RESEARCH ARTICLE SUMMARY
Loci associated with skin pigmentation
identified in African populations
Nicholas G. Crawford, Derek E. Kelly,* Matthew E. B. Hansen,* Marcia H. Beltrame,*
Shaohua Fan,* Shanna L. Bowman,* Ethan Jewett,* Alessia Ranciaro, Simon Thompson,
Yancy Lo, Susanne P. Pfeifer, Jeffrey D. Jensen, Michael C. Campbell, William Beggs,
Farhad Hormozdiari, Sununguko Wata Mpoloka, Gaonyadiwe George Mokone,
Thomas Nyambo, Dawit Wolde Meskel, Gurja Belay, Jake Haut, NISC Comparative
Sequencing Program, Harriet Rothschild, Leonard Zon, Yi Zhou, Michael A. Kovacs,
Mai Xu, Tongwu Zhang, Kevin Bishop, Jason Sinclair, Cecilia Rivas, Eugene Elliot,
Jiyeon Choi, Shengchao A. Li, Belynda Hicks, Shawn Burgess, Christian Abnet,
Dawn E. Watkins-Chow, Elena Oceana, Yun S. Song, Eleazar Eskin, Kevin M. Brown,
Michael S. Marks,† Stacie K. Loftus,† William J. Pavan,† Meredith Yeager,†
Stephen Chanock,† Sarah A. Tishkoff‡
INTRODUCTION: Variation in pigmentation
among human populations may reflect local
adaptation to regional light environments,
because dark skin is more photoprotective,
whereas pale skin aids the production of vitamin
D. Although genes associated with skin pigmentation have been identified in European populations, little is known about the genetic basis
of skin pigmentation in Africans.
RATIONALE: Genetically and phenotypically
diverse African populations are informative for
mapping genetic variants associated with skin
pigmentation. Analysis of the genetics of skin
pigmentation in Africans informs upon melano-
cyte biology and the evolution of skin pigmen-
tation in humans.
RESULTS: We observe extensive variation in
skin pigmentation in Africa, with lowest melanin levels observed in southern African San
hunter-gatherers and highest levels in East
African Nilo-Saharan pastoralists. A genome-wide association study (GWAS) of 1570 Africans
identified variants significantly associated with
skin pigmentation, which clustered in four genomic regions that together account for almost
30% of the phenotypic variation.
The most significantly associated single-nucleotide polymorphisms were at SLC24A5, a
gene associated with pigmentation in Europeans.
We show that SLC24A5 was introduced into East
Africa >5 thousand years ago (ka) and has risen
to high frequency.
The second most significantly associated region is near the gene MFSD12. Using in vitro and
in vivo analyses, we show that MFSD12 codes for
a lysosomal protein that modifies pigmentation
in human melanocytes, with decreased MFSD12
expression associated with
darker pigmentation. We
also show that genetic
knockouts of MFSD12 orthologs affect pigmentation in both zebrafish
A third highly associated region encompasses
a cluster of genes that play a role in ultraviolet
(UV) response and DNA damage repair. We find
the strongest associations in a regulatory region
upstream of DDB1, the gene encoding damage-specific DNA binding protein 1, and that these
variants are associated with increased expression of DDB1. The alleles associated with light pigmentation swept to near fixation outside of Africa
due to positive selection, and we show that these
lineages coalesce ~60 ka, corresponding with the
time of migration of modern humans out of Africa.
The fourth significantly associated region encompasses the OCA2 and HERC2 loci. We identify
previously uncharacterized variants at HERC2
associated with the expression of OCA2. These
variants arose independently from eye and skin
pigmentation–associated variants in non-Africans.
We also identify variants at OCA2 that are correlated with alternative splicing; alleles associated with light pigmentation are correlated
with a shorter transcript, which lacks a transmembrane domain.
CONCLUSION: We identify previously uncharacterized genes and variants associated with
skin pigmentation in ethnically diverse Africans.
These genes have diverse functions, from repairing UV damage to playing important roles
in melanocyte biology. We show that both dark
and light pigmentation alleles arose before the
origin of modern humans and that both light
and dark pigmented skin has continued to evolve
throughout hominid history. We show that variants associated with dark pigmentation in
Africans are identical by descent in South Asian
and Australo-Melanesian populations. This study
sheds light on the evolutionary history, and
adaptive significance, of skin pigmentation
in humans. ▪
The list of author affiliations is available in the full article online.
*These authors contributed equally to this work.
†These authors contributed equally to this work.
‡Corresponding author. Email: tishkoff@pennmedicine.
Cite this article as N. G. Crawford et al., Science 358, eaan8433
(2017). DOI: 10.1126/science.aan8433
GWAS and functional assays illuminate the genetic basis of pigmentation in Africa. A GWAS identified
four genomic regions associated with skin pigmentation in Africa. Functional assays in melanocytes,
zebrafish, and mice characterized their impact on skin pigmentation. Evolutionary genetic analyses
revealed that most derived variants evolved before the origin of modern humans. Ma, million years ago.
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