EVOLUTION uncovered by the GWAS harbors a series of mostly noncoding SNPs and no known pig- mentation genes. The attention of Crawford Skin color variation in Africa et al. was drawn to the gene MFSD12 (major facilitator superfamily domain containing Genetics of skin color has implications for pigmentary 12) because several SNPs in the surround- ing genomic region are not only associated biology and human evolution with skin color, but also affect the expres- sion of adjacent genes, of which several are By Hua Tang1 and Gregory S. Barsh2 pigmentation genes SLC24A5 (solute carrier highly expressed in melanocytes (the skin family 24 member 5) and OCA2 (oculocu- cells that produce melanin pigment). A se- he remarkable genetic diversity within taneous albinism 2), and a third is close to ries of experiments provided compelling African populations is both a signa- DDB1 (damage-specific DNA binding protein support for the hypothesis that reduced ture and a storybook of human origins 1). SLC24A5 was first identified in zebrafish, expression of MFSD12 causes darker skin because descendants of the earliest where it is responsible for the golden muta- in African populations. MFSD12 encodes a humans who lived in Africa nearly tion, which results in lighter pigmentation transmembrane protein localized to lyso- 200,000 years ago have had the lon- of the zebrafish stripes (3). In humans, a mu- somes; therefore, this finding offers clues to Tgest time to accumulate genetic variation. tated, or derived, SLC24A5 variant contrib- how intracellular organelles may communi- Although studying genetic diversity in Afri- utes to light skin. Complete loss of function cate and affect each other’s function. can populations tells us a great deal about for OCA2 causes severe albinism (4, 5), but Furthermore, the association of MFSD12 Downloaded from human history, there is even more to learn partial loss of function due to alterations in provides insight on the long-standing mys- by juxtaposing the genetic diversity with the OCA2 expression is the major cause of blue- tery of a mouse coat-color mutation known diversity of heritable traits (phenotypes). Yet, versus-brown eye color (6). DDB1 is widely as grizzled (which refers to the streaky ap- there is a paucity of such studies involving expressed, but is involved in the DNA damage pearance of hairs), for which the responsible continental Africans (1). On page 887 of this response to ultraviolet (UV) radiation (7, 8). gene has not been found (9). Like humans, issue, Crawford et al. (2) demonstrate the Although SLC24A5, OCA2, and DDB1 normal mice have two kinds of pigment, potential insights that can come from ame- were strong candidate genes on the basis of black-brown eumelanin and red-yellow phe- http://science.sciencemag.org/ liorating this disparity. They examined skin prior nonhuman studies, the fourth region omelanin. However, laboratory mice with an color variation in 2000 African individuals from different geographic locations and eth- nic groups; the range, from light-skinned San Skin color variants during human history hunter-gatherer populations in southern Af- A skin color map of indigenous African people, based on data collected by the Italian geographer Renato rica to dark-skinned pastoralist populations Biasutti et al. (16). Some variants associated with MFSD12, DDB1, and OCA2 occurred more than 500,000 in eastern Africa, far exceeds pigmentary years ago. Variants associated with SLC24A5, TYRP1 (tyrosinase-related protein 1), and SLC45A2 (solute carrier diversity anywhere else on the planet (see family 45 member 2) are more recent, but SLC24A5 has been introduced by migration back into Africa, where it the figure). Using a genome-wide association contributes to skin color diversity. study (GWAS) that includes 1600 individuals on January 9, 2018 living in Tanzania, Botswana, or Ethiopia, the 2 authors identified regions of the genome that A5 C24 contribute to skin color variation and car- SL ried out a series of analyses to pinpoint the responsible genes. Studying the genetics of human pigmen- tation can provide fundamental insight into the genetic architecture of complex traits and the relationship between adaptive variation and population history, and reveal new aspects of cell biology. Although more than a hundred genes are known to influ- 1 ence pigmentary traits in plants and ani- mals, only a handful have been implicated Timeline in humans. Of note, until now, all human Ancestral 1 2 Recent pigmentation genes were originally discov- ered in nonhuman organisms. Derived (darker) Derived (lighter) In Crawford et al., the GWAS in the Afri- can cohort identifies four regions in which MFSD12 DDB1 OCA2 SLC24A5 TYRP1 SLC45A2 single nucleotide polymorphisms (SNPs) are