Heterozygote mutants of the melanocortin 1 receptor show reduced tanning whilst homozyotes show red hair

Healy, E;, Ray, A;, Flanagan, N;, Birch-Machin, M;, Philips, S;, Todd, C;, Hair, L;, Matthews, J;, Jackson, I;, Rees, J

doi:10.1046/j.1523-1747.1999.00001.x

Heterozygote mutants of the melanocortin 1 receptor show reduced tanning whilst homozyotes show red hair

Lookup NU author(s): Dr Niamh Flanagan, Dr Eugene Healy, Dr Amanda Ray, Professor Mark Birch-Machin ORCiD

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Abstract

Because variants of the melanocortin 1 receptor (MC1R) gene are associated with red hair, we investigated families with red hair to determine the mode of inheritance of MC1R associated traits. 211 individuals from 11 kindreds were studied, sequencing of MC1R showing that 59 of 74 (80%) with red hair were homozygous/compound heterozygous for the R151C, R160W, D294H variants or one of two insertions (ins29 and ins179), indicating that red hair is usually inherited as an autosomal recessive trait. Transfection studies in COS7 cells using lipofection confirmed the inability of alpha-melanocyte stimulating hormone to stimulate intracellular cAMP production through the R151C, R160W, D294H and R142H variants. Importantly however, whilst red-hair is present in ~5% of the UK population, we have shown clear evidence of a heterozygote effect: presence of one mutant allele gives an odds ratio of a lower Fitzpatrick phototype category of 4.1, or decreased tanning odds ratio of 4.8 (p < 0.01). Odds ratios for homozygotes are > 17 and 23, respectively. Such heterozygote advantage may be the driving force for natural selection in Northern Europe at this locus, and reveals the MC1R to be a major determinant of skin phototype even in those without red hair.