Kenny et al. (2012) 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 UV radiation. Although ... Kenny et al. (2012) 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 UV radiation. 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.
Kenny et al. (2012) performed a case-control genomewide association study on 43 blond- and 42 dark-haired Solomon Islanders and observed a single strong association signal on chromosome 9p23; the most significant SNP was dbSNP rs13289810 with a p ... Kenny et al. (2012) performed a case-control genomewide association study on 43 blond- and 42 dark-haired Solomon Islanders and observed a single strong association signal on chromosome 9p23; the most significant SNP was dbSNP rs13289810 with a p value of 1.11 x 10(-19) and a frequency of 0.93 and 0.31 in blond- and dark-haired individuals, respectively. The mapping interval contained 1 known gene, TYRP1. It was known that mutations in TYRP1 lighten skin and/or hair pigmentation in several species, and that TYRP1 null alleles cause rufous albinism (OCA3; 203290) in humans. Resequencing of TYRP1 exons identified a C-to-T transition at chr9:12,694,273 (GRCh37) that corresponds to a predicted arg-to-cys mutation (R93C) in exon 2 of the TYRP1 gene at amino acid position 93 (R93C; 115501.0007). The genotype was TT in blond- and CT or CC in dark-haired individuals. The R93C mutation was more strongly associated with blond hair (p = 9.60 x 10(-23)) than the top GWA SNP, and the GWA signal was lost on conditioning for R93C, suggesting a primary role for the missense mutation. When Kenny et al. (2012) genotyped R93C in 918 Solomon Islanders for whom they had measured hair pigmentation with spectrometry, a recessive model provided the best fit for the data, and the R93C genotypes accounted for 46.4% of the variance in hair color (linear regression; p = 2.19 x 10(-90)). The frequency of the 93C allele in the Solomon Islands was 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. Kenny et al. (2012) found no evidence for recent gene flow from Europe (i.e., admixture) nor a strong signature of recent positive selection for the 93C allele. Kenny et al. (2012) noted that the R93C mutation resides in an EGF-like repeat near the N terminus and is similar to a molecular alteration in TYRP1 observed in the brown(light) mouse (R38C). The R38C mutation is thought to interfere with disulfide bridges formed by the 15-cys EGF repeat. The brown(light) mouse exhibits reduced TYRP1 stability and catalytic function, resulting in decreased melanin content in hair, and Kenny et al. (2012) considered it likely that the human R93C mutation operates via a similar mechanism.