't sit around trying to find mutations in genes. They have a very different sort of strategy. They look for patterns of shared traits among the individuals who have differing degrees of shared genes and infer, related to this, and infer genetic influences from that. OK, what's the simplest most mindless version of doing this? The basic initial rules, centuries ago, when behavior genetics started , was the notion, if you see a trait that is universal in a species, obviously, it's genetic. Obviously, it's hard-wired. Obviously, it's instinctual. Obviously, that's an extremely limited approach. Yes, indeed. You will see some species, like flies, in which certain behavioral traits are determined by relatively small numbers of genes and are universal. This is obviously going to fall apart when you get to something more interesting than a fly. So what's a much more the starting point for the whole field is to say, ooh, look. Here's some behavioral traits that run in families. Genes run in families. Therefore, we may have just found evidence for a genetic influence on these traits. And of course, it takes about an eighth of a second to come up with the retort to that, which is, yes, genes run in families, but environment runs in families as well. So the standard response is to now put a little bit more strictures on it, to say, OK, it's not just that genes run in families, but as we know, from a few weeks ago, the more closely related you are, the more genes you share in common. Our Mendelian rule of half the genes with full sibling, et cetera. Following thus, the logic that, if you have a behavioral trait that becomes more common the more closely related two individuals are, now you're inferring something about genetics. And of course, the problem there is not only, as you become more closely related to somebody, do you share a greater percentage of your genes, you share environment more. Obviously, you are sharing environment on the average, in most cases, much more with a sibling than with a first cousin, than with an eighth cousin. The trouble is shared genes and shared environment tend to co-variant families. So that greatly weakens what was the initial classic approach to the field 70, 80 years ago. OK. So you've got to come up with something fancier, something more informative, something more subtle. And what you wind up doing then is, let's control for environment. Yes, obviously, the eighth cousin is living in a different world than your full sibling. Let's control for environment under circumstances where you examine relatives where they have the same environment, and they differ in terms of the amount of genes they share. And what is this classic approach? Look at identical twins versus fraternal twins, monozygotic twins, from one zygote, monozygotic, identical twins versus dizygotic. And the general notion there is, OK, identical twins share 100% of their genes. Fraternal twins share 50% of their genes. So if identical twins are raised in the exact same environment, and fraternal twins are raised in the exact same environment, they all have environments shared. What's the only difference then to explain any behavioral differences, if you see a trait that is shared to a greater extent in a pair of identical twins, than in fraternal twins? What's the only difference? They all grow up with identical environments. It's because the identical twins have twice the amount of genes in common, 100%. You could thus infer a genetic influence on that trait, because it's the identical environment. Twins get raised absolutely the same. And the only difference is the degree of relatedness, the degree of shared genes between monozygotic and dizygotic twins. That one should take about 2/8 of a second to demolish, for the simple starting point that, oh, yeah, sometimes fraternal twins, dizygotic twins, are different sexes. OK. So that complicates things. So you come back and you're a little bit more rigorous now. And you restrict your comparisons of monozygotic to dizygotic, to same-sex dizygotic pairs. And then you institute this rule, OK, same-sex twins, whether identical or fraternal, are raised essentially in the same environment. The same environment. So if you see a greater sharing of traits among the monozygotic twins than the dizygotic, the only place that greater sharing could be attributed to is the fact that they have more genes in common. Ah. We have just identified a behavior that has a strong genetic component. So the big problem with that approach is-- anyone-- who's a twin in here? Whoa. That's a lot of hands. Identical twins? Dizygotic twins? Any triplets? OK. Just to extend that, armadillos always give birth to four identical offspring at once. [LAUGHTER] OK. [LAUGHTER] So that having been prompted, what we then move on to is the obvious problem with this entire approach. Hurray. Monozygotic twins get raised in virtually the same environment. Dizygotic twins of the same gender get raised in virtually the same environment. That's not true in the slightest. There is far more differentiation of environment for dizygotic twins than for monozygotic twins. They are treated differently, as pairs. Thus, if behavioral traits are more in common between monozygotic twins than between dizygotic, it could be because these guys share more genes in common, and/or because they share more environment, a completely flawed approach in that regard. The next complication. It turns out, monozygotic twins don't always have the exact same environment. Well, yes. Obviously, one of them gets sneezed on at a higher rate by a kid sister, or something. And that's going to produce just decades worth of consequences. But even in other domains, monozygotic twins don't get treated exactly the same, in some circumstances. And here is what it looks like, if I had drawn it. OK. So you've got your twins. And this is during fetal life. And there are fetuses in there. And OK, there's one with a little thing of hair. And there's the other. OK. And what you have is a placenta forms. And here's the deal. With monozygotic twins, if they split during the first five days after conception, they wind up, each one, with their own placenta. On the other hand, if the split occurs between days five and 10, there's already commitment to one placenta, which they then share. So monochorionic pregnancy, or bichorionic. And what does that wind up meaning? In the monochorionic, the two fetuses share a blood stream, to a greater extent, than in the bichorionic circumstance. In these cases, it's separate blood flow from mom. OK, it's still the same mom, and it's still ultimately the same blood, but it's going to be subtle differences in the levels of stuff in the bloodstream. With the monochorionic, the environment for these fetuses are much more similar, in terms of whatever is carried in the bloodstream. OK, great. That's a great factoid. And that's like interesting, things about identical twins. But like different levels of nutrients, whether it's coming off of a blood vessel here, versus there, OK, maybe that makes a difference. But these are going to be minuscule differences. Nothing interesting. As one example of it, monochorionic identical twins have more similar IQs than do bichorionic identical twins. Just one demonstration that this could make a difference. This is relevant. The IQs are more similar. And this has been one reason why marmoset monkeys-- marmoset monkeys, pair bonding, so you know what they're all about-- among other things, marmoset monkey mothers always give birth to twins, because there is two parents around to take care of them. And it's got a completely screwy circulatory system for the twins that are unlike either of these. And there's all sorts of people who've been interested in marmosets over the years-- the ones who couldn't afford to by themselves armadillos-- interested in terms of looking at the differences in blood flow during fetal life there of twins. OK. So we start off here that, just because you see something more in common in monozygotic twins than dizygotic, that doesn't tell you the first thing about whether it's genes involved. They share our environment much more. Then even trying to make sense of what's going on in monozygotic. What you've got there are fundamental potential differences, environment, starting at a very important early state of life. So monochorionic versus bichorionic. What else then? How about another one where you can look at a behavioral trait, looking at traits and traits differences, according to some genetic trait and where environment is the same? How about gender differences? Whoa. OK. So genes have something to do with producing what your gender is. And environment being the same, if you see differences between females and males, that's attributable to the different genetics. OK. And you should be able to nuke that one within seconds, as well, which is the notion of shared environment, the notion of identical environmental experience. To give you a sense of how subtle this is, at one hour of life, on the average, the level of activity, the rate of movement, the amount of movement of limbs, on the average, is greater among newborn boys than newborn girls. Whoa. That's there like within an hour of getting born. That's not a whole lot of time for environment having gone on there. Maybe you're seeing a strong genetic effect. What other studies have shown is, from the first moments of post-natal life, mothers are already interacting differently with baby girls than with baby boys. From the first interaction, from the very first holding of them, there's differences in how long they are held. There are differences in proximity to the body, to the face. So Whoa. Sex differences in behavior at one hour. Sex differences in environment within mere moments after being born. So that weakens that one. And this came through in another realm. This was a study that was done in the '80s, that was enormously influential, by a pair of scientists at Johns Hopkins, Benbow and Stanley. And it had to do with a program that I'd bet a lot of you guys had something or other to do with back when, which is the Johns Hopkins Gifted Youth Program thing, which I bet all sorts of you guys qualified for at various points and got the Johns Hopkins blue ribbons pasted to your forehead. And that was part of this massive study that's been going on for decades and decades of kids who are very gifted, academically, and in a number of different realms. And Benbow and Stanley were some of the senior researchers on this. And this was a study they did when they had 40,000 kids in their database. And they asked a very simple question, which was, well, what does IQ distribution look like in this population as a function of what sex you are? And back came a very interesting finding, which was a highly, highly, highly significant difference in the average IQ between girls and boys, in the direction of boys having a higher IQ. Moreover, when you looked at the tail of the distribution, the highest IQ range, what you saw there was approximately a 13:1 ratio, way out at this extreme. They then followed up and did the exact same thing-- no, they didn't do IQ. What am I talking about? They did math. Ignore that. Erase all of that. OK, let's start over. [LAUGHTER] So lots of you probably got the Benbow and Stanley sweatshirts when you were part of that program. So they were looking at math skills, yes, junior high school kids who were taking the math part of the SATs. That's part of getting into this Hopkins program. So they took the math SATs and they looked at those 40,000 scores and saw that there was a gender difference in the average score on the math SATs, with boys scoring higher. Not only that, but when they looked out at the tail