nd 2018) the Guardian published Last week (May 22018) the Guardian published a piece by me headlined “Why genetic IQ differences between ‘races’ are unlikely”. In it, I argued that the genetic architecture and evolutionary history of intelligence make it different from other traits and inherently unlikely to vary systematically for genetic reasons between large population groups.





Image credit: https://mashable.com/2013/04/02/obama-brain/#kwOQGJUunEqn

I was rather quickly (and, in some cases, rather aggressively) taken to task by a number of population geneticists on Twitter for being vague, overly general and hand-wavy, and for ignoring or not citing relevant papers in population genetics. Or indeed, for being flat out wrong. (See also a critique here ). Some of those criticisms may well be valid, but some reflect the limitations of writing a short piece for the general public, so I wanted to go into more detail here on my reasoning.





The other criticism was that I seemed to be making statements as if they were strong scientific claims or settled positions of the field when actually they were a series of arguments representing what I think about the issue. It wasn’t my intent to misrepresent my arguments as settled facts but I can certainly see how it reads like that, so I’ll have to plead guilty as charged on that one.





The reason I wrote the piece, for a newspaper in particular, is that there has been a lot of recent public debate about the issue of genetic differences in intelligence between ‘races’, which I felt suffered from an overly casual extrapolation from what we know about the genetics of other traits, especially physical ones. If we are going to talk about the genetics of intelligence, we should talk about the genetics of intelligence.





This is liable to get long (and technical in places, though maybe not enough for some people)…









Intelligence is a real thing and is really heritable





one thing, but I think it is probably everyone’s experience that some people are smarter (brighter, quicker, sharper, cleverer) than others and that such differences are apparent from an early age. To begin, there are a few general points to make. First of all, intelligence is a thing . It’s not easy to define precisely and it may not bething, but I think it is probably everyone’s experience that some people are smarter (brighter, quicker, sharper, cleverer) than others and that such differences are apparent from an early age.





There are scores of different definitions of intelligence, including things like : “ the abilities to learn from experience, adapt to new situations, understand and handle abstract concepts, and use knowledge to manipulate one's environment.” To my mind, it is the ability to form abstract concepts of things, types of things, relations between things, and higher-order relations in complex scenarios, and to apply those abstract concepts to solve problems in new situations that is the most crucial aspect of intelligence as a cognitive faculty and of intelligent behaviour.

predict, not just correlate with) a host of real-world outcomes that people care about, such as educational attainment, type of job, income, and even health and longevity. Second, IQ ( intelligence quotient ) tests do measure something real that relates to intelligence. Scores on IQ tests provide a very imperfect proxy of a complicated trait, and clearly over-simplify it to variation along a single dimension. But they give us – especially geneticists – something to work with. If we want to investigate the genetics of a trait, we need some way to measure it and IQ tests provide that. Even if they are imperfect, they are at least quite reliable, in that if the same person takes the test multiple times, the scores are highly correlated. And they seem to also have some validity, in the sense that IQ scores predict (really, not just correlate with) a host of real-world outcomes that people care about, such as educational attainment, type of job, income, and even health and longevity.





They’re not intended to sum up everything about a person’s cognitive abilities in a single number, as sometimes charged. They are simply a rough measure that proves useful as an experimental tool and for real-world predictions. That said, they are not without their biases, which becomes important when interpreting observed differences in IQ scores between people in different cultures.





Third, IQ scores really are heritable. If you measure IQ across any given population, you get the familiar bell-shaped curve or normal distribution. (With a little bump at the low end representing people with intellectual disability). That distribution can be described by the mean, or average value, and by the variance – how wide the bell is. Heritability measures how much of that variance is due to genetic differences between people. It can be estimated by flipping the idea around and asking whether people who are more genetically similar to each other are also more similar in intelligence.





It turns out they are, and twin and adoption studies have shown this is not due to being reared in the same family environment, but is really due to their shared genes. Newer methods confirm this using only very distantly related people across general population cohorts. These methods provide a convergent estimate of 50% for the heritability of the trait. That doesn’t mean 50% of your intelligence comes from your genes, however – it means around 50% of the variation that we see in the trait across the population is due to genetic variation. (In other words, if we were all clones, we’d all be a lot more similar to each other in intelligence).









Group differences in intelligence





Okay, now what has all this to do with ‘races’? (See here for more on the limitations of that term). People have been doing IQ tests in many countries across the world for nearly a century now. The results of those tests show lots of differences in the mean IQ scores between populations, at the level of countries and also at the higher level of continents. These are reflected, to a lesser degree, as differences in IQ scores between various ethnic groups within countries like the United States.





