The human histocompatibility (HLA) system contains a number of closely linked genes whose products control a variety of functions concerned with the regulation of immune responses. The great variety and complexity of molecular, genetic and physiological phenomena present in the HLA region make it an extraordinary resource and testing ground for examining evolutionary processes. To understand the mechanisms by which disease predisposing genes become common in populations, it is essential that we be familiar with the population genetics features and multilocus interaction of specific genetic regions of the human genome in both general and patient population data. This particularly applied to the HLA region which has been shown to influence disease susceptibility to over 40 diseases.
The specific aim of our research is investigation of theoretical and empirical population genetic data of multilocus systems with particular emphasis on the investigation of models to elucidate the evolutionary history of the HLA region. Our research approach will be based on mathematical modelling and development of methods to analyze a number of large population data sets available to us. Our studies will include identification of HLA haplotypes subject to recent selection events, investigation of the relationship of linkage disequilibrium to map distance, ethnic comparison of evolutionary events, establishment of the relative importance of point mutation, gene conversion and intragenic recombination in the evolution of HLA alleles and of a phylogenetic tree incorporating these events, analysis of the apparently different evolutionary histories of genes in the HLA regions, analysis of 11 non-HLA genetic markers from a large French study as well as of restriction fragment length polymorphism (RFLP) data that is accumulating for the human genome; and modelling of life history selection in the HLA region and the effect of finite and variable population size in the context of HLA variation. The methods developed to study the HLA region are in most cases directly applicable to other regions of the human genome. Over 500 RFLP sites have been mapped in the human genome and the number of expected to increase tremendously in the next few years. The rest of our study will contribute to inferences that can be made on the forces acting in natural populations, and how these contribute to the origin, maintenance and evolution of genetic variation, as well as the delineation of possible mechanisms by which disease predisposing genes become common in population.
Showing the most recent 10 out of 65 publications
