Solute carrier family genes are important…but how?

Over the last ten years David Reich and other researchers have been constructing what is basically an atlas of human demographic history. Taking the genealogies written in our DNA, mapping them onto population bifurcations and admixtures, and synthesizing that back together with what we know from history and archaeology.

To a great extent, this is a project of human phylogenomics. Taking genome-wide data and constructing phylogenies out of it (or, perhaps more precisely, graphs, as this is on a intra-species time scale mostly and characterized by lots of gene flow across the “tips” of the tree). But there’s another thing you can do with modern human genomics and evolution: look at patterns of selection within the genome.

The Reich group has already started doing this. For example, they have adduced that CCR5 delta 32 mutation seems to have emerged out of the Yamnaya horizon.

Last fall, a paper came out in MBE, Ancestry-Specific Analyses Reveal Differential Demographic Histories and Opposite Selective Pressures in Modern South Asian Populations, which I gave a cursory read, but which I’ve looked at more closely. It takes a “natural experiment,” the emergence of Indian subcontinental populations from a massive admixture between lineages which diverged 40,000 years ago, and looks to see which genetic regions deviate from what you would expect based on overall genome.

The method is simple: imagine that “Ancestral North Indians” are fixed for an allele at a gene in one state and “Ancestral South Indians” are fixed in the other state. Indian populations are about 50:50 (with a range). If the frequency today in Indian populations is 95% for the allele that is from the “Ancestral North Indians”, one might be suspicious as to what’s going on. Or, vice versa.

In the paper, they used whole genomes to reconstruct the ancestral steppe/Iranian population without any residual “Ancient Ancestral South Indian” (AASI), the latter of which has no West Eurasian. They did the same for the AASI. These reconstructions are always dicey, but they made a good faith effort to check their work. On the whole, that section was impressive. The authors seem to be roughly aligned with the results in Narasimhan et al. 2019. The AASI seems to be homogeneous, with the exception of attempting to model them from donors which were Munda or Burusho, both groups with deep East Asian admixture (illustrating the problem with deconvolution). Second, they show that the AASI are not clustering with the Andamanese, which makes sense since these groups diverged closer to 40,000 years ago. Finally, the steppe/Iranian group looks most like Armenian middle-to-late Bronze Age people. A synthesis of steppe and some Iranian-like ancestry.

But this isn’t the most interesting part of the paper. It’s the selection. Here are the top, top, candidates:

Component# of Pops with Sig ValueGenes (±50-kb Region)
ANI22 (percentile = 99.9949) THUMPD3, SETD5 
21 (percentile = 99.9814) SNAP91, RIPPLY2, CYB5R4, MRAP2, CEP162, TBX18 
21 (percentile = 99.9814) TRIM31, TRIM40, TRIM10, TRIM15, TRIM26, HLA-L 
19 (percentile = 99.9383) Intergenic 
18 (percentile = 99.9195) ZNF681, ZNF726, ZNF254 
ASI−21 (percentile = 0.0057) RXFP3, SLC45A2, AMACR, C1QTNF3, ADAMTS12 
−16 (percentile = 0.038) SRXN1, SCRT2, SLC52A3 
−16 (percentile = 0.038) Intergenic 
−15 (percentile = 0.0757) Intergenic 
−14 (percentile = 0.1268) ATP6V1H, RGS20, TCEA1, LYPLA1, MRPL15 


I’ll quote the authors at length from the “Discussion”:

We also show that the interaction between alleles that were highly polarized between the two ancestry sources that admixed in South Asia caused patterns of admixture imbalance across the majority of sampled groups, hence unlikely explainable by population specific random drift, and perhaps due to positive or negative environmental pressures. Interestingly, we report how loci that include genes involved with diabetes (SETD5), diet (ZNF) and the immune response (HLA) show West Eurasian (N) haplotypes to be significantly more represented compared with the South Asian (S) counterparts. This might be a stark contrast to what is expected, given the long-term history of local adaptation of S haplotypes in local environment. We speculate that the diet-related signal may be linked with post-Neolithic dietary shifts that might have followed the arrival of the West Eurasian component in the area, whereas the overrepresentation of West Eurasian HLA haplotypes might have some similarity, although at a different time scale, with what has happened in Native American populations after recent colonization likely caused by European borne epidemic (Lindo et al. 2016).

