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Cited by 157melanin and skin pigmentationGenetic Associations and EpidemiologyRace, Genetics, and Society

An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

Open access
Martin, Alicia R., Lin, Meng, Granka, Julie M., Myrick, Justin W., Liu, Xiaomin, Sockell, Alexandra, Atkinson, Elizabeth G., Werely, Cedric J. +10 more·2017·Cell
DOI 10.1016/j.cell.2017.11.015PMC PMC5884124

Published version of a preprint

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Abstract

Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed, with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan populations indigenous to southern Africa who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13, using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.

AI snapshot

Written from the paper’s full text.

TL;DR

Skin pigmentation in KhoeSan populations is highly heritable, but known pigmentation loci explain only a small fraction of variation, indicating a more polygenic architecture than in Eurasians. The study identifies both canonical and non-canonical associations and shows that global pigmentation variance varies with latitude.

Key findings

  • In a global survey of 4,712 individuals across 32 populations, absolute latitude was associated with mean skin pigmentation (R²=0.53, β=−1.18 on M index scale, p<2e-16) and negatively associated with the standard deviation in melanin (R²=0.41, p=5.0e-5); lighter populations had reduced phenotypic variance.
  • Among 479 phenotyped KhoeSan (277 ‡Khomani, 202 Nama), baseline upper-arm M index was 57.57±10.12 in ‡Khomani and 52.12±8.93 in Nama; ‡Khomani were significantly darker (p=3.6e-10). Baseline pigmentation was highly heritable: h²pedigree=0.96±0.12, h²g=0.97±0.15, h²exome=0.95±0.26, and h²IBD=0.97±0.15, while tanning-status heritability estimates were not significantly greater than 0.
  • Known pigmentation gene sets explained little heritability: GS1 σ²=0.08 vs genome σ²=0.82 (p=2.7e-5); GS2 σ²=0.09 vs genome σ²=0.79 (p=3.3e-4); GS3 σ²=0.23±0.13 (p=0.027) vs genome σ²=0.64±0.08. Fixed admixture effects explained 34% of skin-color variation.
  • Associations included SLC24A5 rs1426654 (β=−3.58, p=9.8e-9) and rs2470102 (β=−3.4, p=3.6e-12), an upstream TYRP1 signal (chr9:12088112, β=−13.6, p=1.1e-7), SNX13 rs2110015 (β=−3.1, p=1.3e-7), and low-frequency signals near SMARCA2/VLDLR (rs7866411 p=8.91e-5; rs2093835 p=1.17e-4). Most previously identified pigmentation associations did not replicate.

Methods

  • Skin pigmentation was measured quantitatively with a DermaSpectrometer DSMII; baseline M index was taken from upper inner arms, and tanning status was wrist minus baseline. The study phenotyped 479 individuals and genotyped 465 KhoeSan (278 ‡Khomani, 187 Nama), with exome and targeted resequencing in subsets.
  • A two-stage GWAS used imputed variants in phase 1 (107 ‡Khomani, 109 Nama), added 240 individuals in phase 2, and meta-analyzed results. Linear mixed models included admixture covariates and a REAP kinship matrix; targeted resequencing covered candidate pigmentation regions in 451 KhoeSan (269 ‡Khomani, 182 Nama) per the Results.
  • Heritability and variance partitioning used SOLAR pedigree analysis, GCTA REML with REAP/GCTA/IBD/exome matrices, and gene-set comparisons (GS1, GS2, GS3 vs rest of genome). Ancestry was estimated with ADMIXTURE/PCA and local ancestry with RFMix.

Limitations

  • The paper states that most known pigmentation associations did not replicate, potentially due to low allele frequencies, power limitations, differentiated LD structure where tag SNPs are non-causal, or epistatic effects. It also states that three possible evolutionary scenarios for elevated SLC24A5 variant frequencies require future work, and that fuller characterization is needed to distinguish directional versus stabilizing selection.
  • The paper notes that continental Africans remain understudied and that the study focuses on two KhoeSan populations, the ‡Khomani San and Nama, both with recent European and Bantu admixture.
  • Evident from the text: targeted resequencing was limited to candidate regions, imputation relied on reference panels, and GWAS sample sizes were modest relative to large complex-trait studies; baseline phenotype was upper inner-arm M index, while tanning status was largely environmental.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2017.11.015

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Skin pigmentation is strongly associated with absolute latitude; populations further from the equator have lighter skin pigmentation.