here-- OK, I'm back on track-- when they looked out at the tail here at the highest math achievement, there was a ratio of 13:1, boys to girls OK, so that was pretty striking. And in their paper, which was published in Science, was a very, very critical phrase. Their rationale for doing this study on kids that age was the fact that-- at least, at the time in most schools, middle school, junior high school-- kids have not differentiated classes yet. They're not yet at the point where you could choose to take extra math classes, to choose to take the absolute minimum. This was still the stage where most kids in this country are getting the exact same math classes. Everyone is still getting the same. And thus, at that point, they could include in their paper a phrase along the lines of, since all the children had essentially identical educational environments, any gender differences seen in it are reflecting-- and they used the word, "biological"-- are reflecting biological differences. This was one hell of a famous study. This was front page all over the place. This wound up being shown in a very large article in Time, and in Newsweek, the Reader's Digest-- which I know, sort of, everyone is supposed to make fun of-- but the Reader's Digest, at least-- does it still exist? Yes. Yes, it does. OK. Throughout the 1980s, the Reader's Digest was the most widely read magazine in this country, which is astonishing, showing what percentage of people read in the bathroom, so having to go with the Reader's Digest there. And the Reader's Digest covered this and used the phrase, "The math gene," and discussing how this was the definitive study showing that more boys have the "math gene." Like, you already know that's like nonsense on so many different levels. But this was all over the place. This was the study that definitively showed genetic differences in math skills by sex, and definitively showed that this was manifest at a stage before there were different educational environments, in terms of math. And what, of course, completely rips apart that study-- and it was shameful that thing was ever published, let alone got as much attention as it did-- is the fact that the environment was not exactly the same. Endless number of studies have shown, beginning by first grade, if it is a simple math problem at that stage for the same hands put up, a boy is more likely to be called on than a girl. Studies showing that, for the same correct answer, boys in elementary schools are more likely to be praised for the correct answer than are girls. By the time junior high school is coming around, guidance counselors are already differentially, by sex, advising, once you get into high school, to take more elective math. Tremendous, massive differences in environment. And this study, using this whole argument of, if there's an identical environment, and you see differences, it's due to genes. And predicated on that, if that's not true in our afterlife, it was ludicrous that they were making this argument about 13-year-olds. So this was a paper with enormous influence in every major newspaper in the country. Scientists have discovered the "math gene." And boys have them more than girls. We will come back to that study later on, because something much, much more interesting was going on. OK. So those were the limits in the sex difference end of it. So what can you do next? There's a flip side, another approach, that the behavior geneticists use, which is basically the converse. Now, you look at individuals getting raised in the same environment who don't share genes. Same environment, different genes. Rather than just now the different genes, same environment nonsense about gender differences, even down to monozygotic twins, all of that, but now the flip side, same environment and different genes. What was the paradigm for this? The one that is used over, and over, and over again, the standard approach in this part of the field is adoption studies. You take someone who is adopted as a child, and they are now raised in a household of people who they are not related to, their adoptive, non-biological parents. And what you now begin to look at are patterns of shared traits. Specifically, what is looked at is, when you see a trait in someone who was adopted, who are they more likely to share that trait with? Their biological parents, or parent? Or with an adoptive parent? Now, the logic of this is completely straightforward. And this has been sort of the standard paradigm in animal studies of the genetics of behavior for centuries, something called cross-fostering. You take a newborn litter and another newborn litter, and you switch them between moms so that they were raised by different moms. And they're raised with, thus, someone they're not related to, but someone who they now have environmental shared with them. Or in the litter cross-fostering studies, you will take half of a litter and switch it to another mother, half-- so you see how the iterations there go. So that was essentially the rationale for how this would be done in humans. And this was the basis of one study in the late '60s, early '70s, which was the landmark study in genetic psychiatry, in behavioral genetics as a whole, a study carried out by a guy at Harvard, named Seymour Kety. And this was a phenomenal study and phenomenally important. Here's what Kety did. Kety was dealing with the notion at the time of making sense of schizophrenia. And as we will see when we get to the schizophrenia lecture, the number of nutty ideas out there as to what the cause of this disease is is just staggering. But what he was interested in was getting at the notion that was kind of floating around in some corners of the field at the time, which is schizophrenia has a biological component, a genetic component. And what that was was viewed as very unlikely. But what Kety did was try to go and test this. So what's he going to do? He's going to look at adopted individuals who are schizophrenic and see are they more likely to share that trait with a biological parent or adoptive parent. You see the logic already. OK, how many schizophrenic adoptees are you going to find out there where you also were able to figure out who the biological parents were. This was not an easy task. And Kety's insight, his intuition, was to go to one of the places on Earth where that was most easily done, which is Scandinavia, where all the Scandinavian countries keep records like you cannot believe about everything on Earth. People understanding, for example, how the age of puberty onset in girls have been decreasing for centuries. They're always using Scandinavian data, because every single thing that could possibly be recorded has been written down and stored someplace there in moth-proof vaults. And what he was able to do in ways that no human subjects committee on earth would approve these days, is go through the entire database of adoptees in Denmark and identify all of the cases where somebody adopted had wound up with schizophrenia, and then able to go back and see who the biological parents and the adoptive parents were. Was a staggeringly large study. He and a team of psychiatrists spent years in Denmark doing this, because one of the things they did was they then did follow-ups. And they themselves interviewed all of the potentially schizophrenic individuals on there, so that they would have the same diagnostic standards all across the board. As we'll see in the schizophrenia lecture, it's a very squishy diagnosis. So having the same psychiatrists interviewing every possible person, hugely important control. This is part of what took them years and years. And then they finally were able to say what the patterns of similarity were. And here's what they wound up saying. You take any random person on the street who is schizophrenic, and you take any other random person off the street, and you ask what are the odds that the second person shares this trait with the first person? About 1% likelihood. What's that another way of stating? In the population as a whole, there's about a 1% incidence of schizophrenia. So you start with the circumstance where the biological parents, neither of them had schizophrenia, and neither of the adoptive parents do. And what's the incidence in this population among adoptees? A 1% schizophrenia rate. That's just average people off the street. That's the usual rate across Western European population. So 1% rate. Now, let's have the person growing up in a different sort of household. This is a person who has no biological legacy of schizophrenia, but was brought up in an adoptive household with a schizophrenic parent. And what you saw then was a 3% chance, which, with this enormous sample size, was a highly significant, reliable number. So in a rough kind of way, being raised in a household with an adoptive parent who is schizophrenic approximately triples your risk of a schizophrenia diagnosis. But then, the really critical one, which is you were raised in a household where neither parent, adoptive parent, is schizophrenic, but you have a biological legacy among your biological parents of schizophrenia. What do you see? A 9% incidence. Approximately a three-fold increase above that, almost a 10-fold difference now over what you see in the general population. This one number was what roared through the field. This was viewed as the clearest evidence to date for a genetic component to a psychiatric disorder. Regular old person off the street, 1% rate. Have a biological parent with schizophrenia and share no environment with them, because you got adopted away, and almost 10-fold higher chance of getting the disease. Then, final thing, looking at the incredibly rare people who got screwed on more different fronts than you can imagine, who had a biological parent with schizophrenia, and phew, got out of there, and landed in an adoptive household with a schizophrenic parent. [LAUGHTER] So you get the double whammy there. And what you saw was a 17% incidence. What's interesting about that number? OK, what this cell does, what this number does, is reflect the increased risk by having a biological legacy of schizophrenia, plus the increased risk of having an adoptive environmental legacy of schizophrenia. So let's see. What's the difference between 1 and 3? That's 2. So the difference between 1 and 9, that's 8. So thus, it should be about 10 percentage points. It should be about a 10% rate. What are you seeing here? A synergism. Get yourself a biological legacy and get yourself a schizophrenia household to grow up in, and it is not just adding the two degrees of risk. There was a synergism, a non-additive synergism. That is an important hint for us of stuff to come. So this was this landmark study. This was phenomenally difficult to have pulled off. It got Kety a number of Nobel Prize nominations. This was the study that showed the first definitive modern science evidence for a heritable basis to a psychiatric disorder. And this became the gold standard for how to do behavioral genetic studies. And in the aftermath of that, people began to do adoptive studies on heritability between biological and adoptive households, heritability of depression, heritability of alcoholism, heritability of criminality. And you can see heading off in all sorts of interesting directions from there all sorts of interesting ones, and them always producing a number that would be higher in this cell of the matrix than that cell, and always producing the notion that one has just shown a strong genetic component to whatever that trait is. That trait-- IQ. That trait-- criminal behavior. That trait-- alcoholism. These were some very loaded studies, in terms of the implications. So what is the problem with that approach? A