Functional Analysis of Red Hair Colour Using a Humanised Mouse Model

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Although much of the normal variation between humans is due to genetics, very little is known about the genes that cause this variation. An exception is the genetics of hair colour for which, largely thanks to studies in mice, a number of genes are known that are associated with both blond hair and red hair. The genetics of red hair is the simplest and this study is addressing the genes and interactions between them which result in red hair.We showed a number of years ago that people with red hair have changes in a gene known as MC1R, but not everyone with a variant MC1R gene has red hair; some variants frequently result in red hair whilst others more often than not do not. There must be other genes that determine whether or not MC1R affects hair colour. We have studied the DNA of tens of thousands of people in the UK Biobank study, and identified genes that appear to affect hair colour. There are many different genes associated with blond hair, but only a handful that result in red hair. To study these genes and their interactions in more detail we plan to study the effect of some of the variants in cells grown in culture. In order to fully understand the impact of these variants in the whole body, we will go on to make mice that carry these genetic changes, and look at the impact of the changes on mouse hair colour. This will act as a model system for the study of other traits controlled by more complex genetic interactions.Mice which lack the MC1R gene have yellow fur rather than the normal black or "agouti" (a grey/brown colour). The human and mouse MC1R proteins have somewhat different properties, and the respective genes are regulated differently to compensate. If we engineer one of the "strong" red hair changes into the mouse gene it has surprisingly little impact on the colour of the mice; the differences in gene regulation mask the effect of the variant. We have produced a mouse strain that lacks its own MC1R gene but contains the human gene, along with all the DNA required for the normal function of the gene, and this gives the mice their normal coloured hair. This human gene will allow us to study changes seen in red haired people by engineering changes in the DNA. We will produce mice with a "strong" and a "weak" change in the coding part of the human MC1R gene and assess their impact on mouse hair colour. We have also found changes in the DNA that control the MC1R gene in red-haired people. We will engineer these changes into our "humanised" mouse model and assess it's impact on hair colour.We have also found that DNA changes near a gene called MSX2 are associated with red hair. This gene codes for a protein that can control other genes, and indirect evidence suggests that it may control a gene called ASIP, which codes for an inhibitor of MC1R. We will investigate where MSX2 interacts with DNA around the ASIP gene, and we will ask what is the effect on hair colour of removing those sites in mice.