    “As previously observed (Byard, 1981; Jablonski and Chaplin, 2010; Zaidi et al., 2017), we find that skin pigmentation is strongly associated with absolute latitude (R2=0.53, β=−1.18 on M index scale, p<2e-16); populations further from the equator have lighter skin pigmentation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Byard, 1981 source

      Not checked in the free run.

    • cites Jablonski and Chaplin, 2010 source

      Not checked in the free run.

    • cites Zaidi et al., 2017 source

      Not checked in the free run.

  • Findingown data

    Known pigmentation loci explain only a small fraction of the variance in skin pigmentation in the KhoeSan.

    “We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance.”
    Quote in the paperSubstantial claim
  • Findingown data

    Canonical and non-canonical skin pigmentation loci were identified near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13.

    “Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing.”
    Quote in the paperSubstantial claim
  • Findingown data

    Skin pigmentation is highly heritable in the KhoeSan.

    “We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the larger resequencing sample, more variants are significantly associated with pigmentation than expected by chance in the resequencing regions.

    “In this larger sample, we observe more variants significantly associated with pigmentation than expected by chance in the resequencing regions (Figure 5A).”
    Quote in the paperSubstantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    Skin pigmentation is more complex than previously assumed, with genetic architecture varying by latitude.

    “However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs2555364 is the most strongly associated SNP (β=−3.58, p=6.7e-9) and is tightly linked with rs1426654 (LD R2=0.81).

    “The most strongly associated SNP (rs2555364, β=−3.58 on M index scale, p=6.7e-9) is tightly linked with rs1426654 (LD R2=0.81).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both Nama and ‡Khomani have ~75-80% KhoeSan-specific ancestry.

    “At k=3, we observe distinct clustering between Europeans, Bantu-speaking and West African populations, and KhoeSan populations; both the Nama and the ‡Khomani have ~75–80% KhoeSan-specific ancestry.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both GS1 and GS2 explain more phenotypic variation than random genes with a 10% false discovery rate across both KhoeSan populations.

    “After regressing out the effect of variable numbers of SNPs per gene set (STAR Methods), we find that both GS1 and GS2 explain more than random genes with a 10% false discovery rate (FDR=0.016 and FDR = 0.079, Figure 3C–D, respectively) across both KhoeSan populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs1426654 has β=−3.58 on M index scale, p=9.8e-9.

    “We identify significant associations between lighter skin and derived SLC24A5 SNPs, including the putatively causal p.Thr111Ala rs1426654 allele (β=−3.58 on M index scale, p=9.8e-9), which has previously been associated with skin pigmentation in Eurasians.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The strongest signals across genotyped ‡Khomani and Nama cohorts were near canonical pigmentation genes, genes associated with pigmentation-related disorders, or genes implicated in pigmentation in model organisms and in vitro studies.

    “Further, the strongest signals across the genotyped ‡Khomani and Nama cohorts were near canonical pigmentation genes (e.g. TYRP1 and SLC24A5), genes associated with pigmentation-related disorders (e.g. TYRP1), or genes implicated in pigmentation in model organisms and in vitro studies (e.g. VLDLR, SMARCA2, and others) (Sturm, 2009) (Keenen et al., 2009a; Xia et al., 2013a).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sturm, 2009 source

      Not checked in the free run.

    • cites Keenen et al., 2009a

      Not checked in the free run.

    • cites Xia et al., 2013a

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  • May combine two claims.

    Findingown data

    Europeans and East Asians have significantly less variation than South Asians.

    “Europeans and East Asians have significantly less variation than South Asians (F=0.25, p=1.06e-14 and F=0.30, p=1.27e-10, respectively, Figure 1B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Cape Verdeans with the highest quartile of European admixture have lighter, less variable skin color than individuals with the lowest quartile of European ancestry.