number of problems. The first one is that, under the best of circumstances-- best of circumstances, best of circumstances for people trying to publish papers out of this-- under the cleanest of circumstances, the individuals in the study were adopted away, were taken from the biological parents, a quarter of a second after being born. No postnatal shared environment whatsoever. What one knows, of course, is that's not the case with adoption. And there's varying amounts of lag time before it occurs. And they were never able to factor that into the analyses. OK, so environment-- so you've got two and a half days worth of environment with your biological parents at the beginning there. OK, so that's a confound "give me a break, though." Just a couple of days, that's going to explain differences like these? What, of course, is also linking around in there is the huge, whopping topic of prenatal affects, prenatal environment shared with mom. And we're about to see in a little while some absolutely astonishing realms in which prenatal environment has very long-term effects. OK, so that's a huge confound. So how could you control for that? You see a trait that an individual shares in common with a biological parent, despite being adopted away a second after birth, all of that. And thus, you can infer there's a biological, there's a genetic component to this trait. Uh-oh. Wait a second. Shared environment with the mother, that may explain some of the shared traits. How do you get by that then? The difference in the likelihood of sharing a biological trait, a trait with a biological mother, versus a biological father, is the measure then of the prenatal effect. If a trait is shared 10% with the biological father and 17% with the biological mother, the 7% is attributable to prenatal effects. That was the general conclusion that the field made at that point for dealing with this irksome little problem, this pesky little thing of prenatal environment, which is going to come back big time in a few minutes. That was how they were distinguished. So some more problems with that approach. One is one that absolutely tortures behavior geneticists the world over, one which makes them just want to have people being inbred strains where they could keep them in cages and keep track of them. The problem being that, often, the guy saying he's the father ain't actually the father. Oh, issues of paternity uncertainty. That sure screws up your genetic studies, if you're trying to attribute stuff to someone who turns out not to be related. Very much higher rates than the people at Reader's Digest would have you believe, the rate at which the person claiming to be the father is not actually the biological father. OK, that's a bummer. That makes things more complicated. One other big confound in the adoption approach. And this was something that was emphasized by a guy at Princeton, Leon Kamin, a psychologist there, doing a very good job of showing that adoptive family placements were non-random. When a child is adopted, you don't sit there and close your eyes and spin the globe and put your finger down in some place, and two minutes later this kid born in, like, Shaker Heights, is running around with some camel herders in Rajasthan. This is not done. It is not random placement. Instead, what is a policy in virtually every adoptive agency in this country is to try to match the kids, as much as possible, along a number of different domains. In other words, you are also sharing a lot of biology with the adoptive parents. And that completely screws up the analyses. Adoption is non-random, how it is done. One does not just spin the globe. And instead, there are very intentional attempts to try to match for certain traits, traits which have genetic influences on them. OK. So that's a big problem. So the adoptive approach had tons and tons of interesting findings, enormously influential. But over the years, people have realized, more and more, prenatal effects, paternity uncertainty. And from day one, being pointed out that adoptive parents have higher than random rates of shared genes with the adoptees, in most cases, in this country. OK. So what becomes the next approach? And this one wound up being the gold standard, the high watermark, of how to do behavior genetics. Behavior geneticists who are able to do this sort of study, the rest of the behavior geneticists hate them, because they've got the best toys out there to play with. And they've got the coolest things going. And they're always snotty, because they've got the best possible circumstance, the most perfect thing you can imagine, which is identical twins separated at birth. Whoa. That must be one hell of an experiment to have pulled off, identical twins separated at birth. It turns out, every now and then, a pair of identical twins are adopted very soon after birth where each one is adopted into a different household. Perfect. Perfect. Different environments, different households, identical genes, you could not possibly ask for something better than that. People, like, wet their pants when the identical twins separated at birth paradigm burst on the scene. This was so wonderful. People wrote poems about identical twins separated at birth, sonnets. It was the best. It was so informative, because look at the power of this approach. This is an incredibly powerful approach. The two individuals are raised in different environments, but they've got the exact same genes. So the question becomes, where are you going to find identical twins separated at birth? And there's one obsessive geneticist, behavior geneticist, University of Minnesota, Tom Bouchard, has done an entire career not only studying these folks, but God knows how he finds these people. But he first started publishing when he had 40 pairs of identical twins separated at birth re-united in adulthood. And that made for some incredible, bizarre, heartwarming stories of discovering your long-lost identical sibling and produced a mountain's worth of data. It was a bizarre literature from day one. First one being, that you would get the perfect case there. And what these guys would be reporting in the literature was totally nutty stuff. OK, so you've got one of these pairs of identical twins. And they're born. And Wolfie winds up being raised in Uruguay by neo-Nazis. And Shmuel gets raised in Israel by his highly orthodox whatevers. [LAUGHTER] And then, as a result of a game show quirk of fate, they're suddenly brought back together. And there is Wolfie and Shmuel, who are identical twins. And what do they report? The most amazing thing they have in common, they both flush the toilet both before and after they go to the toilet. [LAUGHTER] You think I'm being facetious. Go back to that literature when that first came out and the coverage in the press. And it would be things like, Wolfie and Shmuel, they both have, like, a poodle named Fluffy. And the flushing the toilet before and after going to the bathroom, that was one of the landmark early findings of these studies. They would find twins that would do that. They would find twins who were both married to somebody named Congolia, or something. [LAUGHTER] And they'd, oh, my god. This is totally amazing. That was what hit the pages, initially, these obscure, little, bizarre similarities within a backdrop of, well, what's the data actually showing? And what's by now a twin registry of probably a couple of hundreds sets of these twins-- and this has become the cottage industry of the best behavior genetics around-- what has come out of that literature is the most solid, reliable findings is about 50% heritability of IQ. About 50% heritability of where you are on the introversion, extroversion scale, and about 50% heritability for degree of aggression. That's kind of interesting. And what we will see is there's all sorts of problems with this approach as well. First one being, starting right off, back to that Kamin guy from Princeton, his critique-- turns out there were not a whole lot of Wolfies and Shmuels. Even though they got adopted into different families, there again was the non-random placement in families, more similar environments than one would have anticipated purely by chance. So that is a confound. OK, so what's the solution for that one? I know. Let's look at monozygotic twins separated at birth and reunited on Oprah at age 50, and then look at dizygotic twins separated at birth and reunited after the commercial break on Oprah, and see what similarities are. And if you see more things in common with the monozygotics, rather than the dizygotics, you've just controlled for the non-random placement in the adoptive homes. The extent to which the monozygotics have traits more in common than the dizygotics, that reflects the identical genes. That was the interpretation. That was a very powerful sort of analysis, one that, nonetheless, winds up being very limited. Because in this case, because of tiny sample size, it's really hard to have done those studies. What's another feature of the whole behavior genetics approach? Here's another one. If you see traits that occur, behavioral traits, in the absence of any learning, in the absence of any environmental experience, in the absence of anything that can count as being non-genetic, if you see that, you're looking at a genetic influence. And what are the examples that are always given? The fact that all babies all over the universe start smiling, and they use the exact same set of muscles. And they always start smiling socially around, roughly, the same age. And what you also see-- I don't want to know how these were done-- but these classic photographs that you can get filming of kids in utero-- I don't know what fiber optic something or other was doing that-- but the demonstration that fetuses smile. Fetuses smile during the third trimester. This is a motoric pattern that is shared among all humans. OK. Well, social smiling, you see the flaw there, which is that is very subject to shaping of behavior. You are three months old, and you're watching all this social smiling going on around you, and how the mannequins they have at home are nowhere near as interesting as the animated faces there. And you sort of try it out yourself. What you see it's the exact same developmental time course for smiling among congenitally blind babies, babies who never see anybody smiling. So you see the motor pattern here being something that is arguably fairly universal and occurring in the absence of any sort of training, how you go about smiling. The other example that's always used is with congenitally deaf babies. And what you get there is another universal, which is beginning to babble at the exact same age that hearing kids begin to babble, and the same argument being made there. Of course, you have a very uphill task there of ruling out any environmental similarities. Because once again, once again, an area that has been utterly under-appreciated in this whole field is the whole world of prenatal environmental effects. And the theme that's going to come out of that is environment does not begin at birth. And some environmental effects prenatally are enormously influential forever after. And if you showed up on the scene one second after that individual was born, all of the tools of modern behavior genetics would tell you that you were looking at a genetic trait, where it is one instead that was brought about by the prenatal environment. OK, let's take a five-minute break, and then we will pick up on that. --good ones. First one being going back to that gender difference business, the assumption running through the field that, OK, boys and girls are raised in the same environment by their parents. And the only thing that differs is the genes. Like even those people, behavior geneticists, believe that could be the case. No, they recognized this was a very limited approach, and thus would limit themselves to circumstances like the first hour of post-natal life, which we already saw is a flawed assumption, or under circumstances where everybody's had the same number of math problems to take in their first 12 years of life. And we see the problem with that. Nonetheless, there was the recognition that that was a very limited set of tools for getting at these issues. The other useful thing that was brought up was somebody pointing out that, in the extended notes for behavior genetics, in the second paragraph, somewhere in there, about the fourth or fifth line, is the very clearly typed out word, "unable." And pointing out that, actually, the word was supposed to be "able." So you might want to take a look at that and kind of keep that one in mind. OK, perhaps I should take a look at it also. Moving on. Moving on now to this business, all of the approaches we've been seeing about comparing monozygotic with dizygotic. By the way, with the identical twins, 2/3 of them have monochorionic. 