Once a genetic determinant of disease susceptibility or resistance is localized, the function of the gene to which it belongs and the identity and effect of the determinant may be established. This process, called positional cloning, depends on the precision of localization, and therefore on the number of variable sites (markers). Fifty years ago only a handful of markers were known, but today there are several million, most of which are single nucleotide polymorphisms (SNPs). Neighbouring markers may be grouped into haplotypes that tend to be inherited together, but the useful length of a haplotype set (haploset) varies in the genome, and to a lesser extent among populations. This variation is an aid or obstacle to positional cloning, depending on how it is used. Association between neighbouring markers is called linkage disequilibrium (LD), which can be used to construct an LD map on which distances are additive and roughly proportional to genetic recombination, but at about 100 times greater resolution. Building on tested methods for positional cloning, our project aims to construct LD maps, determine the impact of population history on them, integrate LD, linkage, and physical maps, and extend these methods to create and apply the most efficient way of combining information from LD maps and haplotypes to localize genetic determinants of disease, beginning the path from understanding to treatment and prevention.
| Gibson, Jane; Collins, Andrew; Morton, Newton (2008) Individual disease risk and multimetric analysis of Crohn disease. Proc Natl Acad Sci U S A 105:15843-7 |
| Gibson, Jane; Tapper, William; Cox, David et al. (2008) A multimetric approach to analysis of genome-wide association by single markers and composite likelihood. Proc Natl Acad Sci U S A 105:2592-7 |
| Morton, Newton; Maniatis, Nikolas; Zhang, Weihua et al. (2007) Genome scanning by composite likelihood. Am J Hum Genet 80:19-28 |