    “Cape Verdeans with the highest quartile of European admixture have lighter, less variable skin color than individuals with the lowest quartile of European ancestry (p=4.28e-9, although notably ancestry proportions are bimodal across individuals).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The derived allele frequencies of the associated SNPs in SLC45A2 and KITLG are low in the KhoeSan, consistent with ~10% admixture from recent European gene flow.

    “The derived allele frequencies of the associated SNPs in SLC45A2 and KITLG are low in the KhoeSan, consistent with ~10% admixture from recent European gene flow.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Tanning status is primarily environmental, with heritability estimates not significantly different from zero.

    “In contrast, tanning status is primarily environmental, with heritability estimates which are not significantly different from zero.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The strongest allelic associations include previously associated variants, noncoding regions near canonical pigmentation genes, and novel genes shown in model organisms to have a role in pigmentation.

    “The strongest allelic associations include previously associated variants, noncoding regions near canonical pigmentation genes, and novel genes shown in model organisms to have a role in pigmentation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    rs34803545 is perfectly linked with multiple conserved variants, one of which exhibits enhancer activity and DNAse hypersensitivity specifically in skin.

    “This variant is perfectly linked with multiple conserved variants, one of which exhibits enhancer activity and DNAse hypersensitivity specifically in skin (Table S6B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Derived variants in SLC24A5 are at high frequency in the KhoeSan, including missense mutations that influence skin and eye pigmentation.

    “We find that derived variants in SLC24A5 are at high frequency in the KhoeSan, including missense mutations that influence skin and eye pigmentation (Table 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Skin pigmentation varies more in Africa than any other continent.

    “Here, we reiterate that skin pigmentation varies more in Africa than any other continent”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Populations at intermediate latitudes have increased variance and higher means than populations in northern Eurasia, but less than equatorial populations.

    “Finally, populations at intermediate latitudes have increased variance and higher means than populations in northern Eurasia, but less than equatorial populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Populations with lighter skin have reduced variation within any given study: populations furthest from the equator have narrower distributions, while populations closest to the equator have wider distributions.

    “We also observe that populations with lighter skin have reduced variation within any given study: populations furthest from the equator have narrower distributions, while populations closest to the equator have wider distributions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Pigmentation variation has been characterized as relatively simple, with only a handful of SNPs highly predictive of skin, eye, and hair color across populations.

    “The relative paucity of loci identified from GWAS efforts has led to the characterization of pigmentation variation as relatively simple, with only a handful of SNPs being highly predictive of skin, eye, and hair color across populations (Hart et al., 2013a; Spichenok et al., 2011; Walsh et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Hart et al., 2013a

      Not checked in the free run.

    • cites Spichenok et al., 2011 source

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    • cites Walsh et al., 2013 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Approximately 15 genes have been directly associated with skin pigmentation variation in humans.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    There is reduced genetic heterogeneity and/or reduced variance in the population distribution of causal effect sizes contributing to lighter versus darker pigmentation.

    “These results suggest that there is reduced genetic heterogeneity and/or reduced variance in the population distribution of causal effect sizes contributing to lighter versus darker pigmentation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Admixture increases phenotypic variance, but pigmentation alleles on KhoeSan haplotypes contribute more to overall heterogeneity than those on European or Bantu haplotypes.

    “These results suggest that while admixture increases phenotypic variance, pigmentation alleles on KhoeSan haplotypes contribute more to the overall heterogeneity than those on European or Bantu haplotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The high baseline pigmentation heritability estimates do not simply arise from pedigree and population structure and socioeconomic factors are unlikely to have significant effect.

    “The stark contrast of the baseline pigmentation and tanning status heritability estimates, and the consistency of h2 across methods indicates that our high baseline pigmentation heritability estimates do not simply arise from pedigree and population structure and that socioeconomic factors are unlikely to have significant effect on our heritability estimates.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The spectrophotometer was calibrated to 0 as suggested by the manufacturer twice a day while sampling.

    “The device was calibrated to 0 as suggested by the manufacturer twice a day while sampling.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SLC24A5 is a well-known pigmentation gene.

    “which is a well-known pigmentation gene (Lamason, 2005)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lamason, 2005 source

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    The proportion of European and Bantu ancestry estimated via ADMIXTURE was included as fixed effect covariates for baseline pigmentation and tanning status, as chosen in forward stepwise regression.