1/3 are split. And how many of you who are identical twins absolutely know in your heart of heart right now whether you were a monochorionic or bichorionic twin? OK. Well, that didn't work very well. OK. So pushing on. What we see here is, with all of these approaches, the adoption, the twins separated at birth, the twins, mono versus dizygotic, et cetera, et cetera, all of those were predicated on one simple assumption, which is, environment begins at birth. And that has been completely destroyed in some incredibly interesting ways in recent years. We have very vibrant literature at this point. First way that it can go down, which is your prenatal environment. What are you having as a prenatal environment? Who are you sharing environment with? Obviously, with your mother. You are sharing blood. You are sharing blood, and thus the things that she is experiencing in the world around her that make for a different environment than the person standing next to her gets translated into effects on the fetus. First domain, hormonal ones. Here's one example of something that you will wind up seeing. This was worked on by a guy named, Fred Vom Saal, at University of Missouri. And what he did was look at the fact that rats give birth to litters of about a dozen kids at a time. And there's some circulatory system thing. They look like a whole necklace of fetuses there. And the circulatory system is such that everybody's getting blood, but you're getting preferentially the blood that is from the siblings right around you. There's some sort of looping thing that occurs with the blood system that looks just like that. And what you wind up getting is you have a particularly shared blood environment with the siblings on either side of you. And what he asked was something very simple. You are a female rat fetus. And in one case, you're sitting there with brothers on each side. In another case, one brother and one sister, or in the final case, obviously, with two sisters on either side. And what you wind up getting is a different hormonal environment. How does that translate out later? The more male siblings you have around you as a fetus, the later you're going to reach puberty. That's interesting, suggesting that very local endocrine effects here play out in something like that. Also, it predicts how estrogen levels are going to drop in you later in life. So this winds up being one very interesting prenatal environment. Here's another one. Here we have, in humans, the age of one's mother when she gave birth-- and extrapolating a little bit here at both ends, but just assume this is kind of the age range. And what we see here is the age of puberty onset in the offspring. And what is seen is very young mothers and very old mothers have offspring who reach puberty later than women in a more intermediate age. What does that appear to be due to? Differing estrogen levels. Higher levels of estrogen at this point in life-- it's actually not symmetrical. It's skewed a little bit this way-- and that seems to be the driving force on it. Whoa. The age at which you reach puberty has to do with how old the fetal sack was that you hung out for nine months? That has an influence? Absolutely. So prenatal effects. More. Another version of it. Suppose now the hormone you're getting inundated with through the bloodstream is a stress hormone. A stress hormone-- glucocorticoids, we will learn all about those down the line-- a stress hormone, because mom is stressed. What are some of the consequences? For the same prenatal stress, as an adult, you will have a smaller brain-- if you're a rat. You will have a thinner cortex. You will have less learning abilities. You will be more prone towards anxiety. You will have fewer of those benzodiazepine receptors that we heard about the other day. You will have more of a cognitive decline when you are a doddering old rat. All sorts of stuff will go differently throughout your entire life. But get this. OK, look at this mechanism. So you are a rat. And your mother was stressed when you were a fetus back when. And you were marinated in those glucocorticoids when you were a fetus. Your brain, overall, will be smaller. There's one particular brain region, which I won't mention right now because it's not really critical, there's one brain region that's particularly hard hit. What does that brain region do? Among other things, it helps to turn off the stress response. So if that part of the brain is smaller, you're not as good at blocking glucocorticoid secretion at the end of stress. And somebody with a normal-sized whatever, something stressful occurs, and they recover. And you do this instead. Because this mysterious part of the brain is smaller, is not giving as much of a negative feedback signal. And for people new to endocrinology, that's something you'll be getting in a couple weeks. The net result is, if this part of the brain is smaller, you will have more lifetime exposure to glucocorticoids. So what happens next? What happens next, in addition, baseline is also elevated in these individuals. So the net result is a lot more cumulative exposure. So you are a female rat. And you were in a mother who was stressed prenatally when you were a fetus. And as a result, in addition to all the other problems that you've got lifelong, you secrete higher than expected glucocorticoid levels. And eventually, you get pregnant. And thus, your fetus is going to be exposed to elevated glucocorticoid levels and will be born with a somewhat smaller brain, thinner cortex, et cetera, et cetera. What have we just shown? An environmental manipulation on a pregnant female manifesting itself two generations later in the grandchildren. And when this was first described in the early '60s, this was called the grandmother effect. And eventually, it was shown to go out about four or five generations. The magnitude the effect would get smaller with each generation, before it disappeared. But look at what this is about. This is inheriting a trait that is not genetic. And this wound up being the first example of what is now called, non-Mendelian inheritance of traits, non-genetic inheritance of traits. And all you've got going here is prenatal environment. Extremely powerful observation. And what you also then have is, your some researcher, and again, you come along one second after the animal is born. And you wind up studying, saying oh, look at this. This rat tends to have elevated glucocorticoid levels, just like mom. And this rat tends to have a thinner cortex, just like mom. And this rat-- and if you've never heard of prenatal environmental effects, what's the only conclusion you could make? There are genetic influences on these traits. So these non-Mendelian, non-genetic transmission of traits are really, really important. Next thing. What else is floating around in mom's bloodstream that gets shared, besides hormones? Nutrients. Nutrients. And this winds up producing something extremely interesting as well. OK, it's all a blur by now. Have we already talked about Dutch Hunger Winter? It was in the video we watched while you were gone. Oh. [BLOWS RASPBERRY] OK. [LAUGHTER] Well, now that you all know about-- what did I say? That was only like 100 people, though. OK. OK, for those of you who didn't-- Dutch Hunger Winter, here's the deal. If you were a fetus in Holland during the winter of 1944, something very interesting happened with you. 1944, Holland is still occupied by the Nazis. Nazis are being pressured on all fronts. In the process of losing, they're falling back. They're losing a lot of the land they've occupied. And what they decide to do that winter is, because they need some food and because they wanted to punish the Dutch for beginning to be more openly in the resistance, what they did was, that winter, they diverted all of the food in Holland to Germany. And historically known as the Dutch Hunger Winter. Essentially, people went from a perfectly fine, healthy-- amid the context of a war-- Western-European diet, down to something like that from out of nowhere. 40,000 people starved to death during the Dutch Hunger Winter. Something very interesting occurred, if you were a third-trimester fetus, during the Dutch Hunger Winter, because it only lasted for the winter. The Allies came in, liberated Holland after that. And it went to something like this, something resembling a step function of starvation for about three months. If you were third-trimester fetus during the Dutch Hunger Winter, your body learned something important, which is here is not a whole lot of calories out there. During third trimester, fetuses are in some way-- and this is metaphorical-- deciding, learning how much, in the way of nutrients out there in the world, how readily do calories come in? How is the fetus finding out? By way of mom's circulation. Mom is starving. And thus, much lower levels of nutrients in the bloodstream. And the fetus, at that point in development, is saying, metaphorically, well, what's it like out there in this place I'm going to be heading to rather soon? What's the nutritional profile like? There's not much in the way of food out there. And as a result, the fetus has-- and the term used now is "metabolic programming." There is metabolic programming, or metabolic imprinting-- notice the word "imprinting" here being used in a completely different sense than we've heard about already-- metabolic programming to produce what is called a thrifty phenotype. The fetus, realizing there is nothing out there in the way of plentiful food, what it does is it programs its pancreas to function in a certain way forever after. What does the pancreas do? The smallest smidgen of food hits the bloodstream, and the pancreas is pumping out insulin, which helps store all that stuff and quickly scarf up every bit of nutrient in the bloodstream and store it away, because you've got to be as efficient as possible. And you've metabolically programmed your kidneys, so that your kidneys are incredibly good at retaining salt. Because along with starvation, there's going to be salt shortages. So really hold on to salt. And you are born with a body with a thrifty metabolism, very good at retaining salt, and spectacular at storing away every bit of nutrients that hits the bloodstream. So at that point, you go back to this sort of diet. And you have that for the rest of your life. And what has now been shown with the Dutch Hunger Winter individuals, the ones who were third-trimester fetuses then, as adults, they have a 19-fold increased incidence of obesity, hypertension, diabetes, and what's called metabolic syndrome. What's that about? Their body has programmed to be extremely thrifty with metabolism. And as such, it is forever after storing away every of the grotesque Westernized diets that we all wallow in. And what you've got then is setting individuals up for a much, much higher risk of these metabolic disorders. If you were a newborn at the time, it didn't happen. A newborn during here, the metabolic programming is already over by then. If you were a first-trimester fetus, didn't happen. The metabolic programming hasn't started yet. Second, the later part or second to third trimester is when the programming goes on. And this was a landmark observation. This was really important. Among other things, you get the people who do not like the notion of these subtle effects. And they're saying, OK, sure. This can happen, but this is subtle. 