Given IQ is a partly heritable trait, the simple conclusion seems to be that the observed differences in mean IQ between different populations will also be partly attributable to genetic differences. This is a fallacy. Heritability measures the proportion of variance in a trait that can be attributed to genetic variation, within the particular population under study. It is not a stable or universal number, but can vary in different populations. In particular, if there is a lot of variation in environmental factors that affect a trait within a given population, then the heritability will be lower, because proportionally more of the variance in phenotype will be due to environmental variation.





This means that if two populations have considerable differences in relevant environmental factors between them, these could completely explain the observed difference in mean IQ, even if much of the variance within populations is due to genetic variation. (And we know there are huge differences between the populations in question in highly relevant factors like infant and maternal health, nutrition and education, for example).





necessarily imply they are driven by genetic differences, they conclude that genetic effects are “highly likely” to be at play (in addition to environmental ones). This point is widely acknowledged, even by proponents of genetic differences like Charles Murray and Richard Herrnstein, the authors of The Bell Curve . However, while conceding that the existence of mean differences between populations in IQ scores does notimply they are driven by genetic differences, they conclude that genetic effects are “highly likely” to be at play (in addition to environmental ones).





This sounds quite reasonable, on the face of it – the explanation is “probably a bit of both”. That position was given some support by geneticist David Reich in a recent Op-Ed piece in The New York Times. He stated:





“ … since all traits influenced by genetics are expected to differ across populations (because the frequencies of genetic variations are rarely exactly the same across populations), the genetic influences on behavior and cognition will differ across populations, too.”





He goes on to say that: “ You will sometimes hear that any biological differences among populations are likely to be small, because humans have diverged too recently from common ancestors for substantial differences to have arisen under the pressure of natural selection. This is not true. The ancestors of East Asians, Europeans, West Africans and Australians were, until recently, almost completely isolated from one another for 40,000 years or longer, which is more than sufficient time for the forces of evolution to work.”





expect there to be genetic differences affecting IQ (indeed, all traits) between populations that were genetically isolated from each other for long periods. The positions of Murray and Herrnstein (and of many other commentators like Sam Harris and Andrew Sullivan ), along with the statements of David Reich, thus state that we should, by default,genetic differences affecting IQ (indeed, all traits) between populations that were genetically isolated from each other for long periods.





Reich’s position is based on an explicit extrapolation from the genetics of physical traits to the genetics of intelligence and this is what I was addressing in my piece in the Guardian. What does the genetics of intelligence really tell us about how to calibrate these expectations?









Intelligence as a special trait





In the Guardian piece, I argued that intelligence is not like most other traits, because of its central role in our evolution:





“ Intelligence is our defining characteristic and our only real advantage over other animals. It gave us an initial leg-up in colonising diverse environments and its usefulness was massively amplified by the invention of culture and language. This increasing selective advantage of ever greater intelligence led to a snowball effect, which was probably only stopped by the limitations of the size of the birth canal and the metabolic demands of a large brain.”





Some people challenged me on that, offering a few other traits that may also have been crucial in our evolutionary success, such as standing upright, the ability to run long distances, and throwing skill, and I guess I would add manual dexterity myself. That’s all fine – it doesn’t really change any of the subsequent arguments.





I contend that intelligence has been more or less maximised over the course of evolution along the lineage leading to humans. That’s a pretty stark claim (the “more or less” is very important there!) and I’m sure will provoke howls of disagreement from some quarters as being essentially untestable or just wrong. To be more specific, what I mean is that intelligence appears to have been under strong directional selection throughout our evolution. Being smarter became advantageous, and, through the snowball effects referred to above, became more and more advantageous over time. So, natural selection progressively selected for greater and greater intelligence, up to a point where the costs became unsustainable.





This is in contrast to most traits, which are effectively optimised, not maximised. I used height as a comparison, but you can think of how thick our skin is, our blood pressure, levels of liver enzymes, how active our immune system is, etc., etc. It wasn’t good, over the course of our evolution, for any of these things to just keep increasing. They are set at a “just right” level, while I argue that intelligence is set at an “as much as you can bear” level. (With the costs including difficult or dangerous births of big-headed babies, extremely long periods of infant helplessness and consequent parental investment, and the energy needs of our metabolically greedy brains).





That’s certainly arguable, but it seems defensible to me, so I’ll stick with it.





