Category: Genetics

Selection happens; but where, when, and why?

By Razib Khan | November 8, 2013 3:49 am
Distribution of SLC452 variation at SNP rs1426654. Credit, HGDP Browser

Distribution of SLC452 variation at SNP rs1426654. Credit, HGDP Browser

Nina Davuluri, Miss America 2014, Credit: Andy Jones

Nina Davuluri, Miss America 2014, Credit: Andy Jones

One of the secondary issues which cropped up with Nina Davuluri winning Miss America is that it seems implausible that someone with her complexion would be able to win any Indian beauty contest. A quick skim of Google images “Miss India” will make clear the reality that I’m alluding to. The Indian beauty ideal, especially for females, is skewed to the lighter end of the complexion distribution of native South Asians. Nina Davuluri herself is not particularly dark skinned if you compared her to the average South Asian; in fact she is likely at the median. But it would be surprising to see a woman who looks like her held up as conventionally beautiful in the mainstream Indian media. When I’ve pointed this peculiar aspect out to Indians* some of them of will submit that there are dark skinned female celebrities, but when I look up the actresses in question they are invariably not very dark skinned, though perhaps by comparison to what is the norm in that industry they may be. But whatever the cultural reality is, the fraught relationship of color variation to aesthetic variation prompts us to ask, why are South Asians so diverse in their complexions in the first place? A new paper in PLoS Genetics, The Light Skin Allele of SLC24A5 in South Asians and Europeans Shares Identity by Descent, explores this genetic question in depth.

Much of the low hanging fruit in this area was picked years ago. A few large effect genetic variants which are known to be polymorphic across many populations in Western Eurasia segregate within South Asian populations. What this means in plainer language is that a few genes which cause major changes in phenotype are floating around in alternative flavors even within families among people of Indian subcontinental origin. Ergo, you can see huge differences between full siblings in complexion (African Americans, as an admixed population, are analogous). While loss of pigmentation in eastern and western Eurasia seems to be a case of convergent evolution (different mutations in overlapping sets of genes), the H. sapiens sapiens ancestral condition of darker skin is well conserved from Melanesia to Africa.

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CATEGORIZED UNDER: Anthroplogy, Genetics, Genomics
MORE ABOUT: Pigmentation

The inferred distribution of grandparental contribution

By Razib Khan | October 21, 2013 10:38 am

In my write up on variation in inheritance patterns for Slate last week I did not explore the likely quantitative distribution in any detail (frankly, I think that part is confused or muddled at best). My primary focus though was on the empirical reality of variation, which people utilizing personal genomic services will receive, perhaps to their surprise. But in part triggered by that Slate piece and follow-up discussions at Twitter with Michael Eisen, Graham Coop decided to crunch the numbers. More concretely he took the known patterns of recombination in the human genome (from a paper he co-authored, Broad-Scale Recombination Patterns Underlying Proper Disjunction in Humans), and input these values into a simulation which generated distributions of contribution from maternal and paternal grandparents, How much of your genome do you inherit from a particular grandparent?

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CATEGORIZED UNDER: Genetics, Human Genetics
MORE ABOUT: Recombination

Why I love genetics

By Razib Khan | October 7, 2013 11:06 pm

Gregor Mendel

A few years ago I had a discussion with a friend about our academic backgrounds. She is a neurobiologist by training, so I remarked in an offhand manner that I’d had an interest in neuroscience years ago. In fact, I admitted that I had even dabbled with the idea of pursuing graduate work in that discipline. More specifically cognitive neuroscience. Stanislas Dehaene’s work, detailed in The Number Sense and Reading in the Brain, was of great fascination for me (cognitive and evolutionary psychology, of the sort outlined in Steven Pinker’s The Language Instinct, has also been something of a personal obsession).

I didn’t go that route…I’ve been writing for 10+ years now, and long time readers can probably attest to the fact that I’ve become more and more focused on genetics as time goes by. This is due to the reality that I really like genetics. Really. The friend with whom I was having the conversation about our various interests admitted she couldn’t even imagine an alternative universe version of me who would nerd out on neuroscience. That would be a bizarro-world Razib.

