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Cited by 257Forensic and Genetic Researchmelanin and skin pigmentationEvolution and Genetic Dynamics

Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y

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Wilde, Sandra, Timpson, Adrian, Kirsanow, Karola, Kaiser, Elke, Kayser, Manfred, Unterländer, Martina, Hollfelder, Nina, Potekhina, Inna D. +3 more·2014·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1316513111PMC PMC3977302
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Abstract

Significance: Eye, hair, and skin pigmentation are highly variable in humans, particularly in western Eurasian populations. This diversity may be explained by population history, the relaxation of selection pressures, or positive selection. To investigate whether positive natural selection is responsible for depigmentation within Europe, we estimated the strength of selection acting on three genes known to have significant effects on human pigmentation. In a direct approach, these estimates were made using ancient DNA from prehistoric Europeans and computer simulations. This allowed us to determine selection coefficients for a precisely bounded period in the deep past. Our results indicate that strong selection has been operating on pigmentation-related genes within western Eurasia for the past 5,000 y.

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Written from the paper’s full text.

TL;DR

Using ancient DNA from Eneolithic/Bronze Age Eastern Europeans and forward simulations, the authors directly estimate selection on three pigmentation-associated alleles. They reject neutrality for all three and infer strong positive selection favoring lighter skin, hair, and eye pigmentation in Europeans over the last 5,000 y.

Key findings

  • Derived allele frequencies increased sharply between ancient and modern Ukrainian samples: HERC2 rs12913832 G from 0.160 to 0.651, SLC45A2 rs16891982 G from 0.432 to 0.927, and TYR rs1042602 A from 0.043 to 0.367.
  • Neutrality was overwhelmingly rejected for all three alleles under all modeled ancestral effective population sizes: SLC45A2 P < 1 × 10⁻⁵, TYR P < 2 × 10⁻⁵, and HERC2 P < 1 × 10⁻⁵.
  • Best-fitting selection coefficients were 0.030 for SLC45A2 rs16891982 G, 0.026 for TYR rs1042602 A, and 0.036 for HERC2 rs12913832 G, with point estimates across models ranging from about 2–10% per generation.
  • The authors conclude that selection on pigmentation variants was still ongoing after 6,500–4,000 y ago and that these selection coefficients are comparable to those for strongly selected loci such as LCT and G6PD.

Methods

  • Ancient DNA was extracted from 150 Eneolithic (ca. 6,500–5,000 y ago) and Bronze Age (ca. 5,000–4,000 y ago) skeletal samples from the Pontic–Caspian steppe, mainly modern-day Ukraine; DNA was retrieved from 63 samples, and pigmentation gene data were obtained from 48 samples.
  • The three SNPs were genotyped by multiplex-PCR enrichment and next-generation sequencing, alongside mtDNA HVR1 and coding-region markers; the same SNPs were genotyped in 60 modern Ukrainians.
  • Population continuity was tested by comparing 60 ancient mtDNA HVR1 sequences with 246 modern homologous sequences (FST = 0.00551; P = 0.0663) and coalescent simulations; selection was tested with forward simulations of drift plus selection, accommodating uncertainty in allele frequency, population size, and ancient sample age.

Limitations

  • The paper states that the approach requires the assumption of population continuity and cannot provide direct estimates of when a selective sweep began.
  • The paper states that the actual nature of the selection pressure remains unknown, and that population stratification in the ancient sample cannot be excluded without additional neutral SNPs.
  • The paper notes uncertainty about the dominance model for SLC45A2 and TYR, so selection estimates vary under recessive, codominant, or dominant assumptions; it also describes the ancient and modern sample sizes as relatively small for Hardy–Weinberg tests.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.1316513111

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    Point estimates of selection for the three studied pigmentation alleles range from around 2-10% per generation.

    “Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    The selection coefficient that best explained the observed derived allele frequency change for HERC2 rs12913832 G was 0.036.