The upshot is this (again in my opinion): Evolution, over millions of years, selected for a program of neural development that directs formation of our incredibly complex brain. Not just a big brain – size doesn’t get you far by itself – a complicated, sophisticated, highly organised brain, capable of extraordinary things, even being impressed by itself.





protecting its investment. What I mean is that intelligence went from being subject to strong directional selection (which may have exhausted its potential over millions of years) to being subject to strong Once evolution got us to this point, where we were completely reliant on our intelligence to survive in all kinds of environments, I argue that natural selection shifted to. What I mean is that intelligence went from being subject to strong directional selection (which may have exhausted its potential over millions of years) to being subject to strong purifying selection , where keeping that genomic program of neural development free from harmful mutations became the key challenge.









The genetic architecture of intelligence





What does that mean for what we call the genetic architecture of intelligence – the patterns of genetic variation that affect it and the relationship between genotypes and the phenotype of intelligence? I argue that it means that:





“…most genetic random mutations that affect on intelligence will do so negatively.

Statistically speaking, random mutations are vastly more likely to mess up the complicated genetic program for brain development than improve it, especially in ways that natural selection has not already fixed in our species. For the same reason, random tinkering with the highly tuned engine of a Formula One car is vanishingly unlikely to improve performance. Similarly, we shouldn’t expect intelligence to be affected by a balance of IQ-boosting mutations and IQ-harming mutations. Instead, genetic differences in intelligence may largely reflect the burden of mutations that drag it down.

”

balance between height-decreasing and height-increasing genetic variants, my contention is that the genetic contribution to variation in intelligence is determined mainly by the burden of intelligence-decreasing genetic variants. (That’s why I previously suggested, only partly tongue-in-cheek, that we should call it “the So, unlike a trait like height, which we can think of as being determined in any individual by abetween height-decreasing and height-increasing genetic variants, my contention is that the genetic contribution to variation in intelligence is determined mainly by theof intelligence-decreasing genetic variants. (That’s why I previously suggested, only partly tongue-in-cheek, that we should call it “the genetics of stupidity ”).





I went on to say that:

“Because most random mutations that affect intelligence will reduce it, evolution will tend to select against them. Inevitably, new mutations will always arise in the population, but ones with a large effect on intelligence – that cause frank intellectual disability, for example – will be swiftly removed by natural selection. Mutations with moderate effects may persist for a few generations, and ones with small effects may last even longer. But because many thousands of genes are involved in brain development, natural selection can’t keep them all free of mutations all the time. It’s like trying to play multiple games of Whack-a-mole at once, with only one hammer.”

There are a few intertwined points here. First, the program of neural development is incredibly complicated and can therefore be affected by mutations in thousands of genes. This means that intelligence will be a highly polygenic trait. I clearly gave the impression that I thought this alone meant it would be difficult to select for intelligence. This is not the case at all and not what I was trying (and clearly failing) to say.

Polygenicity

Polygenic traits can, of course, be selected for. Most of the traits selected for in animal or plant breeding are highly polygenic. This includes behavioral traits, as in the case of dog breeds. Different breeds of dogs were selected for all kinds of behaviors, including herding, guarding, retrieving, chasing, tracking, fighting, etc. And it also includes cognitive traits. For example, rats can be selectively bred from animals that are better or worse at completing a maze. After multiple generations you can end up with lines of “maze-bright” and “maze-dull” rats that have a huge difference in how well they can perform this task.

However, these examples required intense artificial selection to induce a change in phenotype. Moreover, though I don’t know if this has been tested in these cases, my guess is that that selective pressure would have to be sustained for the phenotypic difference to be maintained. (That is certainly typical for lab-based artificial selection experiments). My expectation is that if you left these populations of rats or dogs alone for multiple generations they would naturally drift back towards the species-typical set point of the trait.

In any case, I’m explicitly not trying to say that selection on intelligence is impossible. I’m trying to assess whether the circumstances required for it to happen are, a priori, likely or not. In fact, I’m trying to do something even more specific – assess whether it is plausible that such circumstances might have pertained in a differential way between continents but in a systematic and consistent way within continents over long periods of time. That is the scenario required to end up with the supposed systematic genetic differences in intelligence between populations with different continental ancestry.

The reason I think polygenicity is important in this case is that it means there is a huge mutational target that natural selection has to keep an eye on. The constant production of new mutations in sperm and egg cells, the fact that so many of them could affect intelligence, and the fact that they will tend to do so negatively, should, in my opinion, make it harder to push intelligence consistently upwards, when new mutations will constantly be pulling it back down.

Again, I would argue this is a different situation to many other traits. For any trait, new mutations are likely to degrade, rather than improve, the developmental program and biological pathways underlying it. But for some traits, the “goal” of that program is to hit a species-optimal set point. Mutations affecting that program could mean you miss high or miss low – there’s no reason to expect to go one way or the other, really (as far as I can see).

