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Cited by 131melanin and skin pigmentationForensic and Genetic ResearchGenetic Associations and Epidemiology

A global view of the OCA2-HERC2 region and pigmentation

Open access
Donnelly, Michael P., Paschou, Peristera, Grigorenko, Elena, Gurwitz, David, Barta, Csaba, Lu, Ru-Band, Zhukova, Olga V., Kim, Jong-Jin +9 more·2012·Human Genetics
DOI 10.1007/s00439-011-1110-xPMC PMC3325407
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Abstract

Mutations in the gene OCA2 are responsible for oculocutaneous albinism type 2, but polymorphisms in and around OCA2 have also been associated with normal pigment variation. In Europeans, three haplotypes in the region have been shown to be associated with eye pigmentation and a missense SNP (rs1800407) has been associated with green/hazel eyes (Branicki et al. in Ann Hum Genet 73:160-170, 2009). In addition, a missense mutation (rs1800414) is a candidate for light skin pigmentation in East Asia (Yuasa et al. in Biochem Genet 45:535-542, 2007; Anno et al. in Int J Biol Sci 4, 2008). We have genotyped 3,432 individuals from 72 populations for 21 SNPs in the OCA2-HERC2 region including those previously associated with eye or skin pigmentation. We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe; however, one is restricted to Europe and surrounding regions, while the other two are found at moderate to high frequencies throughout the world. We also observed that the derived allele of rs1800414 is essentially limited to East Asia where it is found at high frequencies. Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele. We also saw evidence of selection at the derived allele of rs1800414 in East Asia. Our data suggest that the haplotype restricted to Europe is the strongest marker for blue eyes globally and add further inferential evidence that the derived allele of rs1800414 is an East Asian skin pigmentation allele.

AI snapshot

Written from the paper’s full text.

TL;DR

Genotyping 21 SNPs across the OCA2-HERC2 region in global populations shows that blue-eye-associated haplotypes differ sharply in geographic range, with the BEH2 TG allele essentially restricted to Europe and carrying the strongest selection signal. The derived rs1800414 C allele is essentially limited to East Asia and shows evidence of selection, supporting it as an East Asian skin-pigmentation allele.

Key findings

  • The blue-eye-associated alleles at BEH1 (ACA), BEH2 (TG), and BEH3 (CA) all reach highest frequencies in Northwestern Europe, but BEH2 TG is essentially observed only in Europe; BEH1 ACA and BEH3 CA are found globally, with frequencies <20% in most of Central and East Asia but 40% and higher in the Americas.
  • The derived rs1800407 allele is rare and mostly restricted to Europe (0–11%), Southwest Asia (0–9.4%), and Central Asia (0–9.3%); no evidence of selection was seen at rs1800407.
  • The derived rs1800414 C allele is found almost exclusively in East and Southeast Asia at frequencies from 0 to 76%, higher in eastern East Asia (62–76.1%) than Southeast Asia (0–54.3%) or Western China (15.5–37.5%); outside this region it appears at low frequencies in Adygei, Chuvash, and Hungarians (>1–3.6%), Yakut (8.8%), and Micronesians (4.2%).
  • Long-range haplotype tests show the strongest selection signal at BEH2 TG in Europe and Southwest Asia; BEH1 and BEH3 signals are weak and within the false-positive grouping, while rs1800414 C shows strong selection evidence in East Asia, confirmed by nHS in Western China and Southeast Asia.

Methods

  • The abstract reports 3,432 individuals from 72 populations; the methods and Table 1 describe 73 populations and 3,931 total samples including HGDP data. The study typed 21 SNPs spanning 398,549 bp in OCA2-HERC2, including nine previously pigmentation-associated SNPs.
  • SNPs were typed with Applied Biosystems TaqMan assays; haplotypes were estimated with fastPHASE, frequency maps with Surfer, and LD with HAPLOT.
  • Selection was tested using relative extended haplotype homozygosity (REHH) and normalized haplosimilarity (nHS), with 1,000 neutral simulations under a constant population size model and a bottleneck-plus-exponential-expansion model.