    “We included the proportion of European and Bantu ancestry estimated via ADMIXTURE as fixed effect covariates for baseline pigmentation and tanning status, as chosen in forward stepwise regression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    There may be biological constraints on the lower boundary of skin pigmentation, and/or due to strong positive selection acting on a few large-effect alleles, there is little genetic variability left at these pigmentation loci.

    “There may be biological constraints on the lower boundary of skin pigmentation, and/or due to the strong positive selection acting on a few large-effect alleles, there is little genetic variability left at these pigmentation loci.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The Nama and ‡Khomani San appear to be two instances of intermediate variation within Africa, likely attributable to their geographic distance from the equator in far southern Africa (~24-29 degrees South).

    “The Nama and ‡Khomani San appear to be two such instances of this intermediate variation within Africa, likely attributable to their geographic distance from the equator in far southern Africa (~24–29 degrees South).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    IRB approval was obtained from Stanford University, Stony Brook University, and the University of Stellenbosch, South Africa.

    “Institutional review board (IRB) approval was obtained from Stanford University, Stony Brook University, and the University of Stellenbosch, South Africa.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Imputation accuracy was assessed by concordance with low-pass genome sequences and high-coverage exome sequencing, and by PCA; the primary source of aggregated imputed variation was concluded to be population/familial structure rather than technical artifacts.

    “We assessed the accuracy of the imputation in three ways. First, we assessed the homozygous reference, heterozygous, and homozygous non-reference concordance between the imputed output and two low-pass genome sequences from individuals SA1000 and SA1025 at sites that passed variant call filters and with > 5 reads.”
    • Also stated in: § METHOD DETAILS · plain
      “By investigating the top PCs, we concluded the latter.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    The observed mean and variance differences across the full spectrum of skin pigmentation by latitude may be driven by imbalanced opposing adaptive pressures, where selective forces to produce vitamin D and protect folate from photolysis are unequal and change in response to UV radiation exposure.

    “The observed mean and variance differences across the full spectrum of skin pigmentation by latitude may be driven by imbalanced opposing adaptive pressures, where selective forces to produce vitamin D and protect folate from photolysis are unequal and change in response to UV radiation exposure.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Selective forces to produce vitamin D and protect folate from photolysis are unequal and change in response to UV radiation exposure.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Age and sex covariates were included for tanning, and they were significantly associated with the phenotype.

    “We also included age and sex covariates for tanning, which were significantly associated with the phenotype.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In equatorial regions, strong directional selection for darker pigmentation has shifted the distribution means in some populations to M indices greater than 90, but with wide variances.

    “In equatorial regions, strong directional selection for darker pigmentation has shifted the distribution means in some populations to M indices greater than 90, but with wide variances.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Pigmentation has been described previously as a relatively simple trait with few loci of large effect contributing to the phenotype.

    “Pigmentation has been described previously as a relatively simple trait with few loci of large effect contributing to the phenotype (Sulem et al., 2007; Walsh et al., 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sulem et al., 2007 source

      Not checked in the free run.

    • cites Walsh et al., 2013 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SLC24A5 is among the most differentiated regions of the genome between European and African populations, indicative of strong positive selection in northern Europeans.

    “and is among the most differentiated regions of the genome between European and African populations–indicative of strong positive selection in northern Europeans (Sturm and Duffy, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sturm and Duffy, 2012

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The total genomic length of inferred cumulative IBD between pairs of individuals was verified by comparing to pedigree relationships identified from ethnographic interviews and verified with IBD inferred from genotyping arrays.

    “We verified the total genomic length of the inferred cumulative IBD between pairs of individuals by comparing to pedigree relationships identified from ethnographic interviews and verified with IBD inferred here from the genotyping arrays.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Skin pigmentation is a far more complex trait than previously discussed, analogous to numerous other complex traits discussed in biomedical literature.

    “This suggests that skin pigmentation is a far more complex trait than previously discussed, analogous to numerous other complex traits discussed in biomedical literature.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All individuals gave signed written and verbal consent with a witness present before participating.

    “All individuals gave signed written and verbal consent with a witness present before participating.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The REAP kinship matrix correlated best with true relationships and was used to correct for kinship in all regression models unless otherwise noted.

