Genome evolution: a study of MHC paralogous genes in the human genome.

One of the interesting findings of the Human Genome Project was that approximately 10% of the genome has arisen by duplication. This is exemplified by the clusters of genes, on chromosomes 1q21-q25, 9q32-q34.3 and 19p13, paralogous to genes located within the Major Histocompatibility Complex (MHC) region, on 6p22.2- p21.3. By definition, paralogues are genes within the same species that have originated through duplication of an ancestral gene. The survey of the human genome identified 82 MHC paralogues based on sequence similarity and conserved gene structure. Analysis of the distribution of the paralogues identified clusters on chromosomes 1q21-q25, 9q32-q34.3 and 19p13 (38/82), and revealed paralogues located elsewhere in the genome (44/82). In total, 44% of the paralogues identified are novel discoveries, of which 89% are located outside the previously known clusters. Evidence from my phylogenetic analyses indicates that the MHC paralogues located within the regions on 1, 9 and 19 arose by two ancient duplication events, either by duplication of the whole genome or of chromosomal segments, prior to vertebrate emergence. Expansion of paralogous gene families has occurred by additional duplications involving individual loci or chromosomal regions resulting in paralogues outside the clusters. In-depth analysis of the chromosomal region 9q32-q34.3 revealed that the order of paralogues is not conserved and that they are interspersed by other genes, indicating the region has been subjected to genomic rearrangements. Comparison of the expression profiles of a selected set of MHC paralogues revealed that some have functionally diverged since duplication; with members of the same paralogous gene family being ubiquitously expressed, and others, having anexpression profile restricted to only a few tissues. Evidence of co-expression of paralogues in some tissues suggests a similar function and involvement in the same pathways. This thesis highlights the importance of understanding paralogy, particularly for future investigations of phenotypes associated with paralogous genes.