Red hair in humans is associated with variant alleles of the alphaMSH receptor 
gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair 
pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which 
contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that 
overexpression of the receptor suppresses the effect of the endogenous 
antagonist, agouti protein. We engineered the BAC to replace the mouse coding 
region with the human MC1R sequence and used this in the transgenic assay. The 
human receptor also efficiently rescued Mc1r deficiency, and in addition, 
appeared to be completely resistant to the effects of agouti, suggesting agouti 
protein may not play a role in human pigmentary variation. Three human variant 
alleles account for 60% of all cases of red hair. We engineered each of these in 
turn into the BAC and find that they have reduced, but not completely absent, 
function in transgenic mice. Comparison of the phenotypes of alphaMSH-deficient 
mice and humans in conjunction with this data suggests that red hair may not be 
the null phenotype of MC1R.