19-fold is not subtle. And this was the landmark study that ushered in what is now called a whole field of fetal origins of adult disease. Fetal origins of adult disease, which a lot of realms of medicine think is outrageous and couldn't possibly work this way. And it is popping up in more and more domains. Elevated levels of stress hormones during fetal life, increased likelihood of anxiety disorders as an adult, independent of post-natal environment. Other examples like that, all of these being ones of programming around that time. And the Dutch Hunger Winter one is the iconic example. You know, what we're all accustomed to is yeah, you study something in, like, a planaria. And then you study it in a rat. And you study it in a monkey. And then you study it in a college freshman. And finally, when it's-- now, you can conclude something maybe, maybe about humans. This was first discovered in this population of humans. This was no, is this relevant to humans. Interestingly, there was another population at the time that went through something or other like that, which was people in the city of Stalingrad who were under siege by the Nazis and had essentially years worth of severe starvation. They didn't get a Dutch Hunger Winter phenomenon, because the food coasted off like this. And afterward, it took years for it to reach a Western-European average. You don't get it under those circumstances. It's a step function like this. OK. So think about this now. So you were a Dutch Hunger Winter fetus. And as a result, you have a very thrifty metabolism. And 30 years later, you've gotten pregnant. You're having a perfectly normal diet, normal intake of calories. But you've got this thrifty metabolism. And as a result, your body is really good at pulling nutrients out of the bloodstream, because you secrete more insulin than most people would. With your thrifty metabolism, you are pulling a disproportionate share of the calories out of the bloodstream. And thus, your fetus is getting a disproportionately smaller amount of calories. And thus, your fetus is born with a milder version of the Dutch Hunger Winter phenomenon. And this has now been shown in the grandchildren of Dutch Hunger Winter fetuses. This is that exact same deal. This is non-Mendelian, non-genetic transmission of traits, multigenerationally. Absolutely astonishing that this could work. And the biology is all in place for it. What we will see in a little while is what the mechanism is, and it's been identified down to the molecular level of what went on in these Dutch Hunger Winter-- OK, I'll give it away. Remember that epigenetic business the other day? There are epigenetic changes in the gene's coding for things related to insulin in the Dutch Hunger Winter babies. So enormous effect. Another example of it, another dietary one, which is, if you are female-- and female human, among other species, this has been shown in-- there's an issue of how much estrogen does your mother consume when you were a fetus. Where's estrogen coming from in the diet? From a lot of different types of plants, phytoestrogens. And what the studies show is that increased exposure to estrogen derived from phytoestrogens during fetal life, and there is a small but consistent increased risk of estrogen-dependent breast cancer, 20 years later, 90 years later. Again, very subtle prenatal environmental effects playing out forever, even unto the generations after you. Another realm of prenatal effects, learning. OK, this sounds ludicrous right off the bat, that you can have learning prenatally. You have learning prenatally. You can show this first in rats. Here's what you do. You take a rat fetus, and you can inject into it a particular flavor of water along with sucrose. And the fetus absorbs it. The fetus actually drinks amniotic fluid, which I find to be deeply creepy. But nonetheless, you inject this stuff in there. And you are doing this a number of days running. And this fetus is now drinking this flavor that has a lot of sucrose in it. It tastes good. It tastes good? You're a fetus. What do you mean, it tastes good? The fetus learns about it. Because after birth, given a choice between two neutral flavors, it will prefer the flavor it was exposed to that it was drinking when it was a fetus. How weird is that? More ones-- more ones? OK, that was good grammar. More ones. Here's one from humans. And this was a study, which is as strange as you can get, looking at the fact that the diaphragm is a very good resonating membrane, something or other. Mother's voices are heard in the fetal sack quite readily. And if I don't know how they got the fiber-optic camera in there, I have no idea how they got the microphones in there for recording that. But it is a very resonant chamber, the diaphragm and the amniotic fluid. Fetuses hear a lot of what's going on out there, most notably mom's voice. So this was a study, a totally inspired one. And what you had was, in this one, pregnant women spent their last trimester loudly reading either The Cat in the Hat over and over, like four times a day or something, until they went mad, absolutely mad-- and that's before the kid was even born-- or reading some random collection of sentences that controlled for word length, that controlled for rhythmicity, all of that. Then, you get the newborn some time later, and you give them a test of which they prefer to listen to. How do you do that with a newborn? Something you can do is, when newborns like something, they make more sucking motions with their mouth. So you've got a sucko-meter thing in there measuring it. And the newborns prefer hearing The Cat in the Hat. They learned it. Not a huge effect, but nonetheless, what is up with that? Of course, a follow-up question that maybe half the people in here would be wondering is, well, what about the fathers? And they have the study with the fathers reading Cat In The Hat and, you know, like a megaphone on mom's belly and reading. And it doesn't work. It doesn't resonate enough that side. Sounds from the mother. OK, so what we see here is this whole world of stuff going on before behavior geneticists show up and say, environment is just started. All these prenatal effects of hormones, nutrition, sensory stimulation, amazing, in some cases, multigenerational. Yeah? Did they catch up with those children later, The Cat in the Hat children, and see if they had a tendency to rhyme more? [LAUGHTER] Where are they now? Remarkably, all of them are heads of states of countries. [LAUGHTER] People are still trying to understand that one. But very good follow-ups on that. So we've got this punch line here, over and over, showing the power of prenatal effects. One final study. And this was one carried out by a scientist at Berkeley named, Darlene Francis, which took some amazing surgical skills. So there are different strains of rats that have been bred for different levels of anxiety. And we've already heard about one possibility for that. It turns out some genetic differences in the promoter to the gene for the benzodiazepine receptor. There's all sorts of strains that have been bred for high, low levels of anxiety that people have studied. They've been bred. These are transmissible traits. These are heritable, these are genetic traits. Here's what Darlene Francis did, which was she did an adoption study. What's the adoption paradigm we've heard already? Right after birth, you cross-foster the rats, or the kids get adopted. That's not the adoption study she did. She transferred fetuses. She figured out how to do the surgery to remove a fetus early on in development from one rat mom to another rat mom where they developed perfectly normally, once she had this surgery down. And you know what turns out to be the case? It's not a genetic trait. It was not a genetic trait. You grew up with the anxiety levels matching the strain of your mother, even if the strain of the individual whose body you fetally developed in-- you take a mom from the high anxiety strain, and you take a mom from the low anxiety strain. And you take fetuses from the high anxiety mom, and they go through gestation in the low anxiety mom. And as adults, they are low anxiety. It was not a genetic trait, it was a prenatal one having to do with another one of those multigenerational begatting by having early experience influencing the nature of the pregnancy you would eventually have, and thus, influencing your fetus, producing a different pregnancy for them down the line. This demonstration of cross-fostering, of adopting, as early as you possibly could, enormously important study. One really difficult one. Yet another wave pounding on this point, environment does not begin at birth. And some of the most important environment is not occurring starting at birth. And everything about behavior genetics, classically, was predicated on there's no environment before that. OK, so what do they come back with? What's the response? We've already seen a possible way of controlling for that, which is, if you see traits shared in common with the biological father, and then you see more traits shared in common with the biological mother, the increased degree of sharedness with the mom reflects, not the genes, because you're getting the same amount of genes from each parent. It reflects the prenatal environment. That would be the control that would be used in these studies. The extent to which a trait is more shared with a biological mother than with a biological father is a reflection of prenatal effects, because you get the same amount of genes from each parent. Naturally, this turns out to be vastly messier than this. Because there's a whole world in which you're getting more genetic influences from your mother than from your father. OK. First one is, once again, if it turns out the person who's claiming to be the father isn't actually the father, that kind of changes the whole map. And once again, that is a problem running through all of human behavior genetics literature. But here, here's the next one. Here, we have-- just make sure we've got our cliche in place here-- what is this? This is the-- OK, which is the what of the cell? Powerhouse, The powerhouse. OK, here we have the powerhouse of the cell, mitochondria. And in this rather odd cell, there's one mitochondrion, but it is standing in for all of the powerhouses. And we've got mitochondria. Something that, when you first learn about this, is just flabbergasting, which is, here you've got a cell with its DNA, and its nucleus, and its double helix thingy happening there. And it turns out that mitochondria have their own DNA. And this is part of explaining one of the, like, truly amazing, adventurous, nutty ideas that have turned out to be true. Scientist, named Lynn Margulis, University of Massachusetts, 30 years ago or so, she noted that this business of mitochondria having their own DNA, and came up with this hypothesis that mitochondria used to