On the other hand, the top region for significant enrichment of South Asian ancestry includes the rs16891982-G allele of SLC45A2 gene (associated with light skin pigmentation in West Eurasians), suggesting purifying selection at this locus following admixture…the overall abundance of these West Eurasian alleles is drastically reduced in 21 out of 25 South Asian populations analyzed here…Such a strong negative pressure against a light pigmentation allele may be explained by the high ultraviolet (UV) radiation at South Asian latitudes and this result seems to be further corroborated by similar N ancestry deficiencies in TYRP1 and BNC2 genes for as many as 11 South Asian populations (supplementary table 4, Supplementary Material online). However, purifying selection against maladaptive light pigmentation alleles in high UV environment is not observed for all pigmentation alleles; in fact, the rs1426654-A allele of the SLC24A5 gene…shows instead an increase of frequency in South Asian…Taken together, our results point to opposite pressures on some West Eurasian alleles involved in skin and eye pigmentation. On one hand, SLC45A2 seem to have undergone some selective pressure that removed most of West Eurasian alleles that arrived in the area after the admixture event. Conversely, the SLC24A5 (rs1426654-A) West Eurasian allele seems to have escaped such a negative pressure perhaps thanks to its apparent neutral role with respect to susceptibility to skin carcinoma caused by UV radiation…

As I said, in the phylogenomic analysis above the authors suggest that the AASI population was homogeneous. I think this suggests that a single ancestral population was absorbed into expanding Iranian-related-farmers in NW South Asia. The prevalence of deeply diverged haplogroup M on the mtDNA in subcontinental peoples points to female mediated admixture. The positive selection for various “lifestyle” alleles indicates to me that expanding Iranian-related-farmers absorbed AASI tribes, in particular the women, and assimilated them to the new lifestyle.

The results from pigmentation are surprising, but not shocking. Knowing what I know about the ancestral frequency distribution of the various alleles, it was clear that the derived fraction of SLC24A5 was enriched. A lot of the other ones that are responsible for variation in Europeans looked either selected against or, the ancestral Indo-Aryans et al. were not quite like modern Europeans. These data point to in situ selection.

But why selection for some pigmentation alleles and not others? First, I don’t think cancer is a major selective pressure. That happens late in life. Rather, I think SLC24A5 in the derived variant does something that has nothing to do with pigmentation. It was positively selected among the Khoisan people of Southern Africa and looks to have been selected in Ethiopia as well after the admixture event. In Europe itself its frequency is so high that there has clearly been lots of positive selection since the “great admixture.”

As far as the other alleles, perhaps it is pigmentation. But perhaps it is something else?

Round and round we’ve been going with these genome-wide studies, but in the 2020s I think biologists who know the molecular pathways in a way that plumbs the depths of pleiotropy need to get involved.


20 thoughts on “Solute carrier family genes are important…but how?

  1. I am aware that I am asking questions about things that I know nothing about etc., in case you choose to reply:

    1. As far as the other alleles, perhaps it is pigmentation. But perhaps it is something else?

    Is this assertion saying that the other one, the variant of SLC45A2, was selected against because dark pigmentation was somehow helpful (even though cancer is not a major selective pressure)?

    2. By your comment about absorption into Iranian farmers are you diverging from the authors’ thesis about the dietary shift being post-neolithic (or in consonance say considering that iron-age clearing of gangetic forests could have popularized the dietary shifts)?

  2. Frequency of SLC45A2 seems extremely high for masked GIH-N in their Fig 3, with allele difference from GIH-S of about 0.9.

    That seems very high relative to what we would expect in from closest matching pops to the composite of West Eurasian ancestry (e.g. Tajiks).