For intelligence, following my argument above, the goal is to hit the maximal level possible. New mutations will thus not just replenish genetic variation affecting the trait (in either direction, as in standard models of stabilising selection); they will tend to push it downwards.

Now, maybe someone will tell me why that actually doesn’t matter, but it seems to me that this will tend to oppose any efforts of directional selection to push intelligence upwards in any given population. Whether that is true or not (or the size of the effect it could have) may depend on how much the trait is dominated by the effects of rare mutations. Various lines of evidence suggest that the collective influence of such mutations on intelligence is very substantial.

For example:





Chromosomal deletions and duplications that cause clinical intellectual disability in some carriers, are associated with a more subtle reduction in cognitive performance in others in the "general population":





Kendall KM, et al. Cognitive Performance Among Carriers of Pathogenic Copy Number Variants: Analysis of 152,000 UK Biobank Subjects. Biol Psychiatry. 2017 Jul 15;82(2):103-110.





Similarly, ultra-rare mutations that disrupt brain-expressed proteins are associated with decreased educational attainment:





Ganna A, et al. Ultra-rare disruptive and damaging mutations influence educational attainment in the general population. Nat Neurosci. 2016 Dec;19(12):1563-1565.





Those studies relate to very rare classes of mutations but the logic extends across the whole spectrum – rarer mutations will have larger effects on the phenotype. The collective importance of these effects is illustrated by the fact that pedigree-based analyses using identity-by-descent captures significantly more heritability than SNP-based methods:





Hill WD, et al. Genomic analysis of family data reveals additional genetic effects on intelligence and personality. Mol Psychiatry. 2018 Jan 10. doi: 10.1038/s41380-017-0005-1. https://www.ncbi.nlm.nih.gov/pubmed/?term=29321673





Moreover, even for the common variants that have been associated with intelligence or one of its proxies, there is evidence that these are under negative selection, with comparatively rarer and newer ones explaining disproportionately more of the variance:

Zeng J, et al. Signatures of negative selection in the genetic architecture of human complex traits. Nat Genet. 2018 May;50(5):746-753. https://www.nature.com/articles/s41588-018-0101-4









Pleiotropy

One of the other points I made in the Guardian relates to the way in which genetic variants affect intelligence, at a biological level, which is likely to be highly indirect and non-specific:

“

Another crucial point is that genetics tends to affect intelligence in a much more indirect way than it does skin colour, height, and other physical traits. Like that Formula One car’s performance, intelligence is an emergent property of the whole system. There is no dedicated genetic module “for intelligence” that can be acted on independently by natural selection – not without affecting many other traits at the same time, often negatively.”

The key part there is that intelligence is an emergent property of the whole system. At a neural level, there are no specific local parameters that correlate well with intelligence. Instead, it correlates with global properties such as overall brain size, white matter “integrity” across the whole brain, and various parameters of whole brain networks, such as global efficiency. This may seem a bit vague, but effectively intelligence reflects how well the brain is put together.

This view is supported by the fact that genes with functions in neural development are highly enriched among those found to be associated with intelligence in genome-wide association studies or analyses of rare mutations.

However, there are two important points about the apparent specificity of that finding: first, many proteins involved in the cellular processes of neural development, such as cell migration, axon guidance or synapse formation, for example, are also involved in other processes in other tissues. This is the norm, in fact. Second, mutations in genes whose products are not directly involved in neurodevelopmental processes (like metabolic enzymes, for example) can nevertheless indirectly affect those processes. (The genes don’t have to be “for neural development” for mutations in them to affect neural development).

As a result, many of the genetic variants that affect intelligence will also affect other traits (a situation known as pleiotropy ). I argued, in the Guardian piece, that this widespread pleiotropy would tend to act as a brake on directional selection on intelligence, due to potentially negative offsetting effects on other traits.

A number of people criticized that point, and criticized me for making it apparently casually and not citing any relevant literature on the issue. That contention was not plucked out of the air but based on my reading of papers like these:

McGuigan K, Collet JM, Allen SL, Chenoweth SF, Blows MW. Pleiotropic mutations are subject to strong stabilizing

selection. Genetics. 2014 Jul;197(3):1051-62.

242, 95–100. Keightley , P.D., and Hill, W.G. (1990). Variation maintained in quantitative traits with mutation–selection balance: pleiotropic side-effects on fitness traits. Proc. R. Soc. Lond. B, 95–100.





Eyre-Walker A. Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1752-6.





Zhang XS, Hill WG. Joint effects of pleiotropic selection and stabilizing selection on the maintenance of quantitative genetic variation at mutation-selection balance. Genetics. 2002 Sep;162(1):459-71.





