Adaptation is subtle, and that’s the problem


The figure above is from a very important new preprint, Human local adaptation of the TRPM8 cold receptor along a latitudinal cline. A marker in 09TRPM8, rs10166942, seem to be correlated with adaptation to cold.

The abstract:

Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabits territories under a wide range of temperatures. Focusing on cold perception, which is central to thermoregulation and survival in cold environments, we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analysed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent, precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today.

The mechanism and adaptive story make sense. They used several methods which corrected/accounted for population structure, and noted that the allele frequency difference was still significantly predicted by variation in latitude (though not temperature).

In the plot above you can see that South Asian populations share allele frequency distributions closer to East Asians, though genetically they are somewhat closer to Europeans. Looking at the haplotype structure this variant looks to be old variation that has been under selection in Eurasia. Additionally if you look at the frequencies it doesn’t look like the sweeps are completing. Since migraines are one correlated side effect that probably makes sense.

The problem I have with this preprint is a simple one. The SNP seems to be in the HGDP browser (it’s in your 23andMe genotype if you have one, I checked). The geographic distribution doesn’t look as clear as it does in the 1000 Genomes data. In particular in the New World populations the latitudinal cline is reversed from what we’d expect.

These sorts of objections are pretty typical. And they authors did do a sophisticated statistical analysis…but sometimes visual inspection of the raw frequencies is still important when the effect is subtle. Over the next decade there is going to be a lot of sophisticated analysis of adaptation, because the low hanging fruit has been picked. But we need to still look over the results with care….

Out of Africa-Out of Asia-Out of Africa

Roberta Estes recenty posted about the fact that Spencer & I will be revisiting The Journey of Man, fifteen years after he wrote the book and made the documentary.

As part of the preparation, I’m revisiting some uniparental results, in particular, recent ones. This preprint in bioRxiv Carriers of mitochondrial DNA macrohaplogroup L3 basic lineages migrated back to Africa from Asia around 70,000 years ago., caught my attention:

Background: After three decades of mtDNA studies on human evolution the only incontrovertible main result is the African origin of all extant modern humans. In addition, a southern coastal route has been relentlessly imposed to explain the Eurasian colonization of these African pioneers. Based on the age of macrohaplogroup L3, from which all maternal Eurasian and the majority of African lineages originated, that out-of-Africa event has been dated around 60-70 kya. On the opposite side, we have proposed a northern route through Central Asia across the Levant for that expansion. Consistent with the fossil record, we have dated it around 125 kya. To help bridge differences between the molecular and fossil record ages, in this article we assess the possibility that mtDNA macrohaplogroup L3 matured in Eurasia and returned to Africa as basic L3 lineages around 70 kya. Results: The coalescence ages of all Eurasian (M,N) and African L3 lineages, both around 71 kya, are not significantly different. The oldest M and N Eurasian clades are found in southeastern Asia instead near of Africa as expected by the southern route hypothesis. The split of the Y-chromosome composite DE haplogroup is very similar to the age of mtDNA L3. A Eurasian origin and back migration to Africa has been proposed for the African Y-chromosome haplogroup E. Inside Africa, frequency distributions of maternal L3 and paternal E lineages are positively correlated. This correlation is not fully explained by geographic or ethnic affinities. It seems better to be the result of a joint and global replacement of the old autochthonous male and female African lineages by the new Eurasian incomers. Conclusions: These results are congruent with a model proposing an out-of-Africa of early anatomically modern humans around 125 kya. A return to Africa of Eurasian fully modern humans around 70 kya, and a second Eurasian global expansion by 60 kya. Climatic conditions and the presence of Neanderthals played key roles in these human movements.

It was really hard for me to parse all the coalescene and phylogenies here. I know some readers are pretty well versed in this area so I’m curious about critiques and reactions to the above.

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 cryptic 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

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.