significantly associated with skin color varia- tion: Two of these occur in the well-known NCE IE C S / U O Y 1 . J Department of Genetics, Stanford University, 300 Pasteur 2 C: I Drive, Stanford, CA 94305, USA. HudsonAlpha Institute for Human skin color distribution H Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA. AP R Lighter Darker G Email: [email protected]; [email protected] SCIENCE sciencemag.org 17 NOVEMBER 2017 • VOL 358 ISSUE 6365 867 Published by AAAS DA_1117Perspectives.indd 867 11/15/17 12:13 PM INSIGHTS | PERSPECTIVES experimentally induced mutation of Mfsd12 explore the extent to which interaction be- POLYMER CHEMISTRY feature streaky hairs that contain eumelanin, tween genes and interaction between genes but not pheomelanin, identical to what has and environment contribute to phenotypic been described for grizzled. Indeed, Craw- variation. But such studies require larger The promise ford et al. demonstrate that Mfsd12 mutant samples and new analytic frameworks: Like mice are unable to produce pheomelanin and other studies on skin pigmentation (12–14), that grizzled mice have a deletion of Mfsd12. Crawford et al. focus on additive effects of plastics Hence, the identification of MFSD12 marks a across loci—approximately one-third of the victory for phenotype-driven human genetics. total phenotypic variation was accounted for The MFSD12 findings from Crawford et by four loci. What accounts for the other two- from plants al. raise several intriguing questions. How thirds? Some of the “missing” heritability does this transporter-like protein expressed could represent measurement noise or envi- Plant-derived feedstocks in lysosomes affect what happens in me- ronmental factors. A study of an African-Eu- are increasingly competitive lanosomes (the organelle that stores and ropean cohort from the Cape Verde Islands transports melanin)? Why does reduced points to an oligogenic model with four in plastics production expression of MFSD12 cause increased syn- major gene variants and many additional thesis of black-brown eumelanin in humans, gene variants of small effect (14). It should By Marc A. Hillmyer but loss of Mfsd12 in mice does not affect be emphasized, however, that estimates of eumelanin synthesis? Finally, is it a coinci- heritability are meaningful only to the popu- olymers protect us from the elements, dence that human MFSD12 variants affect lation being studied. For example, Crawford increase the fuel efficiency of cars, Downloaded from gene expression rather than protein struc- et al. estimate that 12.8% of the phenotypic protect food from pathogens, help ture? A potential answer to the last ques- variance in skin pigmentation in Africans is cure disease, and enable renewable- tion is apparent from grizzled mice, which attributable to SLC24A5, which reflects both energy technologies. To promote, fos- not only exhibit streaky hair but also have the strength of allelic substitution and allele ter, and enable a sustainable society, occasional developmental and growth ab- frequency. By contrast, SLC24A5 contributes Pwe need polymers. Yet polymers can also normalities (9). It seems possible that regula- almost nothing to skin color variation in create serious environmental challenges. tory variants in MFSD12 that reduce, but do Europeans because the derived allele occurs Nearly all plastic packaging produced— http://science.sciencemag.org/ not ablate, protein function confer positive essentially at a frequency of one. Success of more than 80 billion kg annually—origi- selection due to the ability of dark skin to the endeavor described in Crawford et al. de- nates from fossil resources and is disposed block the damaging effects of UV radiation, pends on a diversity of approaches, diversity of after a relatively short period of use (1, 2). but avoid negative selection due to impaired of genetic variation, and, especially, diversity An increasing fraction of plastic is recycled development and/or growth. of phenotypic variation. Perhaps paradoxi- or incinerated to recover energy, but most It is interesting to contrast MFSD12 se- cally, the strongest association signal for skin ends up in landfills, littering cities or land- lection in African populations with that for color comes from SLC24A5, for which varia- scapes, and in the oceans (3). New recycling SLC24A5 in European populations. The re- tion is of relatively recent origin in Europe. concepts (4), clean incineration, and the gions surrounding both genes exhibit strong Thus, the power of continental Africa as a development of polymers that can rapidly divergence between continents, but the substrate for human genetics is enhanced by degrade (5) will be key to addressing these on January 9, 2018 derived variant of SLC24A5, which occurs human