Research Projects

Analysis of complex traits in Mouse and Rat models of human disease

(i) Heterogeneous Stocks (with Jonathan Flint)

The main focus of our research is the analysis of rich datasets of phenotypes, genotypes and gene expression measured in a population of 2000 heterogeneous stock mice (Mott et al 2000, PNAS; Valdar et al 2006, Nature Genetics; Solberg et al 2006 Mammalian Genome; Valdar et al 2006 Genetics; Shifman et al 2006 PLoS Biology; Huang et al 2009 Genome Research; Goodson et al 2011 PLoS Genetics ). Latterly we have begun to reeat this approach in 1400 heterogeneous stock rats (Baud et al 2013 Nature Genetics).

(ii) The Collaborative Cross (with Dr Fuad Iraqi, Tel Aviv University Israel, Dr Fernando Pardo-Manuel de Villeneva, University of North Caroline, USA )

With Fuad Iraqi we are breeding approximately 100 recombinant inbred lines of mice descended from eight diverse inbred strains (Iraqi at el, 2008 Mammalian Genome, Durrant et al 2011 Genome Research, Aylor et al 2011 Genome Research). These lines, once completed, will form part of the Collaborative Cross, an international programme to generate a genetic reference panel for systems genetics. The breeding work is carried out at Tel Aviv University by Dr Fuad Iraqi. Currently most lines are about 80-90% inbred some are already available for distribution from UNC.

Complex Trait Analysis in Arabidopsis thaliana

From a statistical genetics perspective, the model plant A thaliana has many similarities with the mouse. Both can form genetically stable inbred strains and can be crossed to generate complex populations which are ideal for mapping quantitative traits. Many of the analytical techniques our group have developed are applicable to both systems. One advantage of working with A thaliana (apart from its intrinsic importance as a model plant) is that it is possible to make recombinant inbred lines very quickly in comparison with the mouse, and therefore to generate genetic reference panels and devise and test statistical methods, and then apply the lessons learnt to the mouse.

With Dr Paula Kover (University of Manchester) we have developed a genetic reference panel of over 500 recombinant inbred lines of A thaliana, descended from 19 genetically diverse inbred founder accessions (Kover et al, 2009 submitted). This work is funded by the BBSRC.

I hold a BBSRC grant to resequence the genomes of the founders using Illumina GAII short-read sequencing. The compact size of the reference genome (120 Mb) means it is possible to generate high coverage easily in comparison to the mouse. We are developing algorithms to assemble the reads (with Dr Xiangchao Gan) and will make the data available in 2009. Using this data we can impute the genome of each recombinant inbred line (which is a mosaic of the 19 founders) in order to perform high-resolution genetic association.