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CATEGORIZED UNDER: Genetics
MORE ABOUT: Genetics

Taboo genetic truths

By Razib Khan | October 3, 2013 11:59 am

Have no fear

There has been a lot of attention to Erika Check Hayden’s piece Ethics: Taboo genetics, at least judging by people commenting on my Facebook feed. In some ways this is not an incredibly empirically grounded argument, because the biological basis of complex traits is going to be rather difficult to untangle on a gene-by-gene basis. In other words, this isn’t a clear and present “concern.” The heritability of many behavioral traits has long been known. This is not revolutionary, though for cultural reasons may well educated people are totally surprised when confronted with data that many traits, such as intelligence and personality, have robust heritabilities* (the proportion of trait variation explained by variation in genes across the population). The literature reviewed in The Nurture Assumption makes clear that a surprising proportion of contribution any parents make to their offspring is through their genetic composition, and not their modeled example. You wouldn’t know this if you read someone like Brian Palmer of Slate, who seems to be getting paid to reaffirm the biases of the current age among the smart set (pretty much every single one of his pieces that touch upon genetics is larded with phrases which could have been written by a software program designed to sooth the concerns of the cultural Zeitgeist). But the new genomics is confirming the broad outlines of the findings from behavior genetics. There’s nothing really to see there. The bigger issue of any interest is normative; the values we hold dear as a culture.

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The Central Dogma goes YouTube

By Razib Khan | September 17, 2013 3:36 pm

You have probably seen these animations at some point, but if not, I encourage you to check them out. They certainly make abstractions such as DNA → RNA → Protein “come to life.” Below you have transcription, and then translation.

Though the DNA replication visualization is probably the most impressive to me:

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CATEGORIZED UNDER: Genetics

Evolution has a simple genetic skeleton

By Razib Khan | September 17, 2013 3:39 am

Citation: Keinan, Alon, and Andrew G. Clark. “Recent explosive human population growth has resulted in an excess of rare genetic variants.” science 336.6082 (2012): 740-743.
APA

Some of the topics that I discuss in this space may seem abstruse, but really they’re often elaborations upon rather elementary basic models of the world. When it comes to a subject like evolutionary genetics deep thinking extending from a few simple conceptual anchors yields great insight. Those anchors trace back to the foundations of Mendelian genetics. For diploid organisms the law of equal segregation states that of the two gene copies organisms have there is an equal probability of contribution of either to their offspring. This explains the simple power of Punnett squares and the inheritance patterns of recessive traits. The law of independent assortment states that genes (and therefore implicitly Mendelian traits) are passed independently from each other from parents to offspring. These abstractions are concretized on the cytological and molecular genetic scale during meiosis, as homlogous chromosomes which are composed of packed sequences of genes partition themselves into separate haploid gametes (sperm and egg*). Early in meiosis, during prophase 1, crossing-over between homologs results in genetic recombination, which preserves the law of independent assortment even when genes are on the same chromosome by breaking apart associations between specific physical genetic regions which might exhibit co-inherited distinctiveness (if the genes are very close they are linked).

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CATEGORIZED UNDER: Genetics
MORE ABOUT: Genetics

Man still evolves

By Razib Khan | September 12, 2013 8:02 pm

Still a great book!

Sir David Attenborough is the latest public intellectual who should know better than to opine that evolution has ended for human beings. Here are the quotes from The Telgraph: “Because if natural selection, as proposed by Darwin, is the main mechanism of evolution – there may be other things, but it does look as though that’s the case – then we’ve stopped natural selection. We stopped natural selection as soon as we started being able to rear 95–99 per cent of our babies that are born.

John Hawks does a good job hitting back the balls hanging just over the plate. There are still many parts of the world where 95-99 percent of babies being born do not reach adult. Second, there is still a great deal of variation in fertility. Some people choose not to have any children, while others are quite prolific. For adaptation by natural selection to occur what you need is heritable variation of some sort to correlate with this fertility variation. It seems highly plausible that indeed heritable variation does correlate with fertility variation. As John notes the advancement of genome sequencing over the population will probably answer these questions definitively within the next 10 years (e.g., I am willing to bet that siblings who score higher on impulsiveness and lower on IQ tests will be more reproductively fit than their less impulsive and more intelligent brothers and sisters).