be independent organisms. That in some symbiotic whatever, billions of years ago, got into cells that had no mitochrondia at the time, and that there's been a symbiosis ever since. Mitochondria have DNA, which are related to mitochondrial function. Not a ton of the stuff, nonetheless, you have every gene that is critical for mitochondrial function. No, that's not true. A few of them have wound up in here. But all of the genes in here are pretty important for mitochondrial powerhousing, all that sort of thing. And these are derived from a completely different world of DNA than these. So now consider this. This cell is an egg. This cell is not an egg. This cell is just merely carrying genetic information that looks like that. What you've got is sperm, all they are carrying are the DNAs, the genes, the DNA. And they don't have cytoplasm, the fluid-y environment in a cell. This is one major dense packing job. Here's the critical implication. Eggs have mitochondria, sperm don't. So right at the point of fertilization, you have gotten all of your mitochondria from your mother. And thus, all of the genes related to mitochondrial function that are contained in the mitochondria you don't get from fathers. It is exclusively inherited from mothers. Mitochondrial DNA solely comes from the mother. So what we've just seen as a first pass is it's not an even 50/50 split. You get a disproportionate share of your DNA coming from the mother. Really important. And one that's been used by all sorts of evolutionary geneticists to trace legacies. If these mitochondrial DNA is only passed along female lines, that allows you to figure out all sorts of stuff about evolution. It has given rise to the Eve hypothesis, that somewhere back then was a woman, probably some sort of early hominid, who is ultimately the ancestor, the great, great, great, great, great, grandmother of every single human on Earth. And it can be traced through the mitochondrial DNA. So that's an asymmetry. Next one. Next source of asymmetry is back to that business about imprinted genes. From a couple of weeks ago, you remember that one, genes that are working differently, depending on which parent you are getting them from. So that one's a violation as well of this rule that you get all of your DNA in equal amounts from each parent. This is another thing that possibly skews the ratio. Now, here's another very interesting thing. So you've got the egg here. And not only does it have this cytoplasm with mitochondria floating around, but in addition, there's other stuff floating around in there, like transcription factors. Sperm don't have transcription factors. Sperm, all they're doing is on this, like, suicide swimming mission there. And they're not making any new genes. All they're doing is this one, long spurt of racing for the end. And in the case of the eggs, though, you have transcription factors. You have all sorts of proteins in the cytoplasm. You've got a fully functioning cell, instead of this, sort of, much more streamlined version. All the transcription factors that come in a fertilized egg are coming from the mother. So what does that wind up meaning? Transcription factors, those are proteins. We're not talking about genes here. We just saw how you get more genes from your mother than your father, these mitochondrial genes. OK, but transcription factors, the father has genes for transcription factors. The mother has genes for transcription factors. What's the significance of getting your transcription factors from your mother in the fertilized egg? OK. Consider here two genes. The first one codes for transcription factor A. We know that already. Transcription factors are typically proteins, so they have their own genes all the way down. And this codes for gene X, whatever that is. So here's what you've got. There are promoters responsive to transcription factor A. Transcription factor A turns on the synthesis of the protein coded for by gene X. And in addition, transcription factor A turns on transcription factor A gene. It's a positive feedback loop where it makes more and more of the stuff. That's the way this particular transcription factor works. So suppose this is the only thing that can activate transcription of gene X. So suppose you've got some environmental event which, as a result of it, knocks out the activity of transcription factor X in an egg. The egg is fertilized. And as a result of transcription factor A not being expressed, it doesn't express more. This is the only thing that drives more expression. And you never make gene X. Now, somewhere along the line in your body, you are soon making eggs which contain these genes, of course, but where you have never expressed transcription factor A, because this was knocked out in the egg. So because of that, you never express gene X. And that egg gets fertilized. And you pass on that trait to your offspring. You pass that on, this acquired trait of transcription factor A not working. If this is the circuitry that you have, it doesn't matter which version of gene X you get, you are never going to express that gene for generations and generations, forever, if this is the loop. What's going on here, what a lot of people think is relevant, are some environmental toxins that are known to disrupt the activity of certain transcription factors. And what that does is induce heritability in a non-genetic way of non-expressing of a gene. The gene's being inherited, but it will never ever be expressed. What have you just acquired? A Lamarckian trait. You remember Lamarck. Everybody learns about Lamarck, in order to mock him viciously. And Lamarck had the notion that the way evolutionary change works, the way inheritance works, is you experience something, and it causes a change in your body. And as a result, you pass on that acquired trait to your offspring. Ludicrous. Lamarckians have been mocked and pilloried for centuries, except in the Soviet Union in the 1930s, where it gave rise to Lysenkoism, a very horrific piece of genetic history. But what you've got is this complete trashing of the notion of you acquire some trait from the environment, and you pass it on to your offspring. This is Lamarckian inheritance. This is an environmental factor that knocks this transcription factor out of action. And if this is the wiring that you've got, this gene will never be expressed. And as a result, it will never be expressed in your offspring, in your grandkids, et cetera, all the way down. This is Lamarckian inheritance of a trait. And again, where the best evidence for this has been is with environmental toxins that knock out, that have some of these mutating effects in eggs. They are not mutations in a classical DNA sense. But nonetheless, they are now heritable. So that pops up also. So have we got here? We have the simple assumption that, if you see more sharing of a trait with the mother than with the father, that's reflecting prenatal environment. And what we've seen here is totally messing this up is the fact that you do not get equal genetic influences from each parent. You are getting more genetic material, you are getting more genes from your mother, because the mitochondrial DNA. Even if you are getting equal amounts of DNA, expression of them will have different consequences because of imprinted genes. Finally, in this world, having nothing to do with the amount of genes or the actual DNA, you can have this Lamarckian inheritance of traits due to environmental perturbations. What we see here are ways ranging from extremely subtle and rare to some rather substantial ones with the mitochondria where you are not getting equivalent inheritance from both parents. So that confuses things a lot. OK. So after all of that, you do, nonetheless, get circumstances where behavior is influenced by genes. And by every rule, it could be shown. And by the most contemporary of techniques where people find the gene and the DNA, and they've traced out the steps in showing that there really are genetic influences on behavior, and ones that withstand every single one of these criticisms. OK. So sometimes, you've got genes regulating or genes influencing behavior. But now we bring in a whole other possibility. And this is something that was emphasized by a psychologist named, Judith Rich Harris, a number of years ago, in a very important book of hers, called The Nurture Assumption, which has a lot to do with arguing the relative importance of influences of peer versus parents. Nonetheless, she focused in one section of the book on the genetics of behavior and focused on what she calls indirect genetic effects. What would indirect genetic effects be? OK. You've got that trait that I referred to before, one of the most reliable of traits in the identical twins separated at birth business, 50% heritability of where you are on the introversion, extroversion continuum. OK. So that one has held up pretty well. Amid all the possible complaints about these various approaches, that one appears to be quite solid. And you're immediately off and running with, OK, genes for extroversion, for sociality, for all of that. What she shows instead is something else is happening. There's a very, very heritable trait from parent to offspring, one of the most heritable physical traits out there, which is your height and your appearance in general, that those are highly heritable traits. And suddenly, you have a phenomenon that is well-documented, which is people who are taller are treated better and considered more attractive, comma, he says bitterly. [LAUGHTER] What you've got is people are treated differently along those lines. And what is known also is, people who are treated more positively during development, during childhood, become more extroverted. What we have here is not heritability of the trait where you are in the introversion, extroversion continuum. What you have is heritability of a physical trait, which causes you to be treated differently in the world, which then brings about changes in personality. And studies have since shown that most of the heritability of the introversion, extroversion is mediated by physical traits in between. So that's a completely indirect way in which you could have gotten to this. More cases. More cases of this. Let's see. OK, you can show, in various bird, turkey, hen species, that there are chicks, that there is heritability of rank. You could be born to a low-ranking mom in the pecking order, high-ranking, all the perfect studies, and controls, and cross-fostering, all of that, and there is heritability of rank. But another indirect genetic effect that was subsequently demonstrated, which is it's not the rank that's being inherited, it's a particular version of genes related to melanism of your feathers, the color and iridescence of your feathers. And it turns out, if you have a certain color pattern, all the other like roosters, and chicks, and hens, and poultry, peck at you more often. And you're reduced to subordination. This is not inheritance of a social dominant trait or a social subordination trait. This is inheritance of a gene having to do with the color and iridescence of your feathers, which wind up producing your social rank. Another example. Here's another one. OK, back to chicks again, which is chicks appear to be intuitively able to peck at grubs shortly after birth. That they're able to peck down and get grubs. And by all the rules of behavior genetics, with all the constraints and criticisms answered, this appears to be a heritable trait. But it turns out that this is not what is heritable. What is heritable, bizarrely, is the tendency of newborn chicks to find their toes to be very interesting and to peck at their toes. And they quickly learn that this doesn't feel all that great. But