    “The values of selection acting on the SLC45A2 rs16891982 G allele, the TYR rs1042602 A allele, and the HERC2 rs12913832 G allele that best explained the observed derived allele frequency changes were 0.030, 0.026, and 0.036, respectively (Fig. 2).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Population continuity between the ancient and modern samples from the same geographic region.
    • The authors state this as an assumption: The derived HERC2 rs12913832 G allele is recessive.
  • Findingown data
    § Abstract

    Neutrality was overwhelmingly rejected for all three studied pigmentation alleles (HERC2 rs12913832, SLC45A2 rs16891982, and TYR rs1042602).

    “Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Neutrality (S = 0) was rejected under all assumed ancestral effective population sizes ranging from 10^3 to 10^5 at the time of the ancient sample for SLC45A2, TYR, and HERC2.

    “Using these simulations, neutrality (S = 0) was rejected under all assumed ancestral effective population sizes—ranging from 103 to 105 at the time of the ancient sample (SLC45A2 P < 1 × 10−5, TYR P < 2 × 10−5, and HERC2 P < 1 × 10−5).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Population continuity between the ancient and modern samples from the same geographic region.
    • The authors state this as an assumption: The SLC45A2 rs16891982 G and TYR rs1042602 A alleles are codominant.
    • The authors state this as an assumption: The derived HERC2 rs12913832 G allele is recessive.
  • Findingown data
    § Results

    Under the assumption that both SLC45A2 and TYR derived alleles are dominant, the selection values that best explain the observed frequency changes are 0.088 and 0.016, respectively.

    “and under the assumption that they are dominant the selection values are 0.088 and 0.016, respectively”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Population continuity between the ancient and modern samples from the same geographic region.
    • The authors state this as an assumption: The SLC45A2 rs16891982 G and TYR rs1042602 A alleles are codominant.
  • May combine two claims. 3
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingcitation
    § Results

    The Eneolithic and Bronze Age sequences presented here are ∼500-2,000 y younger than the early Neolithic and belong to lineages identified both in early farmers and late hunter-gatherers from central Europe.

    “However, the Eneolithic and Bronze Age sequences presented here are ∼500–2,000 y younger than the early Neolithic and belong to lineages identified both in early farmers and late hunter–gatherers from central Europe (33).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Bramanti B, et al. Genetic discontinuity between local hunter-gatherers and central Europe’s first farmers. Science. 2009;326(5949):137–140. doi: 10.1126/science.1176869. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Interpretationreasoning
    § Results

    This admixture possibly also shaped the variability observed in European hair, eye, and skin color.

    “and possibly also the variability observed in European hair, eye, and skin color.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Results

    Continuity between early central European farmers and modern Europeans has been rejected in a previous study.

    “Conversely, continuity between early central European farmers and modern Europeans has been rejected in a previous study (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Bramanti B, et al. Genetic discontinuity between local hunter-gatherers and central Europe’s first farmers. Science. 2009;326(5949):137–140. doi: 10.1126/science.1176869. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductreasoning
    § Methods

    We also performed the same simulations assuming both dominance and recessivity for the SLC45A2 and TYR derived alleles.

    “For this reason we also performed the same simulations assuming both dominance and recessivity for the SLC45A2 and TYR derived alleles (Fig. S2).”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Discussion

    Selection favoring rare pigmentation morphs could have driven alleles associated with lighter hair and eye colors to higher frequency.

    “Frequency-dependent sexual selection in favor of rare variants has been observed in vertebrates (55, 56), and such selection favoring rare pigmentation morphs could have driven alleles associated with lighter hair and eye colors to higher frequency.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Methods

    In cases where the authentication scheme could not be fulfilled using the available 454 data, those loci were additionally amplified in single-locus PCRs, followed by direct sequencing after Sanger.

