Much of my research uses synthetic populations for statistical genetics. These are populations of individuals descended from a known set of inbred founders. The genomes of the individuals in the population are therefore mosaics of these founders. Synthetic populations differ from natural populations because rare variants are virtually absent and because the haplotype space is tightly defined. Their mapping properties are intermediate bewteen simple F2 intercrosses and natural populations (like humans). See Mott and Flint 2013 for a recent review of the field.
My group has developed statistical methods for mapping in synthetic populations (Mott et al 2000, Yalcin et al 2005, Valdar et al 2006, Valdar et 2009, Durrant and Mott 2010). Below we describe some of the applications of this approach.
Analysis of complex traits in Mouse and Rat models of human disease
(i) Heterogeneous Stocks (with Jonathan Flint)
One of the foci of our research is the analysis of rich datasets of phenotypes, genotypes and gene expression measured in a population of 2000 heterogeneous stock (HS) mice. This has led to a wide variety of analyses, encompassing (a) quantitative trait locus (QTL) mapping (Valdar et al 2006, Solberg et al 2006, Valdar et al 2006a), genetic maps (Shifman et al 2006), gene expression (Huang et al 2009), phenotype meta analysis (Goodson et al 2011), variation in DNAaseI hypersensitive sites in the eight founders of the HS (Hosseini et al 2013), and parent of origin effects (Mott el al 2013; Cell In press) (funded by Wellcome Trust).
Latterly we have begun to repeat this approach in 1400 heterogeneous stock rats (Baud et al 2013) (funded by EU EURATRANS FP7)
(ii) The Collaborative Cross (with Dr Fuad Iraqi, Tel Aviv University (TAU) Israel, Dr Fernando Pardo-Manuel de Villeneva, University of North Carolina (UNC), USA )
With Fuad Iraqi we are breeding approximately 100 recombinant inbred lines of mice descended from eight diverse inbred strains (Iraqi at el, 2008, Durrant et al 2011, Aylor et al 2011). 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 (funded by Wellcome Trust). Currently most lines are about 80-90% inbred. Some are already available for distribution from UNC .
Representative genome mosaic of one Collaborative Cross line, IL-18, in terms of the eight founder haplotypes (y-axis). X-axis is autosome position. From Durrant et al 2011.
(iii) Sequencing inbred mouse strains
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). This work is funded by the BBSRC.
The BBSRC also funded us to resequence the genomes of the founders using Illumina GAII short-read sequencing (Gan et al 2011).
Please see my old web pages for links to previous research projects. I am in the process of updating these pages.