if you do it in somewhat more sloppy of a way, you get one of these things that's squirmy that tastes good. They start off, what is genetic is the tendency to peck at your feet. God knows why. If you are a newborn chick, because of extremely elegant high technology studies in which newborn chicks are put in galoshes or something and they don't pack, and they don't show the seemingly innate ability to peck for grubs. So here, we have a behavioral trait which, in fact, is indirectly mediated by something else. More examples. There is, by now, a literature showing approximately 70% heritability-- and I keep using this word. We are going to dissect the word, "heritability" big time in a short while-- There's about 70% heritability of political party affiliation in this country. Sharing that behavioral trait with your parents. Whoa. What is that about? That's sure disturbing. And that sure makes you want to procreate in the name of your political stances, or whatever. And this appears to hold up pretty well to some of the standard criticisms in the literature. And it's got nothing to do with this. What's the mediating variable? A large really interesting literature showing, when you compare political or social progressives with political or social conservatives, one of the most reliable personality differences is how they feel about ambiguity. Conservatives, on the average do not like ambiguity. They are much more ambiguity-averse. And you can start it with showing ambiguous sensory stimuli in kids and looking at heart rate responses to it. And that tends to be a stable personality difference at political extremes. You will see, some time later on, that there's a whole world of moral development in kids where there's various scales measuring. One's Kohlberg's Stage of Moral Development. There was an old literature suggesting political differences as to how fancy of a Kohlberg stage you got to. We will see that, despite what struck me as the intuitive sort of logic of what was found. That one hasn't held up. But one that does hold up is difference in ambiguity tolerance. And that's probably the mediating trait. It is not inheriting a tendency to like elephants, or donkeys, or whatever. It is instead having this intermediate trait. Final example of what would be an intermediate trait. There's a whole bunch of rat and mouse strains that have been developed that have differing levels of aggression, high aggression strains. And you do all the proper controls, and you can show that this is a genetic trait. Whoa, heritability of aggression. We're suddenly back to twin adoption studies and Kety with heritability of criminality, all of that, heritability of aggression, what's actually going on in all of the strains identified to date by spontaneous traits coming up and then breeding for it. What you see instead is the strain that is so aggressive, and so pissy, and so impossible, and so constrained by the law and order of rodent society, and all of that. They've got a lower threshold for pain sensitivity. Things hurt them more readily. And they're more likely to become aggressive at that point. It turns out it's genetic differences in the neurobiology of pain sensitivity. So what we're seeing here, over and over is, amid the gazillion of criticisms we've had about when does environment actually start, and when do environmental assumptions and being treated the same go down the tubes, and differential inheritance of genes, yeah some traits do appear to have some fairly strong genetic components. But even once you get that far, they very often are through some very indirect routes. OK more things here. More things? We just covered that. OK, a little bit more on epigenetics, which is that whole business, you remember, from the other day, which is after you've got the DNA, and then you have that whole world of protein coatings, which I've been very careful not to give the jargony name for, because it's not important. But what you've got is this whole world where regulation is not so much at the level of genes-- and in 95% of the DNA, that's the on/off switches-- but whether the transcription factors can even get in there, and this world of epigenetic changes that will cause lifelong differences in how readily transcription factors get to something or other. What have you got at that point? The exact same possibilities as this one here. If instead of, due to some environmental toxin, you knock a transcription factor out of business in a fertilized egg where there's the set up of genes, if for some reason, whatever, you do not have access to it because of an epigenetic change, it's going to be the exact same consequence, multigenerational inheritance of non-genetic traits due to epigenetic, rather than genetic differences. That is turning out to be what went on in the Dutch Hunger Winter people and the animal models of epigenetic differences and access of transcription factors to genes related to insulin metabolism. That turns out to be a critical one. Here is one of the coolest examples of this to date. And this is work done by a guy at McGill University, named Michael Meaney. And what he has focused on is what started off as a very artificial literature, which is, take yourself a newborn rat, and for the first two weeks or so of its life, every day, you pick it up for three minutes and you pet it. And now, you put it back. And all else being equal, it will have a bigger brain in adulthood, better learning abilities, more resistance to a whole bunch of neurological insults, lower glucocorticoid levels, et cetera, that whole world of what came to be known as neonatal handling. On the other hand, pick up the rat, take it away from mom for, instead of 3 minutes, an hour and a half. Then each day, put him back. And as an adult, it's going to have a smaller brain and a shorter life expectancy. Three minutes away from mom does wonders. An hour and a half of being petted does not. That, in and of itself, is interesting in terms of what counts as stimulation, what counts as stress. OK, so hurray. What we've just learned is just how generations of rat-petting graduate students can influence the lineages of rat brains and all of that. And what Meanie started looking at with this phenomenon being one that was around forever-- first identified around 1960 by a guy named Seymour Levine in the Psychiatry Department here, and no longer alive-- but that started this whole world of neonatal handling. What Meanie did was say, well, rats did not evolve, whatever is going on here, for the purpose of doctoral theses, what's the natural equivalent in the world of a rodent? And it turns out that what happens when you pick up a rat for three minutes and do this and put it back, mom is all excited and goes and checks out the pup and nestles it, and licks it, and whatever other stuff there. And it has all this attention. Whereas, if you take the pup out for an hour and a half, when you put him back with mom, mom basically ignores the pup for long periods of time. You're changing the mother's behavior. OK, so that's an indirect effect. And what he proceeded to show was the critical thing about the handling was not what you're doing to the rat during that time, it's the fact that you're causing dramatic changes in maternal behavior based on that. So that's interesting. But that still doesn't solve the problem of why did the system evolve for grad students manipulating maternal behavior. And what he then proceeded to look at was normal variation in rat mothering styles, because some rat mothers are-- OK, I know this is a value judgement-- but some rat mothers are better mothers than other mothers. Some rat mothers, they simply are better. They're better. They're nicer they have better souls. [LAUGHTER] And in these rat mothers, how do you determine that by these sorts of measures? Licking and grooming. How much time do you spend licking your baby? And how much time do you spend grooming your baby? And what Meanie proceeded to show is that's what the neonatal handling phenomenon was about. When you have moms who lick and groom their kids an awful lot, what you do is produce the same sort of better outcome. From the three minutes of petting deal there, you get the kid who is bigger, and healthier, and smarter, that sort of thing. Moms who hardly ever lick and groom their pups, they produce pups that, as adults, are like the ones that were separated for an hour and a half a day. It is a reflection of mothering style in the rats and the variability there. Next thing he showed was that this was multigenerational. If you lick and groom your baby rat daughter a whole lot, as an adult, she will be more of a licker and groomer. And he's already shown what some of the neurological mechanisms are for that. For development, what have we got? Yet again, one of these non-Mendelian inheritance of traits deals going on. In this case, not even prenatal. Your early experience is going to cause lifelong changes in your brain, which will make you more likely to reproduce the same early experience for your offspring. Off you go. The final thing he did, which stands as a landmark in the field of behavioral neurobiology, is he figured out what the epigenetic change is. One of them, or rather two of them is identified by now, what gets changed by how mom often or un-often licks you, grooms you, all of that? You change the access of transcription factors relevant to activating genes for making receptors for stress hormones, making receptors for estrogen, making receptors for a whole bunch of different hormones. Showing the epigenetic changes there, that's how you go from moms differing maternal style to lifelong differences in expression of all sorts of genes. How's this? What you wind up seeing there as this permanent mechanism, it is also reversible, what he has since shown, which is you have a baby rat who spends the first half of its infancy with some totally terrible, negligent, distracted mom who pays no attention and doesn't do any licking. Now cross-foster the pup to a more attentive mother, and you can change the epigenetic pattern. So all of this has two themes going on. Early experience, causing really persistent differences in how this stuff works long after, and experience later on having the potential to reverse some of this. All of this stuff, once again, would be mistaken for genetic. What we have here is what appears to be a genetic style of what sort of mother rat you are. And it's not genes, it's the mothering style setting up the offspring for being a similar type of mother. Incredibly important studies demonstrating this. What remains unclear is how you get from mom licking you to something epigenetic happening here. His crew is pounding away at that. OK, so what have we got at this point? We have gone through over and over here-- where have we gotten to at this point? We've gone over and over here at all of the classical techniques in the field of behavior genetics, does it run in families, adoptive studies, identical versus monozygotic twins, twins separated at birth. We saw all of the problems with it. And most dramatically, most excitingly these days, prenatal environmental effects. We saw that trying to separate maternal prenatal effects from paternal genetic effects hits a wall, when you get all of these weird-o hereditary things, including potentially non-genetic Lamarckian inheritance of a trait. And what we've seen is how this stuff playing out early in life has multigenerational consequences. What we're going to pick up with on Wednesday is now looking at how people in this business find the actual genes, and ultimately, gene environment interactions that make the last two hours basically irrelevant. OK. For more, please visit us at stanford.edu.