    “In cases where the authentication scheme could not be fulfilled using the available 454 data, those loci were additionally amplified in single-locus PCRs, followed by direct sequencing after Sanger.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Methods

    For authentication purposes mitochondrial haplotypes are based on at least three, and SNP genotypes on at least four, independent amplification products from two extracts.

    “For authentication purposes mitochondrial haplotypes are based on at least three, and SNP genotypes on at least four, independent amplification products from two extracts.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Methods

    It is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant.

    “However, although there is strong evidence that the derived HERC2 rs12913832 G allele is recessive (36), it is less clear whether the SLC45A2 and TYR derived alleles are codominant, recessive, or dominant (22, 35).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Cook AL, et al. Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci. J Invest Dermatol. 2009;129(2):392–405. doi: 10.1038/jid.2008.211. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [35] Stokowski RP, et al. A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet. 2007;81(6):1119–1132. doi: 10.1086/522235. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Interpretationreasoning
    § Discussion

    The observed excess of HERC2 rs12913832 homozygotes in the ancient sample might be explained by population stratification in a temporally heterogeneous population sample.

    “The observed excess of HERC2 rs12913832 homozygotes in the ancient sample might be explained by population stratification in a temporally heterogeneous population sample.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Discussion

    We cannot exclude population stratification in the absence of additional neutral SNPs.

    “Although we do not observe any chronological or spatial patterning of the pigmentation markers in our prehistoric sample, we cannot exclude population stratification in the absence of additional neutral SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    A combination of selective pressures associated with living in northern latitudes, the adoption of an agriculturalist diet, and assortative mating may sufficiently explain the observed change from a darker phenotype during the Eneolithic/Early Bronze age to a generally lighter one in modern Eastern Europeans, although other selective factors cannot be discounted.

    “In sum, a combination of selective pressures associated with living in northern latitudes, the adoption of an agriculturalist diet, and assortative mating may sufficiently explain the observed change from a darker phenotype during the Eneolithic/Early Bronze age to a generally lighter one in modern Eastern Europeans, although other selective factors cannot be discounted.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The derived HERC2 rs12913832 G allele is recessive.
    • The authors state this as an assumption: SLC45A2 rs16891982 G and TYR rs1042602 A alleles are codominant.

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

    Interpretationcitation
    § Discussion

    Depigmented irises and the various hair colors observed in Europeans possibly arose through sexual selection.

    “Given that intraspecific pigmentation variability in other taxa, particularly avians, has been attributed to signaling and other factors associated with mate choice (54) it is possible that depigmented irises and the various hair colors observed in Europeans arose through sexual selection (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Darwin C. The Descent of Man, and Selection in Relation to Sex. London: John Murray; 1871. [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    There is some evidence that lighter iris colors, because of their recessive mode of inheritance, may be preferred by males in assortative mating regimes to improve paternity confidence.

    “In addition, there is some evidence that lighter iris colors, because of their recessive mode of inheritance, may be preferred by males in assortative mating regimes to improve paternity confidence (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Laeng B, Mathisen R, Johnsen J-A. Why do blue-eyed men prefer women with the same eye color? Behav Ecol Sociobiol. 2007;61(3):371–384. [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    Intraspecific pigmentation variability in other taxa, particularly avians, has been attributed to signaling and other factors associated with mate choice.

    “Given that intraspecific pigmentation variability in other taxa, particularly avians, has been attributed to signaling and other factors associated with mate choice (54) it is possible that depigmented irises and the various hair colors observed in Europeans arose through sexual selection (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Dale J. Intraspecific variation in coloration. Bird Coloration. 2006;2:36–86. [Google Scholar]

      Not checked in the free run.

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

    Interpretationreasoning
    § Discussion

    Once lighter hair and eye pigmentation phenotypes reached appreciable frequencies in European populations, these novel traits may have continued to be preferred as indicators of group membership, facilitating assortative mating.

    “Once lighter hair and eye pigmentation phenotypes reached appreciable frequencies in European populations, these novel traits may have continued to be preferred as indicators of group membership, facilitating assortative mating.”
    Quote in the paperNot a substantial claim
15 of 15

  • The authors state this as an assumption.

