Functional variation of MC1R alleles from red-haired individuals

Red hair in humans is associated with variant alleles of the alpha MSH rece ptor gene, MC1R. Loss of MC1R function in other mammals results in red or y ellow hair pigmentation. We show that a mouse bacterial artificial chromoso me (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transg enic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replac e the mouse coding region with the human MC1Rsequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficien cy, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary v ariation. Three human variant alleles account for 60% of all cases of red h air. We engineered each of these in turn into the BAC and find that they ha ve reduced, but not completely absent, function in transgenic mice. Compari son of the phenotypes of alpha MSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1 R.