Channel: Stanford

Views: 560,645

Rating: 4.8681107 out of 5

Keywords: Science, Interdisciplinary, Bioengineering, Genetic, Sociobiology, Darwin, Evolution, Sexual, Species, Natural Selection, Genetically Based Traits, Environment, John Hopkins Study, Heritability, Reproduce, Reproduction, Survive, Gene, Mutation, Trait, DNA

Id: e0WZx7lUOrY

Length: 98min 35sec (5915 seconds)

Published: Tue Feb 01 2011

Reddit Comments

[u/salsacaljente]

In this two part lecture Robert Sapolsky gives a rundown on how geneticist try to pin down behavioral tendencies to genes. And ultimately shows how hard this is in practise.

edit: pls dont miss part 2 its very important

Bonus meme: If you want a reliable navigator, who stirs you without any ideological baggage through the water of highly contested topics, Robert Sapolsky is the best memer.

[u/MuslimSJW]

Steven's gonna love him https://www.youtube.com/watch?v=SthfBxQ0vZ0

[u/BlutigeBaumwolle]

20 minutes in, this is so interesting, thanks for the link. Great professor.

e: he even does memes https://youtu.be/e0WZx7lUOrY?t=4238

[u/salsacaljente]

bonus meme: https://youtu.be/P388gUPSq_I?t=9m27s sapolsky is a god of storytelling in the classroom

[u/nablachez]

this one with jo hogan

https://www.youtube.com/watch?v=obmt_PkIfBE

[u/Option_Select]

Steven already did that with part of the lectures after the last time Ryan Faulk was on.

[u/Mentioned_Videos]

Other videos in this thread: Watch Playlist ▶

VIDEO	COMMENT
Why You Don't Have Free Will: Your Breakfast Food, Biology, and Culture Robert Sapolsky	+6 - Steven's gonna love him
6. Behavioral Genetics I	+2 - 20 minutes in, this is so interesting, thanks for the link. Great professor. e: he even does memes
Joe Rogan Experience #965 - Robert Sapolsky	+1 - this one with jo hogan
8. Recognizing Relatives	+1 - bonus meme: sapolsky is a god of storytelling in the classroom

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[u/atargo2]

pretty interesting lecture

[u/darkhindu]

watch the lectures read the book or listen to the book on tape