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CATEGORIZED UNDER: Evolution, Genetics

The allelomorphs of genetics

By Razib Khan | September 11, 2013 12:41 am

Google’s Ngrams viewer yields some interesting results when you query the mentions of various fields within genetics over the past century or so. Nothing too surprising, though I would have thought that molecular genetics would have surpassed population genetics even earlier than it did.

Click To Enlarge

Note that the default settings go to 2000. But I was curious about genomics’ trajectory, and I pushed it to the max (2008). The qualitative result was not a surprise to me, but the magnitude did take me aback:

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CATEGORIZED UNDER: Genetics, Social Science

Distributed variation prefers the golden mean

By Razib Khan | September 8, 2013 1:54 am

One of the things that people like to do when thinking about evolutionary processes is to consider future predictions of a model. The problem with this is that evolutionary trajectories are not defined just by linear transitions driven by powerful positive selection. There are long term balancing forces which result in modulated equilibria. In some cases the power of selection to reshape the genome under the impetus of a new adaptation is clear and evident. Lactase persistence and malaria come to mind. But in other domains the outcomes are not so clear. For example, human intuition may tell us that higher intelligence, or in the case of men greater height, are beneficial. But the reality is that these are heritable traits which exhibit a great deal of genetic variation. The latest research also suggests that variation on these traits are controlled by innumerable genes, rather than a few of large effect. Going back to what I learned in Principles of Population Genetics, my initial impulse is to assume that continuous quantitative traits which are highly heritable are not subject to strong positive selection. But sometimes textbook wisdom needs to be updated.

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CATEGORIZED UNDER: Genetics

Indo-Aryans, Dravidians, and waves of admixture (migration?)

By Razib Khan | August 8, 2013 12:46 pm

Citation: Genetic Evidence for Recent Population Mixture in India
Moorjani et al.
10.1016/j.ajhg.2013.07.006

The Pith:In India 5,000 years ago there were the hunter-gathers. Then came the Dravidian farmers. Finally came the Indo-Aryan cattle herders.

There is a new paper out of the Reich lab, Genetic Evidence for Recent Population Mixture in India, which follows up on their seminal 2009 work, Reconstructing Indian Population History. I don’t have time right now to do justice to it, but as noted this morning in the press, it is “carefully and cautiously crafted.” Since I am not associated with the study, I do not have to be cautious and careful, so I will be frank in terms of what I think these results imply (note that confidence on many assertions below are modest). Though less crazy in a bald-faced sense than another recent result which came out of the Reich lab, this paper is arguably more explosive because of its historical and social valence in the Indian subcontinent. There has been a trend over the past few years of scholars in the humanities engaging in deconstruction and intellectual archaeology which overturns old historical orthodoxies, understandings, and leaves the historiography of a particular topic of study in a chaotic mess. From where I stand the Reich lab and its confederates are doing the same, but instead of attacking the past with cunning verbal sophistry (I’m looking at you postcolonial“theorists”), they are taking a sledge-hammer of statistical genetics and ripping apart paradigms woven together by innumerable threads. I am not sure that they even understand the depths of the havoc they’re going to unleash, but all the argumentation in the world will not stand up to science in the end, we know that.

Since the paper is not open access, let me give you the abstract first:

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Where the oldest of the old are no more, and are

By Razib Khan | July 20, 2013 7:35 pm

Malaysian “Negritos,” presumably the indigenous people of the Malay peninsula

A few days ago Dienekes pointed to a paper which reports on the presence of anatomically modern humans in China 80-100,000 years before the present. I say “anatomically modern” because there is a presumable distinction between populations which resemble moderns in their gross morphology, which first emerged in southern and eastern Africa 100 to 200 thousand years ago (and were dominant all across the world after 40,000 years before the present), and “behaviorally modern” societies, which exhibit all the hallmarks of protean symbolic cultural expression that are the hallmarks of humanity. The paper reporting on such old specimens is not particularly revolutionary. Rather, it’s part of a growing corpus which contributes to a “counter-narrative” to the dominant model, whereby behaviorally modern humans swept across Eurasia (and Australia) ~50,000 years B.P. after the “Out of Africa” event. Obviously the problem here is that if there were anatomically modern humans in China tens of thousands years before this expansion, were they replaced? Or is the chronology wrong? (e.g. the mutation rate controversy, though please note that the dominant model has many physical anthropologists who support it as well). On Twitter I pointed out to Aylwyn Scally that we do have evidence of substantial population replacement across East and Southeast Asia.