    Population continuity between the ancient and modern samples from the same geographic region.

    “Inferring natural selection based on temporal differences in allele frequency requires the assumption of population continuity.”
    “However, our approach does require the assumption of population continuity”

  • The authors state this as an assumption.

    The SLC45A2 rs16891982 G and TYR rs1042602 A alleles are codominant.

    “We assumed codominance for both SLC45A2 rs16891982 G and TYR rs1042602 A alleles (22, 35)”

  • The authors state this as an assumption.

    The derived HERC2 rs12913832 G allele is recessive.

    “and that the derived HERC2 rs12913832 G allele is recessive (36).”
    “We assumed codominance for both SLC45A2 rs16891982 G and TYR rs1042602 A alleles (22, 35) and that the derived HERC2 rs12913832 G allele is recessive (36) (Fig. 2).”

  • The authors state this as an assumption.

    SLC45A2 rs16891982 G and TYR rs1042602 A alleles are codominant.

    “We assumed codominance for both SLC45A2 rs16891982 G and TYR rs1042602 A alleles (22, 35) and that the derived HERC2 rs12913832 G allele is recessive (36) (Fig. 2).”
4 of 4

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?

  • Wilde et al. found intermediate frequencies for SLC45A2 in ancient Ukrainian Eneolithic and Early Bronze Age samples.

    “Wilde et al.32 also found intermediate frequencies for SLC45A2 in ancient Ukranian Eneolithic and Early Bronze Age samples.”

    From Genome flux and stasis in a five millennium transect of European prehistory (2014) · cites this paper as [32]

  • The pigmentation-associated allele combination characteristic of many present-day Europeans is a relatively recent outcome of Holocene migration, admixture, and strong selection, reaching its current high frequency only within the past approximately 5 kya and involving a limited number of large-effect loci.

    “Collectively, these findings indicate that the pigmentation-associated allele combination characteristic of many present-day Europeans is a relatively recent outcome of Holocene migration, admixture, and strong selection, reaching its current high frequency only within the past ∼5 kya and involving a limited number of large-effect loci ( Wilde et al., 2014 ; Skoglund and Mathieson, 2018 ).”

    From The genetic architecture of human skin pigmentation: evolution and adaptation across global populations (2026) · cites this paper as Wilde et al., 2014

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Authors
Wilde, S., Timpson, A., Kirsanow, K., Kaiser, E., Kayser, M., Unterländer, M., Hollfelder, N., Potekhina, I. D., Schier, W., Thomas, M. G., & Burger, J.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • University College London (GB)
  • Freie Universität Berlin (DE)
  • Erasmus MC (NL)
  • National Academy of Sciences of Ukraine (UA)
  • Institute of Anthropology, Johannes Gutenberg University Mainz, 55128 Mainz, Germany;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2014-03-10
Volume
111
Issue
13
Pages
4832-4837
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1316513111
PMC
PMC3977302
OpenAlex
W2139162658
Semantic Scholar
69489da3e24f63b7bdc747edd60c7b1aa0ad21fe
Cited by
257
References
71
Citations by year
2026: 11 · 2025: 16 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 20 · 2020: 18 · 2019: 27 · 2018: 26 · 2017: 30 · 2016: 16 · 2015: 32 · 2014: 14 · 2012: 1
FWCI
20.14
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
human pigmentation, positive selection, skin pigmentation, hair pigmentation, eye pigmentation, HERC2, SLC45A2, TYR, allele frequency estimation, Chalcolithic, Bronze Age, Eastern Europe, forward modeling
MeSH terms
Alleles, Antigens, Neoplasm, Eye Color, Gene Frequency, Hair Color, Humans, Selection, Genetic, Skin Pigmentation, Time Factors, Polymorphism, Single Nucleotide, Membrane Transport Proteins, White People

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