Human DNA sequence variation in a 6.6-kb region containing the melanocortin 1 receptor promoter

An similar to6.6-kb region located upstream from the melanocortin 1 recepto r (MC1R) gene and containing its promoter was sequenced in 54 humans (18 Af ricans, 18 Asians, and 18 Europeans) and in one chimpanzee, gorilla, and or angutan. Seventy-six polymorphic sites were found among the human sequences and the average nucleotide diversity (pi) was 0.141%, one of the highest a mong all studies of nuclear sequence variation in humans. Opposite to the p attern observed in the MC1R coding region, in the present region a is highe st in Africans (0.136%) compared to Asians (0.116%) and Europeans (0.122%). The distributions of pi, theta, and Fu and Li's F-statistic are nonuniform along the sequence and among continents. The pattern of genetic variation is consistent with a population expansion in Africans. We also suggest a po ssible phase of population size reduction in non-Africans and purifying sel ection acting in the middle subregion and parts of the 5 ' subregion in Afr icans. We hypothesize diversifying selection acting on some sites in the 5 ' and 3 ' subregions or in the MC1R coding region in Asians and Europeans, though we cannot reject the possibility of relaxation of functional constra ints in the MC1R gene in Asians and Europeans. The mutation rate in the seq uenced region is 1.65 X 10(-9) per site per year. The age of the most recen t common ancestor for this region is similar to that for the other long non coding regions studied to date, providing evidence for ancient gene genealo gies. Our population screening and phylogenetic footprinting suggest potent ially important sites for the MC1R promoter function.