RECOMBINATION HOT SPOTS ARE ASSOCIATED WITH DIMINISHED LEVELS OF LINKAGE DISEQUILIBRIUM WITHIN THE HUMAN MHC

Abstract

The Major Histocompatability Complex (MHC) serves as an excellent model for studying patterns of recombination. It is the most thoroughly characterized region of the entire genome in terms of nucleotide sequence, protein structure and function, immunological role and disease association. Ten highly polymorphic genes encoding the Human Leukocyte Antigen (BLA) molecules are mapped within the MHC. These molecules are cell surface glycoproteins that present either foreign Ag or self-peptide to T cells. Cooperative interactions between alleles of specific HLA genes may lead to a more favorable immune response against a specific class of pathogen or tumor cell, which may account for why some alleles of different HLA genes are found linked on a chromosome more frequently than expected by chance. Formally stated, linkage disequilibrium (LD) is the non-random association of alleles at linked loci. Genomic segments exhibiting high levels of LD correlate with lower levels of recombination. Thus for a given genomic segment, levels of LD increase as levels of recombination decline. LD between pairs of polymorphic loci within the MHC may result from selective forces acting upon pairs of alleles at distinct loci that confer a beneficial trait. In the present study, eight polymorphic short tandem repeats (STRs) were selected to accurately assess levels of LD across specific regions of the MHC characterized by high and low levels of recombination. These recombinational hot spots and cold spots were defined by our laboratory using high-resolution microsatellite typing in sperm. By carefully selecting microsatellites that are evenly spaced across the MHC, comparisons can be made between the levels of LD across hot spots as well as cold spots. It is commonly thought that levels of LD will decrease over areas of high recombination. This study examines the question of whether the relationship between LD and genetic distance is maintained throughout the MHC given the selective pressures on HLA genes. The data confirms that LD does decrease over recombinational hot spots located within the MHC and that it is these same hot spots, not genetic distance, that play the most significant role in the degree of LD. This analysis of LD patterns across the MHC in the context of recombination patterns will enhance our understanding of the selective pressures driving MHC evolution.