Limitations

  • The paper has no explicit limitations section. Evident from the text: this study reports genotype and allele-frequency data but does not directly measure pigmentation phenotypes, so pigmentation associations are inferred from prior studies.
  • Some population samples are very small (e.g., Lisongo N=8, Samoans N=8, Malaysians N=11, Orcadians N=16, Kuwaiti N=16), and some HGDP samples were combined, which may make allele-frequency estimates for rare variants unstable.
  • The paper states that several questions remain, including whether BEH2 SNPs are causal or only in strong LD with the causative allele, whether BEH2 lies in an OCA2 promoter region, and whether blue eyes are under sexual selection or linked to another selected phenotype such as light skin pigmentation.

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

Integrity signals

Registry

Crossref · 10.1007/s00439-011-1110-x

Cites

35 of 35 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The TG allele at BEH2 is essentially observed only in Europe.

    “the TG allele at BEH2 is essentially observed only in Europe”
    Quote in the paperNot a substantial claim
  • Findingown data

    The T allele of rs1800407, when seen, is commonly paired with the blue-eye associated TG allele at BEH2 only in Northern and Eastern Europeans.

    “The T allele of rs1800407, when seen, is commonly paired with the blue-eye associated TG allele at BEH2 only in Northern and Eastern Europeans.”
    Quote in the paperSubstantial claim
  • Findingown data

    Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems.

    “Long-range haplotype tests provide evidence of selection for the blue-eye allele at the three haplotyped systems but not for the green/hazel eye SNP allele.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: A variant under selection will rise to high frequency quickly before recombination has time to break down the extended haplotype on which the variant initially arose.
    • The authors state this as an assumption: A neutral variant will take longer to reach a high frequency, allowing the extended haplotype time to be degraded by recombination.
  • Findingown data

    With the exception of a low frequency haplotype in Africa, rs916977 and rs1667394 are in nearly complete LD.

    “In our data, with the exception of a low frequency haplotype in Africa, rs916977 and rs1667394 are in nearly complete LD.”
    Quote in the paperSubstantial claim
  • Findingown data

    The blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe.

    “We report that the blue-eye associated alleles at all three haplotypes were found at high frequencies in Europe”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    The ACA allele of BEH1 and the CA allele at BEH3 are at their highest frequencies in Europe, particularly in Northern and Western Europe, and have much lower frequencies elsewhere.

    “the ACA allele of BEH1 and the CA allele at BEH3 are at their highest frequencies in Europe, particularly in Northern and Western Europe, and have much lower frequencies elsewhere.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In most of Central and East Asia, the ACA and CA alleles have frequencies of <20% but reach frequencies of 40% and higher in the Americas.

    “In most of Central and East Asia, these alleles have frequencies of <20% but reach frequencies of 40% and higher in the Americas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The putative light skin allele of rs1800414 (C) is found almost exclusively in East and Southeast Asia, at frequencies ranging from 0 to 76%, at higher levels in eastern East Asia (62-76.1%) compared with Southeast Asia (0-54.3%) and Western China (15.5-37.5%).

    “Our data confirm that the putative light skin allele of rs1800414 (C) is found almost exclusively in East and Southeast Asia, at frequencies ranging from 0 to 76% (Fig. 4) at higher levels in eastern East Asia (62–76.1%) compared with Southeast Asia (0–54.3%) and Western China (15.5–37.5%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Outside of Europe, Southwest Asia, and Central Asia, the derived allele of rs1800407 is found in African Americans (1.7%), San Francisco Chinese (0.9%), the Arizona Pima (1.0%), and the Maya (3.9%).

    “Outside of this region, the derived allele is found in African Americans (1.7%), San Francisco Chinese (0.9%), the Arizona Pima (1.0%), and the Maya (3.9%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At BEH3, the blue-eye associated CA allele commonly pairs with the T allele only in Northwestern and Eastern Europe and the TG allele is its most common partner elsewhere.

    “The blue-eye associated CA allele of BEH3 commonly pairs with the T allele only in Northwestern and Eastern Europe and the TG allele is its most common partner elsewhere.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Africa, the first high LD region encompasses SNP 4 (rs12914687) through SNP 7 (rs2015343) and the second region encompasses SNP 16 (rs7494942) through SNP 21 (rs1667394).