    Is there any possibility that these reconstructions could be inflated by assortative mating and selection within South Asian populations? Such that SLC45A2 derived variant become more associated with the West Eurasian related ancestry, and this leads to inflated frequency estimates.

  3. @Razib:
    “I think SLC24A5 in the derived variant does something that has nothing to do with pigmentation. It was positively selected among the Khoisan people of Southern Africa and looks to have been selected in Ethiopia as well after the admixture event. In Europe itself its frequency is so high that there has clearly been lots of positive selection since the “great admixture.””

    Do you have an idea what other functions this allel could have? Also I would add that both Ethiopia and South Africa have, actually, a climate and lifestyle with effective UV radiation more suitable to light pigmented individuals than some parts of india. If we assume sexual selection plus the regional conditions, I think there is some reason why in Khoisan the allel was spread after the admixture with an Ethiopian-like population.
    Also, some of the Khoisan might have been fairly late newcomers to South Africa, in an already admixed form, in my opinion, and the Khoikhoi are lighter than the more desert living, more regional San probably.

    So I’m curious as to what other functions the allel might have, but want to stress that there is some logic in its spread in Africa.

    Talking even more about sexual selection, I think the skin tone, especially of females, can be more or less attractive not just depending on the lightness or darkness of the skin, but the exact tone. Like what the advertisements always try to create for darker skin tones, its this “golden brown” and “healthy” tone, with the less attractive skin tone being “grey brown”. This works even in the same light:dark category.
    In India I think its apparent on both an individual as well as an subpopulation scale, that there are such differences. I wonder how much some “light skin allels” effect an overall darker pigmentation in this respect, like make the skin tone “more shiny” and the like. I would say its time to look into such details, as well as regional preferences, to really estimate the possible effect of sexual selection.
    The same is true for very light Europeans of course, because a “more greenish or greyish” skin tone was surely not as attractive as the “milk & honey” skin tone associated with a healthy, top hormonal status female. And I think such appearances being effected by some of the “skin color” allels.

    The Khoisan by the way have more often a “golden brown skin tone”, interestingly some of the local Bantu “royals” prefer, if you look at it, females with almost exactly the same skin tone as the local Khoisan have it.

  4. Another aspect of this would be like if the Indian population could choose from more different allels, of which some are more harmless, while the Khoisan for example could not but picked what was available for skin tone change?
    Also, is there any kind of study comparing skin cancer rates of Khoisan people vs. Bantu? My impression is that among the local South African Bantu too there is some kind of selection towards somewhat lighter, more golden brown skin tones going on. This is particularly noticeable in comparison to the Mocambique and upwards, but could be attributed to “neutral admixture” as well.

  5. Could sunburn of both skin and eyes exert some of the pigmentation pressures? Especially if the changed economies required people to spend more time in the sun?
    For Europeans and Khoesan, it could have been a balancing act driven by relative shortages of both dietary and skin produced vitamin D?

  6. Also I would add that both Ethiopia and South Africa have, actually, a climate and lifestyle with effective UV radiation more suitable to light pigmented individuals than some parts of india.

    But Ethiopia is close to the equator and at a fairly high altitude, both of which lead to high UV exposure. What about Ethiopia makes you think it is relatively suitable to light pigmented individuals?

  7. @Roger: Ethiopia has a varied climatic and topographic landscape, with regions which are far cooler and drier than other places in Africa and India in particular. Also the more West Eurasian Afro-Asiatic ethnicities of the region, as a rule, wore more protective clothes. And in the end its needless to say that they are not actually light pigmented for the standards of Europeans or Indo-Aryans if we take Sintashta as a reference, not even Iranians and Iranian related ancestry. There are just lighter than Niger-Kordofan people and less West Eurasian Afro-Asiatics, not as light as Europeans. So its relative to other Subsaharan Africans, not relative to Indians or even Europeans.
    You can come to the same level of depigmentation with different allels, that should be a given.

