We are currently involved in several projects intended to resolve patterns of recombination, linkage disequilibrium, and molecular evolution of interesting human loci, especially the major histocompatibility complex (MHC) region. A principal result of these studies should be the ability to refine many of the current disease associations with large genomic regions, such as the MHC, into the constituent disease locus or loci. The first of these concerns the CCR5- delta32 allele, which our lab has previously shown to be related both to AIDS resistance and postponement of AIDS. We have now estimated that this allele is approximately 4300 years old, and is unique to Caucasians and populations that have admixed with Caucasians. In the course of this work we developed a new method for estimating the age of alleles. Furthermore, the CCR5-delta32 allele is one of several alleles we are studying that is largely unique to Caucasians. Such """"""""Caucasian"""""""" alleles that are segregating in the African-American population define regions that will be especially useful for mapping by admixture linkage disequilibrium (Z01 BC 05681-07 LGD). The molecular evolution of the MHC is something of a paradox regarding recombination, in that the well-documented linkage disequilibrium that extends across the entire MHC suggests a reduced level of recombination, yet phylogenetic analyses of constituent alleles (e.g., HLAB, DPB1) suggest extensive inter-allelic recombination as a major source of allelic diversity. A primary focus of this project is the improvement of existing population genetic and evolutionary theories, especially with regard to interpretation of patterns of linkage disequilibrium under moderate levels of recombination. This includes improvement of the existing algorithms for detecting recombination, and their application to allelic sequences from MHC and other loci. We are currently studying HLAA, -B, -C, and DPB1, with plans to address DRB1, DQA1, and DQB1. For many MHC loci, the collection of alleles can be described as a series of mosaic combinations of variable motifs. In this sense, each allele is a haplotype, which makes linkage disequilibrium theory relevant as well. We are starting to encounter the types of data exemplified by the MHC (allele and haplotype frequencies, large numbers of alternative DNA sequences) from other genomic regions, and these will require a more rigorous approach to understanding their natural history. The immediate challenge is that the analysis of such moderate to long range """"""""haplotypes"""""""" of variants embodies coalescence theory, linkage disequilibrium, and phylogenetics. An underlying objective of these studies is to be able to determine whether observed genic or allelic associations are truly functional (e.g., disease related) or simply a consequence of historic population genetic or evolutionary processes.