    “In Africa, the first region encompasses SNP 4 (rs12914687) through SNP 7 (rs2015343) and the second region encompasses SNP 16 (rs7494942) through SNP 21 (rs1667394).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Southwest Asia and Europe, both high LD regions are larger; the first is composed of SNP 3 (rs11074314) through SNP 8 (rs4778136), and the second is composed of SNP 12 (rs4778138) through SNP 21 (rs1667394).

    “In Southwest Asia and Europe, both high LD regions are larger and the first is composed of SNP 3 (rs11074314) through SNP 8 (rs4778136), and the second is composed of SNP 12 (rs4778138) through SNP 21 (rs1667394).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    On average, globally there are two regions of high LD, though the sizes of each of these regions vary by population group.

    “On average, globally we see two regions of high LD, though the sizes of each of these regions vary by population group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The smallest regions of high LD in the OCA2/HERC2 region are in Africa, whereas the largest regions are in East Asia.

    “The smallest regions are in Africa whereas the largest regions are in East Asia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All three blue-eye associated alleles and homozygotes of these alleles are present in Southern Europe and Southwest Asia at lower frequencies than in Northwestern and Eastern Europe.

    “All three blue-eye associated alleles and homozygotes of these alleles are also present in Southern Europe and Southwest Asia at lower frequencies than those found in Northwestern and Eastern Europe”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Central Asia and the Pacific, the first high LD region is the same as in Africa and the second region is the same as in Southwest Asia and Europe.

    “In Central Asia and the Pacific, the first region is the same as in Africa and the second region is the same as in Southwest Asia and Europe.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Eastern Europe, the evidence for selection is strongest at the TG allele of BEH2; there is no evidence of selection to the centromeric side of BEH1, and weak evidence for selection at the CA allele of BEH3 and to the telomeric side of the ACA allele of BEH1.

    “In Eastern Europe, the evidence for selection is again the strongest at the TG allele BEH2; there is no evidence of selection to the centromeric side of BEH1, and weak evidence for selection at the CA allele of BEH3 and to the telomeric side of the ACA allele of BEH1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At the ACA allele of BEH1 and the CA allele of BEH3 in the European sample, REHH scores are weakly significant and just over the 95th percentile, but both regions are within the false positive grouping of the simulated data.

    “At the ACA allele of BEH1 and the CA allele of BEH3, the REHH scores are weakly significant and just over the 95th percentile; however, both regions are within the false positive grouping of the simulated data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the remaining two haplotypes containing the derived allele of rs1800414, one differs from the most common haplotype at the last site and the other differs at the final four sites.

    “Of the remaining two haplotypes containing the derived allele of rs1800414, one differs from the most common haplotype at the last site and the other differs at the final four sites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Southern Europe, the TG allele at BEH2 has a strongly significant REHH score, the CA allele at BEH3 is weakly significant, and there is no evidence of selection at BEH1.

    “In Southern Europe, the TG allele at BEH2 has a strongly significant REHH score, at BEH3 the CA allele is weakly significant, and there is no evidence of selection at BEH1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    On average, there are two regions of high LD in the OCA2/HERC2 region across the studied populations, one near the East Asian light-skin SNP rs1800414 and one in the BEH region.

    “On average, there are two regions of high LD, one near the East Asian “light skin” SNP (rs1800414) and one in the BEH region.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Northwestern Europe, the TG allele of BEH2 has the strongest signal for selection, the centromeric side of the ACA allele of BEH1 and the CA allele of BEH3 are very weakly significant, and the telomeric side of BEH1 shows no significant evidence of selection.

    “In Northwestern Europe, the TG allele of BEH2 once again has the strongest signal for selection, the centromeric side of the ACA allele of BEH1 and the CA allele of BEH3 are very weakly significant, and the telomeric side of BEH1 shows no significant evidence of selection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Outside Europe, the blue-eye associated alleles of BEH1 and BEH2 are still common and homozygotes of these alleles are still seen, but the blue-eye associated allele of BEH2 is much rarer and blue-eye associated homozygotes are virtually unseen.