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CATEGORIZED UNDER: Genetics, Human Genetics

The inbred lineage you can improve

By Razib Khan | July 18, 2013 3:34 am

Last of the Spanish Habsburgs

Thanks to the efforts of geneticists the story of the extinction of the Spanish Habsburgs is now well known. They are in short a case study in the disastrous consequences of an inbred pedigree. The downsides of inbreeding are to some extent intuitively understood by all, especially consanguineous relations between first order relatives. Though I’m willing to bet that all things equal inbred individuals are not as attractive or intelligent as outbred individuals, the literature in this area for humans is surprisingly thin. A major problem is controlling for confounds; all things are often not equal (e.g., imagine if inbreeding is more common in marginal isolated communities, which is often true in the West. See Consanguinity, Inbreeding, and Genetic Drift in Italy, where it is obvious that the less developed areas of Italy had elevated rates of marriage between relatives despite Catholic discouragement of the practice). But the case that inbreeding results in the expression of deleterious recessive diseases is more straightforward. The rarer the disease, the higher the proportion of individuals who are affected who are the consequence of inbreeding. This is due to the logical fact that very rare alleles tend not to come back together in homozygote form due to the character of the Hardy-Weinberg equilibrium. If the recessive trait is caused by a minor allele with a frequency of p, p2 can converge upon zero very rapidly as p decreases in frequency. At p = 0.1 the recessive trait will express in 1% of the population (so p/p2 = 10). At p = 0.01 the recessive trait will express in 0.01% of the population (so p/p2= 100). And so forth.

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CATEGORIZED UNDER: Genetics

Genetic diversity and intellectual disability

By Razib Khan | July 5, 2013 2:17 am

Illustration of runs of homozygosity for affected and unaffected siblings
Credit: Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

It is generally understood that inbreeding has some negative biological consequences for complex animals. Recessive diseases are the most straightforward. The rarer a recessive disease is the higher and higher fraction of sufferers of that disease will be products of pairings between relatives (the reason for this is straightforward, as extremely rare alleles which express in a deleterious fashion in homozygotes will be unlikely to come together in unrelated individuals). But when it comes to traits associated with inbred individuals recessive diseases are not what comes to mind for most, the boy from the film Deliverance is usually the more gripping image (contrary to what some of the actors claimed the young boy did not have any condition).

Some are curious about the consequences of inbreeding for a trait such as intelligence. The scientific  literature here is somewhat muddled. But it seems likely that all things equal if two people of average intelligence pair up and are first cousins the I.Q. of their offspring will be expected to be 0-5 points lower than would otherwise be the case. By this, I mean that the studies you can find in the literature suggest when correcting for other variables that the inbreeding depression on the phenotypic level is greater than 0 (there is an effect) but less than 5 (it is not that large, less than 1/3 of a standard deviation of the trait value). Presumably for higher levels of inbreeding the consequences are going to be more dire.

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Yes Virginia, trans-ethnic inferences from GWAS are kosher

By Razib Khan | June 24, 2013 12:00 am

Razib’s daughter’s ancestry composition


An F1, r = 0.5 to Razib

Genome-wide associations are rather simple in their methodological philosophy. You take cases (affected) and controls (unaffected) of the same genetic background (i.e. ethnically homogeneous) and look for alleles which diverge greatly between the two pooled populations. Visually the risk alleles, which exhibit higher odds ratios, are represented via Manhattan plots. But please note the clause: ethnically homogeneous study populations. In practice this means white Europeans, and to a lesser extent East Asians and African Americans (the last because of the biomedical industrial complex in the United States performs many GWAS, and the USA is a diverse nation). Looking within ethnic groups eliminates many false positives one might obtain due to population stratification. Basically, alleles which differ between groups because of their history may produce associations when the groups themselves differ in the propensity of the trait of interest (e.g. hypertension in blacks vs. whites).