I am certainly happy to be enlightened if my reading of those papers was incorrect. It is clearly a hugely complex issue that has been debated since the time of Fisher in the 1930’s and that continues to be investigated. Indeed, Michael Eisen and Graham Coop both pointed out some additional papers on the subject, which come to different conclusions:

Johnson T, Barton N. Theoretical models of selection and mutation on quantitative traits. Philos Trans R Soc Lond B Biol Sci. 2005 Jul 29;360(1459):1411-25.





Simons YB, Bullaughey K, Hudson RR, Sella G. A population genetic interpretation of GWAS findings for human quantitative traits. PLoS Biol. 2018 Mar 16;16(3):e2002985.





In particular, Simons et al. find that directional selection can act on a trait, even when the individual variants affecting it are pleiotropic, by slightly increasing the collective frequency of alleles pushing the trait in one direction, while only slightly increasing the frequency of each one.

On the other hand, this paper that just came out on the (completely awesome) preprint server bioRxiv, reinforces the view that pleiotropic alleles will indeed be under stronger stabilising or purifying selection:

Emily S Wong, Steve Chenoweth, Mark Blows and Joseph E Powell

Evidence for stabilizing selection at pleiotropic loci for human complex traits





So, the question of how pleiotropy affects directional selection is clearly a very active one in the field of quantitative genetics. While I admittedly overstated the assertion that pleiotropy will tend to act as a brake on directional selection in my original article, I think it is fair to say that it is at the very least a parameter that should be taken into account and that may differ across traits.

There is, in addition, a more general way in which pleiotropy may be relevant.

Intelligence as a general fitness indicator





There is one other aspect to my argument that I did not have space to go into in the Guardian. It comes back to the idea that the trait that we recognise as intelligence does not reflect the functioning of some specific “cognition module” in the brain, but rather reflects overall “performance” of the brain.





If performance is determined by how well the brain is put together, then the load of mutations affecting neural development will be a crucial factor. Each such mutation could have specific effects on various developmental processes, resulting in a phenotype of brain organisation that is farther from the “wild-type” plan in some particular ways. But another factor is also at play. Each mutation is also expected to reduce the robustness of the developmental program in a much more general way.





The developmental program has evolved to be robust to the inherent noisiness of molecular processes. All of the myriad feedback processes in development are aimed at ensuring that the outcome of development is within the species-typical range. Mutations do not only affect specific processes, they also degrade these general control relationships that normally ensure robustness. (Including the ability to buffer the effects of other mutations).





This means that intelligence may, at least partly, reflect overall mutational load in a very general sense. It may, in fact, be not so much a thing in itself, driven by variation in some dedicated genetic and neural modules, but rather a general fitness indicator. This fits with the observation that intelligence correlates with many aspects of general health and longevity – not because being intelligent makes you healthier, but because greater “genomic fitness” makes you both more intelligent and more healthy.





If that is the case (and it is certainly an arguable point), then intelligence will get at least a partly free ride from natural selection. It will always be beneficial to keep the general mutation load as low as possible and it is hard to see why that would differ in different populations. Indeed, direct measurements of the number of derived non-synonymous variants (new mutations affecting the sequence of a protein) show no difference between large population groups.









The improbability of differential selection on intelligence across continents





For the reasons outlined above, it still seems to me that directional selection will have a harder time operating on intelligence than on many other traits. I contend that it will be difficult to differentially push intelligence upwards in any given population because new mutations will constantly be dragging it down, in every population. And regardless of selection acting directly on intelligence itself, it will always be good to try and keep the load of such mutations to a minimum, in every population.

I recognise that the conceptual framework presented here is unorthodox and people will no doubt take issue with various points. The overall point is that all this stuff is complex and much of it is unsettled.

At the very least, it is therefore important to consider the parameters of polygenicity, mutational target, pleiotropy, mutational load, and general relationship to fitness – as well as how they all interact – in the discussion of whether it is in fact likely – a priori – that systematic genetic differences in intelligence would arise between ancient population groups. (As opposed to simply asserting that any trait that is heritable is subject to directional selection, as if these other factors are irrelevant).

Whether you buy any of the arguments I have made here with regard to the genetics of intelligence, the idea that such pressures would align with continental divisions remains inherently implausible in itself, to my mind. These pressures would have to be consistent across entire continents, each comprising hugely diverse environments, but different across different continents, and also sustained over thousands of years, in order to end up with stable differences between ‘races’. (That is without even going into details of the arbitrariness of such divisions, as discussed here or the environmental and cultural factors which are known to affect intelligence and IQ scores and which clearly do differ in systematic ways between the relevant population groups).