    “Outside of Europe, the blue-eye associated alleles of BEH1 and BEH2 are still common and homozygotes of these alleles are still seen but the blue-eye associated allele of BEH2 is much rarer and blue-eye associated homozygotes are virtually unseen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    In East Asia, significant REHH values are also seen at all three BEHs, but the haplotypes that contain the ancestral alleles are the ones showing evidence of selection.

    “Interestingly, we also get significant REHH values at all three BEHs but the haplotypes that contain the ancestral alleles are the ones showing evidence of selection”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The bottleneck with expansion model had a different distribution of allele frequencies, with more high frequency alleles and fewer midrange frequency alleles compared to the constant population size model, but the 95th percentile line remained the same.

    “In fact, though the bottleneck with expansion model had a different distribution of allele frequencies (more high frequency alleles and fewer midrange frequency alleles compared to the constant population size model) the 95th percentile line remained the same.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Native Americans, there are three regions of high LD: the first from SNP 3 (rs11074314) to SNP 8 (rs4778136), the second from SNP 9 (rs746861) to SNP 12 (rs4778138), and the third from SNP 18 (rs3935591) through SNP 21 (rs1667394).

    “We actually see three regions of high LD in Native Americans, the first from SNP 3 (rs11074314) to SNP 8 (rs4778136), the second from SNP 9 (rs746861) to SNP 12 (rs4778138), and the third from SNP 18 (rs3935591) through SNP 21 (rs1667394).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The derived allele of rs1800414 occurs on three haplotypes in East Asians, though a vast majority occurs on a single haplotype (CACCACT).

    “Here we see the derived allele of rs1800414 occurs on three haplotypes, though a vast majority occurs on a single haplotype (CACCACT).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Europe, the second high LD region covers all three BEHs, and in East Asia, the first region includes rs1800414.

    “In Europe, the second region covers all three BEHs, and in East Asia, the first region includes rs1800414.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In Southwest Asia, there are significant REHH values at the TG allele of BEH2 and the CA allele of BEH3; the BEH2 signal is strong, whereas the BEH3 signal is barely significant.

    “In Southwest Asia, there are significant REHH values at the TG allele of BEH2 and the CA allele BEH3. As in Europe, the BEH2 signal of selection is strong, whereas the BEH3 signal is barely significant”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In East Asia, the first high LD region extends from SNP 2 (rs1800414) to SNP 9 (rs746861) and the second region extends from SNP 10 (rs7170869) to SNP 21 (rs1667394).

    “In East Asia, the first high LD region extends from SNP 2 (rs1800414) to SNP 9 (rs746861) and the second region extends from SNP 10 (rs7170869) to SNP 21 (rs1667394).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Duffy et al. (2007) previously identified a three-SNP haplotype system (rs4778138, rs4778241, and rs7495174) associated with blue eyes.

    “Duffy et al. (2007) previously identified a three-SNP haplotype system (rs4778138, rs4778241, and rs7495174) associated with blue eyes; for the purpose of this paper, we will refer to this system as BEH1, blue-eye associated haplotype #1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Duffy et al. 2007 source

      Not checked in the free run.

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

    Premisecitation

    One HERC2 SNP rs1667394 has been associated with blond hair in Europeans.

    “One of the HERC2 SNPs (rs1667394) has been associated with blond hair in Europeans (Sulem et al. 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sulem et al. 2007 source

      Not checked in the free run.

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

    Premisecitation

    Two other SNPs, rs916977 and rs1667394, have previously been associated with blue eyes.

    “Two other SNPs, rs916977 and rs1667394, have previously been associated with blue eyes (Kayser et al. 2008; Sulem et al. 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kayser et al. 2008 source

      Not checked in the free run.

    • cites Sulem et al. 2007 source

      Not checked in the free run.

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

    Premisecitation

    Edwards et al. (2010) showed an association between the derived allele of rs1800414 (C, 615Arg) and lighter skin pigmentation in a sample of individuals of East Asian ancestry from Canada and confirmed their results using an independent sample of Han Chinese.

    “Edwards et al. (2010) showed an association between the derived allele of rs1800414 (C, 615Arg) and lighter skin pigmentation in a sample of individuals of East Asian ancestry from Canada and confirmed their results using an independent sample of Han Chinese.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Edwards et al. 2010

      Not checked in the free run.

