Razib Khan One-stop-shopping for all of my content

September 10, 2017

Quantitative genomics, adaptation, and cognitive phenotypes

The human brain utilizes about ~20% of the calories you take in per day. It’s a large and metabolically expensive organ. Because of this fact there are lots of evolutionary models which focus on the brain. In Catching Fire: How Cooking Made Us Human Richard Wrangham suggests that our need for calories to feed our brain is one reason we started to use fire to pre-digest our food. In The Mating Mind Geoffrey Miller seems to suggest that all the things our big complex brain does allows for a signaling of mutational load. And in Grooming, Gossip, and the Evolution of Language Robin Dunbar suggests that it’s social complexity which is driving our encephalization.

These are all theories. Interesting hypotheses and models. But how do we test them? A new preprint on bioRxiv is useful because it shows how cutting-edge methods from evolutionary genomics can be used to explore questions relating to cognitive neuroscience and pyschopathology, Polygenic selection underlies evolution of human brain structure and behavioral traits:

…Leveraging publicly available data of unprecedented sample size, we studied twenty-five traits (i.e., ten neuropsychiatric disorders, three personality traits, total intracranial volume, seven subcortical brain structure volume traits, and four complex traits without neuropsychiatric associations) for evidence of several different signatures of selection over a range of evolutionary time scales. Consistent with the largely polygenic architecture of neuropsychiatric traits, we found no enrichment of trait-associated single-nucleotide polymorphisms (SNPs) in regions of the genome that underwent classical selective sweeps (i.e., events which would have driven selected alleles to near fixation). However, we discovered that SNPs associated with some, but not all, behaviors and brain structure volumes are enriched in genomic regions under selection since divergence from Neanderthals ~600,000 years ago, and show further evidence for signatures of ancient and recent polygenic adaptation. Individual subcortical brain structure volumes demonstrate genome-wide evidence in support of a mosaic theory of brain evolution while total intracranial volume and height appear to share evolutionary constraints consistent with concerted evolution…our results suggest that alleles associated with neuropsychiatric, behavioral, and brain volume phenotypes have experienced both ancient and recent polygenic adaptation in human evolution, acting through neurodevelopmental and immune-mediated pathways.

The preprint takes a kitchen-sink approach, throwing a lot of methods of selection at the phenotype of interest. Also, there is always the issue of cryptical population structure generating false positive associations, but they try to address it in the preprint. I am somewhat confused by this passage though:

Paleobiological evidence indicates that the size of the human skull has expanded massively over the last 200,000 years, likely mirroring increases in brain size.

From what I know human cranial sizes leveled off in growth ~200,000 years ago, peaked ~30,000 years ago, and have declined ever since then. That being said, they find signatures of selection around genes associated with ‘intracranial volume.’

There are loads of results using different methods in the paper, but I was curious note that schizophrenia had hits for ancient and recent adaptation. A friend who is a psychologist pointed out to me that when you look within families “unaffected” siblings of schizophrenics often exhibit deviation from the norm in various ways too; so even if they are not impacted by the disease, they are somewhere along a spectrum of ‘wild type’ to schizophrenic. In any case in this paper they found recent selection for alleles ‘protective’ of schizophrenia.

There are lots of theories one could spin out of that singular result. But I’ll just leave you with the fact that when you have a quantitative trait with lots of heritable variation it seems unlikely it’s been subject to a long period of unidirecitional selection. Various forms of balancing selection seem to be at work here, and we’re only in the early stages of understanding what’s going on. Genuine comprehension will require:

– attention to population genetic theory
– large genomic data sets from a wide array of populations
– novel methods developed by population genomicists
– and funcitonal insights which neuroscientists can bring to the table

July 9, 2017

SLC24A5 is very important, but we don’t know why


The golden of pigmentation genetics started in 2005 with SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Prior to that pigmentation genetics was really to a great extent coat color genetics, done in mice and other organisms which have a lot of pelage variation.

Of course there was work on humans, mostly related to melanocortin 1. But more interesting were classical pedigree studies which indicated that the number of loci controlling variation in pigmentation was not that high. This, it was a mildly polygenic trait insofar as some large effect quantitative trait loci could be discerned in the inheritance patterns.

From The Genetics of Human Populations, written in the 1960s, but still useful today because of its comprehensive survey of the classical period:

Depending on what study samples you use variance on a locus of SLC24A5 explains less than 10% or more than 30% of the total variance. But it is probably the biggest effect locus on the whole in human populations when you pool them altogether (obviously it explains little variance in Africans or eastern non-Africans since it is homozygous ancestral by and large in both groups).

One aspect of the derived SNP in this locus is that it seems to be under strong selection. In a European 1000 Genomes sample there are 1003 SNPs of the derived variant, and 3 of the ancestral. Curiously this allele was absent in Western European Mesolithic European hunter-gatherers, though it was present in hunter-gatherers on the northern and eastern fringes of the continent. It was also present in Caucasian hunter-gatherers and farmers from the Middle East who migrated to Europe. It seems very likely that these sorts of high frequencies are due to selection in Europe.

