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Melanesian Blond Hair Is Caused by an Amino Acid Change in TYRP1

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Science  04 May 2012:
Vol. 336, Issue 6081, pp. 554
DOI: 10.1126/science.1217849

Abstract

Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Here, we identify an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) as a major determinant of blond hair in Solomon Islanders. This missense mutation is predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance. The mutation is at a frequency of 26% in the Solomon Islands, is absent outside of Oceania, represents a strong common genetic effect on a complex human phenotype, and highlights the importance of examining genetic associations worldwide.

Human pigmentation varies considerably within and among populations and is a function of both variation in exposure to ultraviolet radiation (UVR) and the type and quantity of melanin produced in melanocytes (1). We examined the genetic basis of blond hair in Solomon Islanders, a population that differs from the general trend of darker skin and hair pigmentation near the equator where there is higher UVR (1). Although individuals from the Solomon Islands and Equatorial Oceania have the darkest skin pigmentation outside of Africa, they also have the highest prevalence of blond hair (5 to 10%) outside of Europe (Fig. 1A) (2).

Fig. 1

(A) Two individuals from the Solomon Islands with dark (left) and blond hair (right). (B) GWA scores comparing blond- and dark-haired individuals show a strong signal at 9p23; the genome-wide significance threshold is indicated by the red line. (C) Association scores at 9p23 with the top GWA SNP (red diamond), TYRP1 R93C (purple diamond), and the TYRP1 gene (arrow) indicated. The degree of red color in each diamond indicates the strength of LD with R93C. (D) Age and sex-corrected hair color by R93C genotype and the result of a linear model assuming a recessive mode of inheritance (boxed in). Boxes denote upper and lower quartiles, and error bars indicate ±2.7 SD.

We performed a case-control genome-wide association (GWA) study on 43 blond- and 42 dark-haired Solomon Islanders and observed a single strong association signal on chromosome 9p23; the most significant single-nucleotide polymorphism (SNP) (rs13289810; P = 1.11 × 10−19) had a frequency of 0.93 and 0.31 in blond- and dark-haired individuals, respectively (Fig. 1B). The mapping interval contained one known gene, tyrosinase-related protein 1 (TYRP1; Fig. 1C), which encodes a melanosomal enzyme involved in mammalian pigmentation and is highly conserved in vertebrates (3). Mutations in TYRP1 lighten skin and/or hair pigmentation in several species (3), and TYRP1 null alleles cause rufous albinism in humans (4, 5).

Resequencing of TYRP1 exons detected a single previously unknown polymorphism, a C-to-T transition at chr9:12,694,273 (GrCH37/hg19), that corresponds to a predicted arginine-to-cysteine mutation (R93C) in exon 2 of TYRP1 at amino acid position 93 (TT in blond- and CT or CC in dark-haired individuals). This variant was genotyped in the GWA panel, and association analyses were repeated, including R93C. R93C was more strongly associated with blond hair (P = 9.60 × 10−23) than the top GWA SNP (Fig. 1C), and the GWA signal was lost on conditioning for R93C (fig. S5). This suggests a primary role for the missense mutation, although the involvement of noncoding and/or regulatory variants in strong linkage disequilibrium (LD) with R93C cannot be ruled out.

We genotyped R93C in 918 Solomon Islanders for whom we had measured hair pigmentation with spectrometry. A recessive model provided the best fit for the data, and R93C genotypes accounted for 46.4% of the variance in hair color (linear regression; P = 2.19 × 10−90; Fig. 1D and table S2). The frequency of the 93C allele in the Solomon Islands is 0.26, and genotyping of R93C in an additional 941 individuals from 52 worldwide populations revealed that the 93C allele is rare or absent outside of Oceania (table S3). Furthermore, we found no evidence for recent gene flow from Europe (i.e., admixture) (figs. S5 and S6) nor a strong signature of recent positive selection for the 93C allele (figs. S9 to S11).

The 93C blond hair mutation in human TYRP1 resides in an epidermal growth factor (EGF)–like repeat near the N terminus and is similar to the molecular alteration observed in the TYRP1 allele in the brownlight mouse (fig. S12). The brownlight phenotype is caused by an Arg→Cys substitution located 55 amino acids upstream of R93C (R38C) and likely interferes with disulfide bridges formed by the 15-Cys EGF repeat. The brownlight mouse exhibits reduced TYRP1 stability and catalytic function, resulting in decreased melanin content in hair (6), and it is likely that the human 93C mutation operates via a similar mechanism.

The present study realizes the benefits of extending genetic mapping to humans worldwide, and we predict that many novel genetic variants with large phenotypic effects remain to be discovered in populations currently underrepresented in genomic research (7). Our results strongly support the notion that the study of diverse populations is crucial to elucidating the genetic basis of phenotypic variation.

Supplementary Materials

www.sciencemag.org/cgi/content/full/336/6081/554/DC1

Materials and Methods

Figs. S1 to S12

Tables S1 to S3

References (829)

References and Notes

  1. Acknowledgments: We are grateful to the people of the Solomon Islands for their participation in this study. We thank the Kosrae consortium for access to genetic data, G. Coop and G. Barsh for helpful comments, and C. Wegener for technical assistance. Funded by a Wenner-Gren Foundation for Anthropological Research grant to S.M., MRC Centre for Causal Analyses in Translational Epidemiology grant RD1634 to N.J.T., National Heart, Lung, and Blood Institute and National Human Genome Research Institute funding to C.D.B., and the Max Planck Society. Allele frequency data for this study are available from dbGAP (study accession phs000493.v1.p1). De-identified genotype data are available through a data access agreement for transfer of genetic data by contacting C.D.B.
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