    “We used the REAP matrix to correct for kinship in all regression models unless otherwise noted because it correlated best with true relationships (e.g. heritability analyses with different kinship matrices).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    More than 50 loci, and likely far more, with a distribution of mostly small effects contribute to variation in pigmentation in the KhoeSan.

    “suggesting that more than 50 loci (and indeed, likely far more, given our genomic heritability estimates) with a distribution of mostly small effects contribute to variation in pigmentation in the KhoeSan.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This would simplify the genomic architecture, with relatively few alleles of large effect driving the phenotype, particularly alleles that lighten skin at extreme northern latitudes, and could explain why prior investigations observed an almost Mendelian inheritance of large effect light pigmentation alleles.

    “This would simplify the genomic architecture, with relatively few alleles of large effect driving the phenotype, particularly alleles that lighten skin at extreme northern latitudes, and could explain why prior investigations observed an almost Mendelian inheritance of large effect light pigmentation alleles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The equatorial pattern is consistent with a threshold model in which the protective benefit of melanin needs to meet some minimum threshold but with no penalty to darker pigmentation; alternatively, diversifying selection could maintain the wide variance.

    “This is consistent with a ‘threshold’ model (Chaplin, 2004) in which the protective benefit of melanin needs to meet some minimum threshold but with no penalty to darker pigmentation; alternatively, diversifying selection could maintain the wide variance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chaplin, 2004 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Sex and age do not significantly correlate with baseline skin pigmentation, suggesting that the quantitative measure of underarm reflectance is not significantly affected by UV exposure.

    “Sex and age do not significantly correlate with baseline skin pigmentation, suggesting that our quantitative measure of underarm reflectance is not significantly affected by UV exposure.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    This recruitment is required for normal expression of many MITF target genes, including TYR, TYRP1, DCT, RAB27A, BCL2, among others.

    “This recruitment is required for normal expression of many MITF target genes, including TYR, TYRP1, DCT, RAB27A, BCL2, among others (Keenen et al., 2009b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Keenen et al., 2009b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SMARCA2 has a known role in folate biosynthesis.

    “SMARCA2 has a known role in folate biosynthesis, in vitamin D-coupled transcription regulation, and is differentially expressed across CEU and YRI populations in lymphoblastoid cell lines (Duan et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duan et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TYRP1 mutations cause nearly Mendelian inheritance of blond hair in Solomon Islanders.

    “TYRP1 mutations in humans have been associated with oculocutaneous albinism and shown to cause nearly Mendelian inheritance of blond hair in Solomon Islanders (Kenny et al., 2012b; Sarangarajan and Boissy, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kenny et al., 2012b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The resequencing efforts yielded large amounts of high-quality data for each pool with on average 84% of reads in target regions, achieving a median depth of coverage of 29× per sample.

    “The resequencing efforts yielded large amounts of high-quality data for each pool with on average 84% of reads in target regions, achieving a median depth of coverage of 29× per sample.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The resequencing design was successful for all targets.

    “The resequencing design was successful for all targets, although the regions targeting SNPs previously associated with pigmentation in MC1R and TPCN2 had significantly lower coverage than the other regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Variant calls and genotypes for samples that were genotyped on an array achieved an average of >99% concordance.

    “We compared variant calls and genotypes for samples that were genotyped on an array and achieved an average of > 99% concordance (Figure S7).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    MITF recruits critical components of the SWI/SNF chromatin remodeling complex (including SMARCA2) to the promoter region of its targets.

    “MITF, the transcription factor known as the “master regulator of melanogenesis” due to its ability to activate many melanocyte-specific genes (Praetorius et al., 2013), recruits critical components of the SWI/SNF chromatin remodeling complex (including SMARCA2), to the promoter region of its targets (Vachtenheim et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vachtenheim et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SMARCA2 has a known role in vitamin D-coupled transcription regulation.

    “SMARCA2 has a known role in folate biosynthesis, in vitamin D-coupled transcription regulation, and is differentially expressed across CEU and YRI populations in lymphoblastoid cell lines (Duan et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duan et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MITF is the transcription factor known as the 'master regulator of melanogenesis' due to its ability to activate many melanocyte-specific genes.