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

    Premisecitation

    The derived allele of rs1800407 has been associated with green/hazel eyes in Europeans.

    “The derived allele of another SNP at OCA2, rs1800407, has been associated with green/hazel eyes in Europeans (Branicki et al. 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Branicki et al. 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Sturm et al. (2008) reported that rs12913832 is associated with blue eyes.

    “Sturm et al. (2008) reported that rs12913832 is associated with blue eyes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sturm et al. 2008 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    OCA2 has been implicated in iris, skin, and hair pigmentation in humans.

    “In humans, it has been implicated in iris, skin, and hair pigmentation (Duffy et al. 2007; Sturm et al. 2008; Kayser et al. 2008; Sulem et al. 2007).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Duffy et al. 2007 source

      Not checked in the free run.

    • cites Sturm et al. 2008 source

      Not checked in the free run.

    • cites Kayser et al. 2008 source

      Not checked in the free run.

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

    Premisecitation

    The derived allele at rs1800414 (His615Arg) in exon 19 of OCA2 has been reported to be specific to East Asia.

    “The derived allele at a missense SNP (rs1800414, His615Arg) in exon 19 of OCA2 has been reported to be specific to East Asia (Yuasa et al. 2007; Anno et al. 2008).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yuasa et al. 2007 source

      Not checked in the free run.

    • cites Anno et al. 2008

      Not checked in the free run.

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

    Premisecitation

    Sturm et al. (2008) concluded that the derived allele of rs1800407 increased the penetrance of the blue eye phenotype associated with the derived allele of rs12913832.

    “Sturm et al. (2008) concluded that the derived allele of rs1800407 increased the penetrance of the blue eye phenotype associated with the derived allele of rs12913832.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sturm et al. 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This evidence suggests that BEH2 may contain the causal allele for blue eyes or at minimum is the best marker for the region in LD that does contain the causal allele.

    “This evidence suggests that BEH2 may contain the causal allele for blue eyes or at minimum is the best marker for the region in LD that does contain the causal allele.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    A likely answer for why blue eyes would be under selection is sexual selection: in Europe and Southwest Asia, individuals with blue eyes are, or were, preferred as mates.

    “Since there is no known biological advantage to having blue eyes, we think a likely answer is sexual selection that in Europe and Southwest Asia individuals with blue eyes are, or were, preferred as mates.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is no known biological advantage to having blue eyes.

  • May combine two claims.

    Study design and conductown data

    The REHH results were confirmed using a bottleneck followed by an exponential expansion model, and the same results were seen.

    “We confirmed these results using a bottleneck followed by an exponential expansion model and saw the same results”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This research provides further evidence for lighter pigmentation evolving by means of selection at least partly independently in Europeans and East Asians but at some genes in common.

    “This research provides further evidence for lighter pigmentation evolving by means of selection at least partly independently in Europeans and East Asians but at some genes in common.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Variants affecting skin pigmentation have previously been shown to be targets of selection.

    “and variants affecting skin pigmentation have previously been shown to be targets of selection”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Edwards et al. 2010

      Not checked in the free run.

    • cites Izagirre et al. 2006 source

      Not checked in the free run.

    • cites Lao et al. 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cook et al. (2009) showed that melanocytes homozygous for the blue-eye associated allele of rs12913832 of BEH2 produced significantly less melanin than heterozygotes or those homozygous for the ancestral allele, but did not control for other SNPs in the region.

    “Cook et al. (2009) showed melanocytes homozygous for the blue-eye associated allele of rs12913832 of BEH2 produced significantly less melanin than heterozygotes or those that were homozygous for the ancestral allele, but did not control for other SNPs in the region.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cook et al. (2009) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liu et al. (2010) found that rs12913832 has the strongest effect when eye color is measured quantitatively and can explain most of the variance in eye color amongst Europeans.

    “A recent study by Liu et al. (2010) found that rs12913832 has the strongest effect when eye color is measured quantitatively and can explain most of the variance in eye color amongst Europeans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liu et al. (2010) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The TG allele at BEH2 may even contain the causal allele for blue eyes, though the actual causative variant could be anywhere in the region of strong LD seen in European populations.