    However, my hypothesis should be easy to test for the Indian example, by comparing the provinces for which the selective purification took place vs. those which did not. If in a tropical Southern zone in which many common people wore little clothing especially at work in the sun it did not happen, but in a Northern, cooler and drier zone with more traditional clothing it did, it would falsify me.
    I did only a quick check so far, couldn’t read the full paper in meantime, but in Fig. 4 you can see that the climate correlation works for SLC24A5 fairly well, but for SLC45A2 its only present in those which have little to no AASI admixture and live in the highlands of the North West. So this is peculiar. In that sense it seems SLC24A5 was adaptive like expected for a pigmentation allel, while SLC45A2 is not.

    So either it has additional unknown consequences unrelated to sheer pigmentation, like Razib suggested, or it “wasn’t used” because of better alternatives available, which suited the region better (including diseases probably?), or both.
    I think there are oftentimes economic ways to the same goal and if you have a better alternative which is even more economic, you pick it. Does anyone have the numbers for SLC24A5 in Ethiopians and Khoisan? Whether its present there at all and at which frequency?

  8. Found it and it also points to my interpretation even within a related group, at least for SLC24A5:
    “Moreover, the genetic, geo-climatic, and demographic differences between the Wolaita and the Ari may have masked the selection signal during combined analysis of the ethnic samples in the previous study.”

  9. Here is one hypothesis for the south Asian specific pattern- the A5 selection happened earlier on, so when A2 arrived with the steppe people, having both A2 and A5 produced skin that is too fair for the general south Asian environment. The lightness brought by A5 was not disadvantageous enough to select against it.

    Though I don’t know why A5 was chosen over A2 among the African populations that were mentioned. I guess for Ethiopians it could be once again because the incoming population only had appreciable frequency of A5. Don’t know bout the case with the Khoisan, where did they get it from? The recent European contact? If it is from the recent European contact then there might be something about A5 being preferred over A2 under certain levels of UV radiation, but if it predates the European contact, then it could be just another case of A5 already being there and A2 in addition just not being useful, and perhaps even counterproductive.

  10. The positive selection for various “lifestyle” alleles indicates to me that expanding Iranian-related-farmers absorbed AASI tribes, in particular the women, and assimilated them to the new lifestyle.
    @Razib wrt the above comments – Are there any Y chromosomes from AASI which are frequent in India or are most of the Y Chromosomes IVC/Aryan/Munda ?

  11. That seems very high relative to what we would expect in from closest matching pops to the composite of West Eurasian ancestry (e.g. Tajiks).

    the tajiks are about 20% east asian now. so i think that’s misleading

  12. Razib,

    I think Matt has the Pamiris in mind; they’re only 5-10% East Asian, and around 40-50% Steppe_MLBA. They’re labeled “Tajik_Shugnan”, “Tajik_Rushan”, etc, so people often forget that they aren’t technically “Tajik” (they don’t speak dialects of Persian). They’re East Iranian speakers, like Pashtuns and Ossetians.


    There are quite a few issues involved here; I agree that this sort of analysis isn’t as straightforward as we’d hope.

    On the brightside, we do have a contemporary South Asian population that is exceddingly close to being “pure” “ANI”: the Jats and Rors of Haryana (not Punjabi Sikh Jatts though, and certainly not Muslim Jutts from Pakistan).

    ^ Based on the samples that we have, these two populations have a mere 15% or so of AASI admixture (which is rather minor, considering that most Indian populations range between 40-60% AASI). And unlike Tajikistanis, those Haryanvi populations are not enriched for BMAC-related admixture. Nor do they have any serious signals of West Asian/Iranian plateau admixture (Tajikistanis show some of that too… later genetic connections with Iran, postdating BMAC).

    Minus the approximately 15% AASI/ENA, the Haryanvi Jats and Rors are essentially South Asian-specific Iran_N-related + Eurasian steppe (35% Steppe_MLBA + 5% Botai/Dali_EBA-related).

    I don’t know anything about their pigmentation genetics though. It might be worth looking into.