The variant is also present in appreciably frequencies in many South Asian populations, and there seems to have been in situ selection there too, as well as the Near East. In Ethiopia it also seems to be under selection.

It could be something due to radiation…but the Near East and South Asia are quite high intensity in that regard. As are the highlands of Ethiopia. About seven years ago I suggested that rather that UV radiation as such the depigmentation that has occurred across the Holocene might be due to agriculture and changes in diet.

But a new result from southern Africa presented at the SMBE meeting this year suggests that this can not be a comprehensive answer. Meng Lin in Brenna Henn’s lab uses a broad panel of KhoeSan populations to find that the derived allele on SLC24A5 reaches ~40% frequency. Probably a high fraction of West Eurasian admixture in these groups is around ~10% being generous. Where did this allele come from? The results from Joe Pickrell a few years back are sufficient to explain: there was a movement of pastoralists with distant West Eurasian ancestry who brought cattle to southern Africa, and so resulted in the ethnogenesis of groups such as the Nama people (there is also Y chromosomal work by Henn on this).

Sad human with two derived alleles of SNP of interest

Lin reports that the haplotype around SLC24A5 is the same one as in Western Eurasia. Iain Mathieson (who is now at Penn if anyone is looking for something to do in grad school or a post-doc) has told me that the haplotype in the Motala Mesolithic hunter-gatherers and in the hunter-gatherers from the Caucasus are the same. It seems that this haplotype was widespread early in the Holocene. Curiously, the Motala hunter-gatherers also carry the East Asian haplotype around their derived EDAR variant.

I don’t know what to make of this. My intuition is that if a haplotype like this is so widespread nearly ~10,000 years ago recombination would have broken it apart into smaller pieces so that haplotype structure would be easier to discern. As it is that doesn’t seem to be the case.

And we also don’t know what’s going on withSLC24A5. Obviously it impacts skin color. It has been shown to do so in admixed populations. But it is hard to believe that that is the sole target of natural selection here.

December 18, 2012

Unveiling the genealogical lattice

To understand nature in all its complexity we have to cut down the riotous variety down to size. For ease of comprehension we formalize with math, verbalize with analogies, and visualize with representations. These approximations of reality are not reality, but when we look through the glass darkly they give us filaments of essential insight. Dalton’s model of the atom is false in important details (e.g., fundamental particles turn out to be divisible into quarks), but it still has conceptual utility.

Likewise, the phylogenetic trees popularized by L. L. Cavalli-Sforza in The History and Geography of Human Genes are still useful in understanding the shape of the human demographic past. But it seems that the bifurcating model of the tree must now be strongly tinted by the shades of reticulation. In a stylized sense inter-specific phylogenies, which assume the approximate truth of the biological species concept (i.e., little gene flow across lineages), mislead us when we think of the phylogeny of species on the microevolutionary scale of population genetics. On an intra-specific scale gene flow is not just a nuisance parameter in the model, it is an essential phenomenon which must be accommodated into the framework.


This is on my mind because of the emergence of packages such as TreeMix and AdmixTools. Using software such as these on the numerous public data sets allows one to perceive the reality of admixture, and overlay lateral gene flow upon the tree as a natural expectation. But perhaps a deeper result is the character of the tree itself is torn asunder. The figure above is from a new paper, Efficient moment-based inference of admixture parameters and sources of gene flow, which debuts MixMapper. The authors bring a lot of mathematical heft to their exposition, and I can’t say I follow all of it (though some of the details are very similar to Pickrell et al.’s). But in short it seems that in comparison to TreeMix MixMapper allows for more powerful inference of a narrower set of populations, selected for exploring very specific questions. In contrast, TreeMix explores the whole landscape with minimal supervision. Having used the latter I can testify that that is true.

The big result from MixMapper is that it extends the result of Patterson et al., and confirms that modern Europeans seem to be an admixture between a “north Eurasian” population, and a vague “west Eurasian” population. Importantly, they find evidence of admixture in Sardinians, which implies that Patterson et al.’s original were not sensitive to admixture in putative reference populations (note that Patterson is a coauthor on this paper as well). The rub, as noted in the paper, is that it is difficult to estimate admixture when you don’t have “pure” ancestral reference populations. And yet here the takeaway for me is that we may need to rethink our whole conception of pure ancestral populations, and imagine a human phylogenetic tree as a series of lattices in eternal flux, with admixed nodes periodically expanding so as to generate the artifice of a diversifying tree. The closer we look, the more likely that it seems that most of the populations which have undergone demographic expansion in the past 10,000 years are also the products of admixture. Any story of the past 10,000 years, and likely the past 100,000 years, must give space at the center of the narrative arc lateral gene flow across populations.

Cite: arXiv:1212.2555 [q-bio.PE]

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