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Ancestry should not be subject to privacy restraints

By Razib Khan | June 17, 2013 3:21 am

Credit: Robert Payne

In my earlier post on Prince William’s mtDNA lineage, and its possible Indian provenance, I didn’t address the issue of genetic privacy in much detail. The discussion is relevant in this case because BritainsDNA inferred his lineage by looking at distant relatives. Assuming that the biological pedigree we have for William is correct, he must share the mtDNA of his relatives who descend in an unbroken line from a common female ancestor.

A concern about the breach of privacy emerged almost immediately. Though I have serious reservations about the sensationalism which BritainsDNA has engaged in, I think it is totally legitimate of them to infer William’s ancestry in the fashion they did. First, Prince William is a public person, and in direct line to the throne of the United Kingdom. Though some of the spin may be distasteful, remember that this is a person who is where he is because of his ancestry. Second, anyone who performs genealogical research is exposing the information of family members, often without their consent. If William’s mtDNA haplogroup was known to be pathogenic than the case for withholding the information from the public seems straightforward. As it is all that was uncovered was relatively banal, that William may have a South Asian ancestress. There’s a lot of information about me that I’d rather not others know first, but that’s not how the world works. In the grand scheme of things this just isn’t a big deal, and we should focus on the more concrete problem of public understanding of science, and long term issues in regards to genetic privacy more generally.

Addendum: I am aware of concerns in regards to paternity. On the whole I generally think in most situations this is probably information that is going to come out in any case, and so it wouldn’t hurt for it to emerge earlier. Additionally, in the cases of historical figures such as Thomas Jefferson’s presumed line of descent there were widely diverging views among the white descendants as to whether they should cooperate because of the possible moral implications. I suspect most would agree it is better to know this information, even though it implied that line of putative black Jefferson descendants may have paternity misassignment in their lineage. Finally, obviously these issues are far diminished in the case of mtDNA, since maternity is guaranteed. Though one never knows if someone who was adopted was never told of his reality.

CATEGORIZED UNDER: Anthroplogy, Genetics
MORE ABOUT: Prince William

Genes not patentable

By Razib Khan | June 13, 2013 10:40 am

Supreme Court Rules Human Genes May Not Be Patented:

“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated,” Justice Clarence Thomas wrote for a unanimous court. But manipulating a gene to create something not found in nature is an invention eligible for patent protection.

The case concerned patents held by Myriad Genetics, a Utah company, on genes that correlate with increased risk of hereditary breast and ovarian cancer.

Believe it or not USA Today was out fast with a long story on this issue with quotes and everything. Here’s the full text of the decision. Needless to say this is a pretty big deal, and I’m somewhat surprised this was a unanimous decision. Perhaps the justices actually listen to scientists and their bleating sometimes?

I’ll be checking in to the Genomics Law Report regularly today….

Update: Just to note, several friends have noted that aspects of the science in the ruling seem to have some howlers. That is not surprising (see Scalia’s admission of ignorance in the concurrence). But from listening to the panel discussion on the Myriad case at ASHG 2012 this ruling is still a huge step forward. Being wrong is preferable to “not even wrong.”

CATEGORIZED UNDER: Genetics, Genomics
MORE ABOUT: Gene Patent, Myriad

Mother of all microsatellites

By Razib Khan | June 13, 2013 9:21 am

MDS of all samples

Noah Rosenberg’s lab has put out the mother of all microsatellite papers, Population Structure in a Comprehensive Genomic Data Set on Human Microsatellite Variation. It seems to me that this is the culmination of all the work with microsatellite markers which has come out of his lab over the past decade, applying all sorts of fancy analytic techniques they’ve developed (for example, Procrustes transformation). The big thing to note is that the human sample size is nearly 6,000 individuals with over 600 loci. Because microsatellites mutate and diverge very fast (mutation rates 10-4 rather than 10-8as with SNPs) 600 loci is more than sufficient to differentiate populations. Because of this rapid mutation I’m a little dubious about their attempt to explore human-chimp differences using a smaller set ascertained on humans, though that may be simply a proof of principle (if the markers evolve too fast they might not tell you much informative about very deep divergences).