    “and may even contain the causal allele though the actual causative variant could be anywhere in the region of strong LD seen in European populations.”
    Quote in the paperNot a substantial claim
42 of 42

  • The authors state this as an assumption.

    A variant under selection will rise to high frequency quickly before recombination has time to break down the extended haplotype on which the variant initially arose.

    “REHH and nHS are both based on the logical assumption that a variant under selection will rise to high frequency quickly before recombination has time to break down the extended haplotype on which the variant initially arose.”

  • The authors state this as an assumption.

    A neutral variant will take longer to reach a high frequency, allowing the extended haplotype time to be degraded by recombination.

    “In contrast, a neutral variant will take longer to reach a high frequency, allowing the extended haplotype time to be degraded by recombination.”

  • The paper relies on this without support.

    Blue eyes are essentially restricted to Europe.

    “the essential restriction of blue eyes to Europe”

  • The paper relies on this without support.

    There is no known biological advantage to having blue eyes.

    “Since there is no known biological advantage to having blue eyes”
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?

  • Our population genetic analysis of HERC2 and APBA2, together with similar work on the HERC2-OCA2 interval from Donnelly et al., is consistent with the possibility that blue eyes were selected independently from fair skin for reasons having to do with reproductive success rather than survival.

    “Finally, our population genetic analysis of HERC2 and APBA2, together with similar work on the HERC2 - OCA2 interval from Donnelly et al. [37], is consistent with the possibility that blue eyes were selected independently from fair skin for reasons having to do with reproductive success rather than survival.”

    From Genetic Architecture of Skin and Eye Color in an African-European Admixed Population (2013) · cites this paper as [37]

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.

  • Table 1 sample subtotals do not equal the reported total

    Minor

    The reported 3,495 Kidd lab samples plus 499 HGDP samples equal 3,994, not the stated total of 3,931.

    Reported 3931 · recomputed 3994

  • The reported number of populations changes from 72 to 73

    Minor

    The abstract reports 72 populations, while the Materials and methods section reports 73.

  • The stated East Asian LD region contains eight SNPs, not seven

    Minor

    An inclusive span from SNP 2 through SNP 9 contains eight SNPs, contradicting the description of seven SNPs composing that region.

  • BEH2 is described as both common and rare outside Europe

    Minor

    The discussion calls the blue-eye-associated BEH2 allele common outside Europe, but the results say it is essentially observed only in Europe. The discussion sentence also calls that same allele much rarer outside Europe.

4 of 4

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Authors
Donnelly, M. P., Paschou, P., Grigorenko, E., Gurwitz, D., Barta, C., Lu, R.-B., Zhukova, O. V., Kim, J.-J., Siniscalco, M., New, M., Li, H., Kajuna, S. L. B., Manolopoulos, V. G., Speed, W. C., Pakstis, A. J., Kidd, J. R., & Kidd, K. K.
Affiliations
  • Yale University (US)
  • Democritus University of Thrace (GR)
  • Tel Aviv University (IL)
  • Semmelweis University (HU)
  • National Cheng Kung University (TW)
  • Vavilov Institute of General Genetics (RU)
  • Rockefeller University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Fudan University (CN)
  • Hubert Kairuki Memorial University (TZ)
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2011-11-08
Volume
131
Issue
5
Pages
683-696
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-011-1110-x
PMC
PMC3325407
OpenAlex
W2043631048
Semantic Scholar
899ecf13f4b1cdf7b01e4dc73a4b70f32b7286d6
Cited by
131
References
35
Citations by year
2026: 4 · 2025: 11 · 2024: 8 · 2023: 4 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 11 · 2013: 6 · 2012: 4
FWCI
3.37
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Genetics (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Justice
  • Tel Aviv University
  • National Institutes of Health
  • Office of Justice Programs
  • National Institute of General Medical Sciences (GM 57672, P01GM057672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
OCA2, HERC2, eye pigmentation, skin pigmentation, blue eyes, single nucleotide polymorphisms, haplotypes, natural selection, European populations
MeSH terms
Europe, Eye Color, Asia, Eastern, Gene Frequency, Haplotypes, Humans, Selection, Genetic, Skin Pigmentation, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Guanine Nucleotide Exchange Factors, Membrane Transport Proteins, Ubiquitin-Protein Ligases

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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