Distributions of single nucleotide polymorphisms in differential chromosome segments of congenic resistant strains that define minor histocompatibility antigens

Abstract

Minor histocompatibility antigens (MiHAs) stimulate the rejection of allografts when donors and recipients are matched at the major histocompatibility complex (MHC). The majority of identified autosomal MiHAs were generated by non-synonymous (NS) substitutions that alter MHC class I-binding peptides. The mosaic distribution of single nucleotide polymorphisms (SNPs) that distinguish inbred mouse strains led us to hypothesize that MiHA genes defined by congenic strains on C57BL/6 and C57BL/10 backgrounds map to chromosomal regions with relatively high numbers of NS SNPs that distinguish C57 strains from other common inbred strains. To test this hypothesis, we mapped the ends of differential chromosome segments of congenic strains, which define 12 MiHAs, relative to microsatellites and SNPs. The lengths of differential segments ranged from 9.7 to 105.9 Mbp in congenic strains where no attempts were made to select recombinants within these segments. There was no apparent correlation between differential segment length and number of backcrosses, suggesting that factors other than the number of opportunities for recombination affected the differential segment lengths in these congenics. These differential segments included higher numbers of NS SNPs that distinguish C57BL/6J from A/J, DBA/2J, and 129S1/J than would be predicted if these SNPs were uniformly distributed along the chromosomes. The most extreme case was the H8 congenic that included 74% of the SNPs on chromosome 14 within its 9.7-11.1 Mbp differential segment. These results point toward a direct relationship between the level of genomic divergence, as indicated by numbers of NS SNPs, and numbers of MiHAs that collectively determine the magnitude of allograft rejection.