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Intelligence is still heritable

By Razib Khan | June 12, 2013 1:23 am

Sir Francis Galton

Modern evolutionary genetics owes its origins to a series of intellectual debates around the turn of the 20th century. Much of this is outlined in Will Provines’ The Origins of Theoretical Population Genetics, though a biography of Francis Galton will do just as well. In short what happened is that during this period there were conflicts between the heirs of Charles Darwin as to the nature of inheritance (an issue Darwin left muddled from what I can tell). On the one side you had a young coterie around William Bateson, the champion of Gregor Mendel’s ideas about discrete and particulate inheritance via the abstraction of genes. Arrayed against them were the acolytes of Charles Darwin’s cousin Francis Galton, led by the mathematician Karl Pearson, and the biologist Walter Weldon. This school of “biometricians” focused on continuous characteristics and Darwinian gradualism, and are arguably the forerunners of quantitative genetics. There is some irony in their espousal of a “Galtonian” view, because Galton was himself not without sympathy for a discrete model of inheritance!

William Bateson

In the end science and truth won out. Young scholars trained in the biometric tradition repeatedly defected to the Mendelian camp (e.g. Charles Davenport). Eventually, R. A. Fisher, one of the founders of modern statistics and evolutionary biology, merged both traditions in his seminal paper The Correlation between Relatives on the Supposition of Mendelian Inheritance. The intuition for why Mendelism does not undermine classical Darwinian theory is simple (granted, some of the original Mendelians did seem to believe that it was a violation!). Many discrete genes of moderate to small effect upon a trait can produce a continuous distribution via the central limit theorem. In fact classical genetic methods often had difficulty perceiving traits with more than half dozen significant loci as anything but quantitative and continuous (consider pigmentation, which we know through genomic methods to vary across populations mostly due to half a dozen segregating genes or so).

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The genetic legacy of the conquistadors

By Razib Khan | June 9, 2013 9:07 pm

Christopher Columbus

A few year ago there was a minor controversy when some evolutionary genomicists reported that they had reconstructed the genome of the extinct Taino people of Puerto Rico by reassembling fragments preserved in contemporary populations long since admixed. The controversy had to do with the fact that some individuals today claim to be Taino, and therefore, they were not an extinct population. Though that controversy eventually blew over, the methods lived on, and continue to be used. Now some of the same people who brought you that have come out with work which reconstructs the recent demographic history of the Caribbean, both maritime and mainland, using genomics.  Even better, it’s totally open access because it’s up on arXiv, Reconstructing the Population Genetic History of the Caribbean (please see the comments at Haldane’s Sieve as well, kicked off by little old me). Though the authors pooled a variety of data sets (e.g., HapMap, POPRES, HGDP) the focus is on the populations highlighted in the map above.

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How the race, intelligence, and genetics question will semi-resolve within the next 10 years

By Razib Khan | May 28, 2013 12:55 am

Prompted by my post Ta-Nehisi Coates reached out to Neil Risch for clarification on the nature (or lack thereof) of human races. All for the good. The interview is wide ranging, and I recommend you check it out. Read the comments too! Very enlightening (take that however you want).

When it comes to this debate I have focused on the issue of population substructure, or race. The reason is simple. Due to Lewontin’s Fallacy it is widely understood among the “well informed general public” that “biology has disproved race.” Actually, this is a disputable assertion. For a non-crank evolutionary biologist who is willing to defend the race concept for humans, see Jerry Coyne. When you move away from the term “race,” then you obtain even more support from biologists for the proposition that population structure matters. For example, a paper in PLoS GENETICS which came out last week: Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration. In other words, it is useful to understand the genetic relationships of populations, and individual population identity, because traits correlate with population history. Barring total omniscience population history will always probably matter to some extent, because population history influences suites of traits. If nothing in evolutionary biology makes sense except in light of phylogeny, much of human biology is illuminated by phylogeny.

But that doesn’t speak to the real third rail, intelligence. Very few people are offended by the idea of the correlation between lactase persistence and particular populations. Neil Risch says in the interview with Coates:

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CATEGORIZED UNDER: Genetics, Psychology
MORE ABOUT: I.Q., Intelligence, Race
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This blog is about evolution, genetics, genomics and their interstices. Please beware that comments are aggressively moderated. Uncivil or churlish comments will likely get you banned immediately, so make any contribution count!
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