    “MITF, the transcription factor known as the “master regulator of melanogenesis” due to its ability to activate many melanocyte-specific genes (Praetorius et al., 2013), recruits critical components of the SWI/SNF chromatin remodeling complex (including SMARCA2), to the promoter region of its targets (Vachtenheim et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Praetorius et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    TYRP1 mutations in humans have been associated with oculocutaneous albinism.

    “TYRP1 mutations in humans have been associated with oculocutaneous albinism and shown to cause nearly Mendelian inheritance of blond hair in Solomon Islanders (Kenny et al., 2012b; Sarangarajan and Boissy, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sarangarajan and Boissy, 2001

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The regions targeting SNPs previously associated with pigmentation in MC1R and TPCN2 had significantly lower coverage than the other regions.

    “The resequencing design was successful for all targets, although the regions targeting SNPs previously associated with pigmentation in MC1R and TPCN2 had significantly lower coverage than the other regions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SMARCA2 is differentially expressed across CEU and YRI populations in lymphoblastoid cell lines.

    “SMARCA2 has a known role in folate biosynthesis, in vitamin D-coupled transcription regulation, and is differentially expressed across CEU and YRI populations in lymphoblastoid cell lines (Duan et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duan et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    A total of 46,429 SNPs and indels with a MAF > 1% passed quality control filters, resulting in a Bonferroni threshold of 1.08e-6.

    “We discovered a total of 46,429 SNPs and indels with a MAF > 1% that passed our quality control filters, resulting in a Bonferoni threshold of 1.08e-6.”
    Quote in the paperSubstantial claim
55 of 55

  • The paper relies on this without support.

    Quantitative skin pigmentation phenotypes aggregated from different studies and populations are comparable enough to analyze together.

    “For comparison, we aggregated quantitative skin pigmentation across 32 globally diverse populations (4,712 individuals) assayed with a Derma Spectrometer (DSMI or DSMII) (Basu Mallick et al., 2013; Beleza et al., 2013; Candille et al., 2012; Coussens et al., 2015; Durazo-Arvizu et al., 2014; Edwards et al., 2010; Norton et al., 2006) (Figure 1A–B, Table S1).”

  • The paper relies on this without support.

    The M index measured on the upper inner arm reflects baseline skin pigmentation.

    “We quantitatively phenotyped baseline skin color in 479 individuals (277 ‡Khomani, 202 Nama, Table S4) via narrow-band reflectometry to measure hemoglobin and melanin of both the left and right upper inner arms (STAR Methods), with M index = log10(1 / % red reflectance).”

  • The paper relies on this without support.

    Populations living in continental Africa have been largely ignored in genetic studies with quantitative phenotypes.

    “However, populations living in continental Africa, where humans have the greatest genetic diversity and pigmentation variability, have been largely ignored in genetic studies with quantitative phenotypes.”

  • The paper relies on this without support.

    EPM2A and FREM1 have no known role in skin pigmentation in humans or model organisms.

    “Two of these loci are near EPM2A and FREM1, neither of which have any known role in skin pigmentation in humans or model organisms.”

  • The paper relies on this without support.

    SNX13 has not previously been associated with skin pigmentation.

    “SNX13 regulates lysosomal degradation and G-protein signaling, but has not previously been associated with skin pigmentation.”

  • The paper relies on this without support.

    African populations often carry the ancestral (i.e. dark) allele for skin pigmentation genes identified in Eurasians.

    “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.”

  • The paper relies on this without support.

    Selective forces to produce vitamin D and protect folate from photolysis are unequal and change in response to UV radiation exposure.

    “where selective forces to produce vitamin D and protect folate from photolysis are unequal and change in response to UV radiation exposure.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Some machine learning approaches may modestly improve PRS accuracy beyond current approaches for some phenotypes, but most likely for atypical traits with simpler architectures, known interactions, and poor prediction generalizability across populations, such as skin pigmentation.

    “Some machine learning approaches may thus modestly improve PRS accuracy beyond current approaches for some phenotypes52, but most likely for atypical traits with simpler architectures, known interactions, and poor prediction generalizability across populations, such as skin pigmentation53.”

