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  1. Evaluation Summary:

    The work reports collection of DNA from 400-plus individuals from the Kalinago territory of Dominica, and shows their relationships with other ancestries, along with a more specific genetic analysis of skin pigmentation. The material is clearly rare and hard to obtain and the analyses are extremely interesting. The work will be of interest to all studying human populations.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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  2. Reviewer #1 (Public Review):

    This work provides new insights into the contribution of Native American ancestry to skin pigmentation in the absence of European ancestry. To investigate potential skin-lightening alleles associated with Native American ancestry, the authors turn to the Kalinago, an admixed population on the Caribbean island of Dominica with predominantly Native American and African ancestry. Additionally, this paper provides an interesting analysis of previously reported albinism alleles, which paints a more complex picture of the genetic architecture of pigmentation.

    This article presents new data on a population with an understudied ancestry composition. Many Native American populations have considerable European admixture. Genetic variance of Native American origin that contributes to decreased skin pigmentation may be hard to distinguish in the presence of European ancestry. Therefore, finding an admixed population with primarily African and Native American ancestry should provide a unique opportunity to explore skin pigmentation-related variation without the overwhelming signal of European alleles. Moreover, this study contributes to the diversification of populations included in genomic research.

    This work provides an intriguing exploration of three Kalinago individuals with albinism, and it reports a novel variant associated with albinism in this population. The authors initially looked at 28 mutations previously reported to be associated with albinism in African and Native American populations. But none of these variants were present in their three Kalinago participants with albinism. They then decided to carry out whole-exome sequencing of one of the albino individuals and one of their parents to search for what specific variants may be associated with albinism in this particular population.

    The authors report 12 candidate variants across seven oculocutaneous albinism (OCA) genes that were heterozygous in the parents and homozygous derived in the albino individual (a criterion for a recessive condition). Of those candidates, they focus on two missense mutations in OCA2: R305W and NW273KV. One of those variants, NW273KV, was previously reported in a compound heterozygote African American individual with albinism.

    This novel variant was homozygous derived in all three Kalinago individuals with albinism. Moreover, the authors were able to ascertain a hypopigmentary effect in heterozygous individuals.

    The genome-wide association study described in this paper provided effect sizes for several variants associated with pigmentation in the Kalinago. However, the predicted effects (based on an additive model) could not explain the measured phenotype in the three albino individuals. This provided concrete quantitative evidence that these pigmentation variants (and likely, others) do not work in a simple additive manner. Overall, this paper contributes significantly to the pigmentation genetics literature and provides further incentive for exploring the genetic architecture of pigmentation in diverse populations.

    My main criticism of this paper is that it only considers the possibility for Native American-derived pigmentation alleles to contribute by decreasing pigmentation. The paper frames Native American and East Asian ancestry as necessarily tied to lighter pigmentation. However, this does not consider that there have been previous reports of Native American-European populations where Native American ancestry has been associated with darker skin.

    Along this line, it is unclear why the authors bring up shared ancestry between East Asians and Native Americans. If they are looking for derived variants in Native American populations that would have arisen after the split from a common ancestor with East Asians, it is unclear why they expect that those variants would have a depigmenting effect, as opposed to increasing pigmentation.

    The exclusive consideration of the adaptive nature of light pigmentation is evident in this paper's discussion of the vitamin D hypothesis, but the omission of the corresponding folate-protection hypothesis, which posits that darker skin would provide critical adaptive benefits in high UV environments. The authors themselves note that the Kalinago would have migrated relatively recently from the northern part of South America (a high UV area). So presumably, if there had been any recent selection relating to pigmentation in this Native American population, the expectation should be that it would have been in the direction of darker skin.

    This criticism does not affect the conclusions of the paper. However, I believe the paper would be stronger if it offered a justification of the search for depigmentation alleles only.

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  3. Reviewer #2 (Public Review):

    This paper investigates the genetic structure and genetic basis of skin pigmentation in the Kalinago population in the Commonwealth of Dominica. The paper makes three main claims.

    1. Kalinago individuals have recent ancestry from Native American, African and European sources.
    2. The identification of a coding variant in OCA2 (likely from the African source population) with a large effect on pigmentation and that causes albinism in heterozygous form.
    3. That a negative correlation between Native American ancestry and skin pigmentation indicates the presence of unknown derived alleles associated with skin pigmentation in that population.

    I think that claim 1 is likely true although the ADMXITURE analysis presented in the paper is less quantitative than presented. This claim could be further tested by local ancestry analysis. Claim 2 is supported. Claim 3 is likely true although I not surprising given the observed differences in pigmentation between Native American and West African populations.

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  4. Reviewer #3 (Public Review):

    This pigmentation study focuses on a community from Kalinago Territory from the Caribbean islands that on average possess high percentages of Indigenous American ancestry, and broadens the effort of quantifying the genetic effects on skin pigmentation in humans. It is appreciable that the authors intended to explore the trait in understudied populations.

    The manuscript has a cohesive and detailed introduction to the population history of the Kalinago Territory community and guided the readers to understand the anthropological background and the formation of the populations' ancestry composition. The layout and logic of the result section is easy for readers to follow. The authors also had an efficient analysis design to narrow down candidate albinism alleles from exome data with three albino individuals in their samples. However, limitation exists on the scope of the study, where the authors characterized variants' effect from only three known genes in Europeans (SLC24A5, SLC45A2, OCA2), whilst a lot more have been documented (e.g. KITLG, TYRP1). It is also surprising that the authors claimed no previous establishment on pigmentation genetics in Native Americans and East Asians while there have been quite a few, and did not provide sufficient discussion or comparison of their results and these studies.

    I also have some remaining concerns about the validity of the major scientific conclusions being supported by the current evidence. Based on the overall study design and very sparse methods description, it is unavoidable for readers to speculate each analysis. For example, the existing methods did not indicate that the authors used the correct statistical model for association analyses to estimate the effect sizes, in presence of close relatedness in their samples; The conclusions on ancestry contribution are ambiguous with regard to the resolution of ancestry decomposition being used in the downstream linear models and association tests; There are technical concerns whether several key methods, including ancestry inference and linear models, have been performed correctly; No replication cohort is used for the novel estimate of population-wide effect size on OCA2NW273KV.

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