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

Kateryna D. Makova, Michele Ramsay, Trefor Jenkins, Wen Hsiung Li

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Abstract

An ∼6.6-kb region located upstream from the melanocortin 1 receptor (MC1R) gene and containing its promoter was sequenced in 54 humans (18 Africans, 18 Asians, and 18 Europeans) and in one chimpanzee, gorilla, and orangutan. Seventy-six polymorphic sites were found among the human sequences and the average nucleotide diversity (π) was 0.141%, one of the highest among all studies of nuclear sequence variation in humans. Opposite to the pattern observed in the MC1R coding region, in the present: region π is highest in Africans (0.136%) compared to Asians (0.116%) and Europeans (0.122%). The distributions of π, θ, 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 possible phase of population size reduction in non-Africans and purifying selection acting in the middle subregion and parts of the 5′ subregion in Africans. 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 constraints in the MC1R gene in Asians and Europeans. The mutation rate in the sequenced region is 1.65 × 10-9 per site per year. The age of the most recent common ancestor for this region is similar to that for the other long noncoding regions studied to date, providing evidence for ancient gene genealogies. Our population screening and phylogenetic footprinting suggest potentially important sites for the MC1R promoter function.

Original languageEnglish (US)
Pages (from-to)1253-1268
Number of pages16
JournalGenetics
Volume158
Issue number3
StatePublished - Aug 1 2001

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All Science Journal Classification (ASJC) codes

  • Genetics

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