    From Clinical use of current polygenic risk scores may exacerbate health disparities (2019) · cites this paper as [53]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • A light skinned phenotype may have been common in the Levant_ChL population.

    “suggesting that a light skinned phenotype may have been common in this population”

    From Ancient DNA from Chalcolithic Israel reveals the role of population mixture in cultural transformation (2018) · cites this paper as [42]

    The Introduction discusses light-skin alleles in western Eurasian populations and light pigmentation among the KhoeSan, but it does not address the Levant_ChL population. Searches for Levant_ChL and Chalcolithic Levantine pigmentation found no passage assessing whether light skin was common in that population. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Recent genomic studies have identified several novel and non-canonical pigmentation genes, such as KLF6, COMMD3, SNX13, SMARCA2, ADAM17, and ADAMTS20, that extend beyond the classical melanogenic pathways.

    “Recent genomic studies ( Bajpai et al., 2023 ; Martin et al., 2017 ) have identified several novel and non-canonical pigmentation genes, such as KLF6 , COMMD3 , SNX13 , SMARCA2 , ADAM17 , ADAMTS20 , that extend beyond the classical melanogenic pathways.”

    From The genetic architecture of human skin pigmentation: evolution and adaptation across global populations (2026) · cites this paper as Martin et al., 2017

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Targeted-resequencing sample counts disagree

    Major

    The Results report 451 resequenced samples, including 182 Nama, whereas the Methods report 441, including 172 Nama. Both give 269 ‡Khomani.

  • Direction of the rs1426654 amino-acid change reverses

    Minor

    The same derived SLC24A5 allele is described as Ala111Thr in the Introduction but as Thr111Ala in the Results. Those names specify opposite amino-acid changes.

  • Genotyped ‡Khomani count exceeds the phenotyped count

    Minor

    The paper describes 278 genotyped ‡Khomani individuals as having matched pigmentation phenotypes, but later reports phenotyping only 277 ‡Khomani individuals.

  • Targeted-resequencing region counts disagree

    Minor

    The Results state that 36 candidate regions were resequenced, but the Methods say 35 regions were chosen for the resequencing capture.

4 of 4

Cites

Flagged first, then by citations

3 of the 117 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Keenen, 2010, Heterogeneous SWI/SNF chromatin remodeling complexes promote expression of microphthalmia-associated transcription factor target genes in melanoma, Oncogene, 29, 81, 10.1038/onc.2009.304 · DOI

Cited by

Sorted by citations

Related

Authors
Martin, A. R., Lin, M., Granka, J. M., Myrick, J. W., Liu, X., Sockell, A., Atkinson, E. G., Werely, C. J., Möller, M., Sandhu, M. S., Kingsley, D. M., Hoal, E. G., Liu, X., Daly, M. J., Feldman, M. W., Gignoux, C. R., Bustamante, C. D., & Henn, B. M.
Affiliations
  • Broad Institute (US)
  • Stony Brook University (US)
  • Stanford University (US)
  • BGI Group (China) (CN)
  • Stellenbosch University (ZA)
  • Wellcome Sanger Institute (GB)
Corresponding author
  • Martin, Alicia R.
  • Henn, Brenna M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2017-11
Volume
171
Issue
6
Pages
1340-1353.e14
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2017.11.015
PMC
PMC5884124
OpenAlex
W2764167548
Cited by
156
References
117
Citations by year
2026: 9 · 2025: 10 · 2024: 16 · 2023: 15 · 2022: 20 · 2021: 29 · 2020: 18 · 2019: 14 · 2018: 25
FWCI
8.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Stanford University
  • NIH (NIA P30 AG017253-12, 5T32GM007790, NIH K12 GM102778)
  • Stanford Center for Computational, Evolutionary and Human Genomics
  • Stanford NIH Genome Training Program (5T32HG000044)
  • South African Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Race, Genetics, and Society
Keywords
skin pigmentation, polygenic architecture, Khoesan, Africans, heritability, latitude, SLC24A5, TRP-1, genetic loci, evolutionary pressure, quantitative phenotypes
MeSH terms
Africa, Humans, Skin Pigmentation, Polymorphism, Single Nucleotide, Black People

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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