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Author Topic: A... Complex Architecture for Skin Pigmentation in Africans
Mansamusa
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An Unexpectedly Complex Architecture for Skin Pigmentation in Africans
Skin Pigmentation in Africans

New study on skin pigmentation in Africa among the San and Nama. Most relevant detail as far as I am concerned:

"We find that derived variants in SLC24A5, including missense mutations that influence skin and eye pigmentation ( Table 2), are at high frequency in the KhoeSan. Notably, these variants are segregating at higher frequency than expected by recent European admixture alone. Three possible evolutionary scenarios that may explain these elevated frequencies are as follows: (1) these variants arose in southern Africa more than 100,000 years ago and were later selected for in Europeans after the out-of-Africa migration in response to northern UVR environments;

(2) these variants arose in Europe and the Near East, were introduced into KhoeSan populations via “back-to-Africa” migration into southern Africa predating 17th century European colonialism ( Pickrell et al., 2014 ; Uren et al., 2016) and have since been positively selected in the KhoeSan; or

(3) a recurrent mutation (G to A transition at the CpG ancestral dinucleotide, a class of mutations shown to have elevated mutation rates) occurred. Considerable future work is needed to definitively disentangle these scenarios."

Please discuss, which one of the three is most likely, and why.

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capra
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3 - no, because G111A mutation is on the same C11 haplotype background in Africa and Eurasia - it is not just that one SNP but other SNPs nearby that match. If it arose more than once independently we'd expect it to occur on more than one SLC24A5 haplotype (there are many).

1 - according to Canfield et al (2013) the C11 haplotype seems to have come about by recombination of Out-of-Africa haplotypes C3 and C10, most likely in the Middle East, followed by the G111A mutation; the derived variant is estimated to be about 30 000 years old (in recent Tishkoff paper); and this same lab (Henn, Lin, et al) in a conference presentation earlier this year argued that the derived allele was introduced recently to Khoisan.

So unless they've made some very recent surprise discovery it's number 2. In fact it seems like they have already done the research they are talking about, they just haven't published it in a journal yet!

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Elite Diasporan
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Very good study and read. In terms of process of elimination it cant be #2 imo. Because if that were the case then East Africans TOO should have this mutation since hunter gatherer Southern African populations aquired their Eurasian admixture from East Africans.
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capra
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East Africans *do* have it. For instance Ethiopian Jews have 54% frequency of the derived allele, Maasai (MKK) 33%, Sandawe 12%, Luhya (LWK) 7%.

From here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815065/bin/supp_g3.113.007484_TableS1.pdf

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Elite Diasporan
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^Didnt know. But thanks. But Khoisans most likely recieved it from them than directly fron Eurasians.
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Elmaestro
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Canfields Haplotypes were based on a handful of Africans.. Most of which lacked the mutation or have a recombine haplotype, iirc.

What is G111A?

Mutation is T > A, aka A111T or Thr111Ala as of the OP.

Also, notice variant(s) is plural. multiple mutations at the loci are now being respected and the divergent frequencies between the samples raises the question. Tbh, there's quite a bit of diversity for less than 2 millenia worth of selection.

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Elmaestro
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Just skimmed the study and TBH at first glance I honestly don't see the need for it, being that it offers no new questions nor answers to those that were already asked. There's straight forward quotable passages though, I'd give it that..

quote:
"Because African populations often carry the ancestral (i.e. dark) allele for skin pigmentation genes identified in Eurasians, allusions to African skin pigmentation have ignored the great variability in this phenotype across Africa. Here, we reiterate that skin pigmentation varies more in Africa than any other continent, and we show that pigmentation in African populations cannot simply be explained by the small number of large effect alleles discovered in Eurasians. Even in light to moderately pigmented KhoeSan populations, the polygenicity of skin pigmentation is much greater than Eurasians, encompassing both known pigmentation genes as well as novel loci. We argue that the distributions of skin pigmentation globally suggest different forces of selection operating at various latitudes. To better understand baseline pigmentation, one of the most rapidly-evolving traits and strongest cases for positive selection in humans, it is essential to quantitatively measure and study pigmentation in a large set of genetically diverged populations that have historically been exposed to different levels of UV radiation. As human genetics moves to ever larger studies of complex traits (Wood et al., 2014), the full picture of genetic architecture will remain incomplete without representation from diverse worldwide populations."
I mean, they don't bother to address the presence or lack off Canfields c11-A111T Hg... So nothing can really be concluded as it relates to SLC24a5... If you ask me, the shit just got more convoluted now that we're seeing all these linked variants and how they differ between populations.


quote:
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"FST in canonical pigmentation genes; Dots indicate SNPs, lines indicate moving averages over 20 kb windows with a step size of 5 kb. Canonical pigmentation loci/genes are shown as: C) the OCA2-HERC2 locus, and D) the SLC24A5 gene."


