Mouse Models of Human Variation and Disease

Laboratory mice are excellent models for the effects of human genetic mutations or variation. New methods now allow us to produce very precise changes in the DNA of mice, to mimic human genetic changes, and to see the effect on the biology of the mouse. This programme has two aspects. The first is to study the effects of genetic mutations on the eye, to understand why loss or change in a gene leads to faults in the retina and to effect on vision. The second aspect is to unravel the genetics of human hair colour. Although hair colour genetics is complicated (we have found more than 100 genes that are involved) it is much simpler than the genetics affecting many common diseases. Understanding hair colour genetics is a “halfway house” to a full understanding of these important disease genetics. In some cases we will introduce genetic changes into mice to see the effect on hair colour biology. In most cases we will use human cells grown in the laboratory and produce changes in them to measure the effect on the genes.

1. Mouse Models of Eye Disease. We study a mouse mutant line which lacks the, Fam151b gene and as a consequence has very rapid photoreceptor degeneration. Fam151b encodes a protein of unknown function, with similarity to glycerophosphodiester phosphodiesterases. We aim to identify the function of the FAM151B protein and understand the basis of the photoreceptor degeneration. We are in addition making mouse models of retinal detachment, by editing changes in mice into genes identified in genome wide association studies (GWAS) of Scottish populations. Analysis of the impact of these genetic changes on retinal histopathology and function will validate the gene identification from the GWAS. These studies will furthermore aid the understanding of the biology of normal retinal function and may indicate therapeutic avenues.
2. Understanding the Genetic Basis of Hair Colour Variation, We have performed a GWAS of several hundred thousand individuals in the UK Biobank, and identified many loci affecting hair colour. We are editing genetic changes in the genomes of mice, melanocytes and keratinocytes in order to determine the effect of these variants on gene expression, cell biology and mouse phenotype. Hair colour variation is an excellent example of a phenotype under complex genetic control. The cells and cellular interactions involved are well understood, and the genotype to phenotype connections are potentially tractable. It serves as a model for more diseases where there may be environmental as well as genetic effects, and where the cell types involved may be not well known or be less accessible.