  13. @Razib, right, like Sein said. There are some different Tajik populations, and I’m aware some have high East Asian ancestry (I think some actually higher than 20%). The ones in Davidski’s Global25 aren’t Burusho like in ENA fraction or anything like this.

    E.g. in PCA using data from the Global25 PCA fed back through PCA:

    The Tajik populations are about 9% displaced towards Han_N_China along an axis between Sintashta (Steppe_MLBA) and Gonur1BA (BMAC). So that suggests about 9% ancestry, as Sein mentions.

    The population labelled Yaghnobi has particularly less ENA ancestry than others.

    Some of that may actually even be a reflux of AASI related ancestry also –

    These are the populations I tend to think of as “Tajiks” since they come up so much in the Eurogenes analyses, but admittedly this is imprecise and there are others. I still think its fair to say that at least for these populations (perhaps not some other Tajiks out there) they’re probably the closest extant population to the overall composite of West Eurasian ancestry in South Asians (however we believe that composite was assembled!).

    @Sein that may be interesting point, though the counterargument would be that, were SLC45A2 derived variant low, it still may due to selection. I don’t know, I like that people are using these methods to compensate for the inherently coverage and sparse sampling of ancient dna, but there may be no substitute.

  14. I wouldn’t count out the Emperor Of Maladies yet…

    Say someone like me gets melanoma at 30 (which I did) and it’s not treated. His sons are orphaned when he’s 35 when they’re aged 1-15. This is a disruption to their development as children and young-adults. Some will be prey to pederasts, as orphaned children too-often are in our world. Others are objects of pity. Their chances of having children of their own are that much hampered.

  15. Its also remarkable that the two regions of Subsaharan Africa which are the most depigmented are also those which have the lowest level of the sickle cell allele, even though that is clearly related to the fact that “Negroid proper” is the most adapted to survive Malaria, but the allele has an interesting distribution nevertheless, even beyond Africa.
    In the same way one could argue that the skin is an important organ for the well being and health of an individual, its immune response and genes which influence the skin could also influnce organs like the intestines or something like that. So probably its related to the skin structure, but not just by making it lighter, but changing it in other ways too? Who knows, talking about pathogens and diseases, there could be totally unexpected effects. Like some y- and mtDNA haplogroups are more susceptible to some dieseases, why not with this allel? Probably in combination with another factor, allele?
    And the conditions in Ethiopia and India must not be the same, like the whole genetic architecture too must not be exactly the same.

  16. Could sunburn of both skin and eyes exert some of the pigmentation pressures? Especially if the changed economies required people to spend more time in the sun?

    I came to comment just that. The tropical sun is unforgiving, especially if you have toil all day in the open field. This would explain the African scenario, where the agricultural Bantu are way darker than the Khoisan.

  17. @moscanarius, the HG Hadza and pygmies are pretty much like the agricultural populations in this trait tho.

  18. An obvious place to look would be the neural crest. Neural crest cells give rise to pigment cells, craniofacial bones and cartilage, parts of the peripheral nervous system and endocrine cells. Among these cell types are catecholamine synthesizing cells of the adrenal medulla (chromatin cells) and peripheral sympathetic and sensory neurons. Interestingly, melanocytes and catecholamines share the same precursor, L-Tyrosine, as depicted here:

    I am wondering if certain aspects of sympathetic nervous system function and depigmentation evolved together due to the possible advantages in lightless environments such as caves. This link to the stress response could also explain the association between depigmentation and the domestication syndrome. I could envision a scenario where some depigmentation is selected for as human population densities have increased but this is greatly modified by UV exposure. Obviously there is a lot of variation in coat color among domesticated animals, though.

  19. How does sexual selection against light pigmentation jive with the normal status of light skin being something associated with wealth?

    Isn’t it also possible there was no sexual selection against and that we are just seeing a lack of sexual selection for?

    Who are the 4 population who don’t exhibit this selection against?

    I’ll read the paper when I can. Maybe my questions will be answered.

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