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Mansamusa
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quote:
Originally posted by capra:
3 - no, because G111A mutation is on the same C11 haplotype background in Africa and Eurasia - it is not just that one SNP but other SNPs nearby that match. If it arose more than once independently we'd expect it to occur on more than one SLC24A5 haplotype (there are many).

1 - according to Canfield et al (2013) the C11 haplotype seems to have come about by recombination of Out-of-Africa haplotypes C3 and C10, most likely in the Middle East, followed by the G111A mutation; the derived variant is estimated to be about 30 000 years old (in recent Tishkoff paper); and this same lab (Henn, Lin, et al) in a conference presentation earlier this year argued that the derived allele was introduced recently to Khoisan.

So unless they've made some very recent surprise discovery it's number 2. In fact it seems like they have already done the research they are talking about, they just haven't published it in a journal yet!

Your standards seem pretty low when it comes to proof of Eurasian aorigin. Just because the date for the derived variant might be younger than out of Africa (30 000 years old) does not automatically rule out an African origin.
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Mansamusa
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I realize the study is behind a pay wall. My university gives free access. So let me post some extracts.
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Mansamusa
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This is the Introduction:

"Skin pigmentation is one of the most strikingly variable and strongly selected phenotypes among human populations, with
darker skin observed closer to the equator and lighter pigmenta- tion observed at high latitudes (Sturm and Duffy, 2012). Researchers have hypothesized that variable exposure to ultravi- olet radiation (UVR) creates opposing selective forces for vitamin D production and folate protection, resulting in variable melanin production and global pigmentation differentiation (Chaplin and Jablonski, 2009; Jablonski and Chaplin, 2010). Skin pigmentation differences at similar latitudes and UV expo- sures indicate that additional evolutionary forces, such as assor- tative mating, drift, and epistasis, are also likely to have affected global skin pigmentation (Po ́spiech et al., 2014; Wilde et al., 2014). While $171 genes have been implicated in variability across model organisms (e.g., the Color Genes database: http://www.espcr.org/micemut/), only $15 genes have been associated with skin color differences in humans (Table 2). The relative paucity of loci identified from genome-wide association study (GWAS) efforts has led to the characterization of pigmenta- tion variation as relatively simple, with only a handful of SNPs be- ing highly predictive of skin, eye, and hair color across populations (Hart et al., 2013; Spichenok et al., 2011; Walsh et al., 2013).

Despite Africa being home to the greatest range of pigmenta- tion globally, remarkably few genetic studies of pigmentation have been published to date in continental Africans (Crawford et al., 2017; Jablonski and Chaplin, 2014; Relethford, 2000). Instead, the genetic basis of skin color has primarily been stud- ied in Eurasians and admixed African Americans (Beleza et al., 2013a, 2013b; Candille et al., 2012; Sturm and Duffy, 2012; Sulem et al., 2007, 2008); selective sweeps in high-latitude pop- ulations have been interpreted as resulting from strong environ- mental selection pressure. For example, the derived Ala111Thr allele (rs1426654) of SLC24A5 that swept to near fixation in
1340 Cell 171, 1340–1353, November 30, 2017 © 2017 Elsevier Inc.
western Eurasian populations confers the largest known effect on skin color variability (Beleza et al., 2013b; Lamason et al., 2005). Loci in/near SLC45A2, GRM5/TYR, and APBA2/OCA2 also have divergent allele frequencies between Europeans and Africans, with large lightening effects in Europeans (Beleza et al., 2013b; Norton et al., 2007). Smaller effects, including associations in/near MC1R, TYR, IRF4, and ASIP, contribute to the relatively narrow variation within Europeans (Sulem et al., 2007, 2008). Light skin pigmentation in Eurasians arose through both convergent evolution (e.g., rs1800414 in OCA2 in East Asians) and similar selective sweeps (e.g., KITLG) (Miller et al., 2007; Yang et al., 2016). Because African populations have been under-studied, the genetic architecture and higher vari- ability of skin pigmentation is poorly understood.

Strong positive selection acting on skin pigmentation has resulted in large effects that explain a large fraction of heritable variation. For example, a previous study in recently admixed Cape Verdeans with European and West African ancestors showed that only 4 loci explain 35% of the variation in skin pigmentation (Beleza et al., 2013b). In contrast, complex traits such as height and schizophrenia require $10,000 independent SNPs derived from GWAS of >100,000 individuals to build predictors that explain $29% and $20% of the variance in inde- pendent cohorts, respectively (Ripke et al., 2014; Wood et al., 2014). Previous studies of positively selected traits—such as pigmentation, high-altitude adaptation, and response to patho- gens—have repeatedly produced larger effect sizes than com- plex common disease; these large-effect loci have typically been discovered with relatively small sample sizes (i.e., approx- imately hundreds of individuals) compared to common diseases (Genovese et al., 2010; Kenny et al., 2012; Yi et al., 2010). It is noteworthy that effect size estimates of significant polymor- phic GWAS loci tend to be directionally consistent across populations (Carlson et al., 2013), but that aggregate prediction accuracy varies across populations (Martin et al., 2017).
Striking skin pigmentation variability among African popula- tions has been underappreciated in genetic studies (Jablonski and Chaplin, 2014; Relethford, 2000). Light skin pigmentation is observed in the far southern latitudes of Africa among KhoeSan hunter-gatherers and pastoralists in and near the Kalahari Desert. The KhoeSan are unique in their early divergence from other pop- ulations, likely dating back at least $100,000 years (Schlebusch et al., 2012; Veeramah et al., 2012); they exhibit extraordinary levels of genetic diversity and low levels of linkage disequilibrium (LD) (Henn et al., 2011). Previous work points to southern Africa as the point of origin for modern humans (Henn et al., 2011; Tishkoff et al., 2009), but it is unknown whether moderate to light skin pigmentation in the different KhoeSan populations is an example of convergent evolution with northern Europeans and Asians or reflects the ancestral human phenotype. Previous studies have noted different pigmentation allele frequencies between the Juj’hoansi San and other Africans, but these have been based on fewer than 7 individuals from the former population without measured phenotypes (Berg and Coop, 2014; Norton et al., 2007). We use the term ‘‘KhoeSan’’ to refer to a diverse array of indigenous populations in southern Africa that carry KhoeSan ancestry and speak Khoe, !Ui-Tuu, or Kx’a languages. ‘‘KhoeSan’’ is not accepted by all such communities; where
possible, we refer to populations by their specific ethnic name. This grouping lumps together populations of different languages, cultures, and variable genetic diversity.

Here, we report an evolutionary and genetic study of skin pigmentation with a total of 465 genotyped KhoeSan individuals (278 zKhomani San and 187 Nama), with targeted resequencing at associated pigmentation loci and matched quantitative spectrophotometric phenotype data (Table S4). The zKhomani San are traditionally a Nju-speaking hunter-gatherer population living in the southern Kalahari Desert, while the Nama are tradi- tionally a Khoekhoe-speaking semi-nomadic pastoralist group of KhoeSan ancestry. We investigate (1) the degree of polygenic- ity and heritability of skin pigmentation, (2) the extent of pigmen- tation variation explained by previously associated or canonical pigmentation genes, and (3) novel pigmentation alleles contrib- uting to variation in the zKhomani San and Nama populations."

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capra
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quote:
Originally posted by Elmaestro:
Canfields Haplotypes were based on a handful of Africans.. Most of which lacked the mutation or have a recombine haplotype, iirc.

What is G111A?

Also, notice variant(s) is plural.

Yeah, I noticed they said plural but then they don't list any other loci in that gene in the table.

G111A is brain fart when you are thinking of the amino acid change and the nucleotide change (G>A) at the same time. [Big Grin]

Canfield had 696 HapMap African samples (counting both chromosomes), not including ASW, that is not exactly a handful. Global coverage is pretty poor overall, sure.

http://meeting.physanth.org/program/2017/session33/henn-2017-rapid-evolution-of-lighter-skin-pigmentation-in-southern-africa.html

"We high-throughput sequenced pigmentation genes in over 400 individuals from South Africa and demonstrate that a canonical skin pigmentation gene, SLC24A5, experienced recent adaptive evolution in the KhoeSan populations of far southern Africa.... Haplotype analysis and demographic models indicate that the allele was introduced into the KhoeSan only within the past 3,000 years likely by eastern African pastoralists. The most common haplotype is shared among the KhoeSan, eastern Africans and Europeans but has risen to a frequency of 25%, far greater than expected given initial gene flow."

So it is the same haplotype.

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