Patterned variation in murine MHC promoters

Abstract

To compare variation in regulatory and coding DNA, promoter sequences have been obtained from wild-derived mice and laboratory rats. The sequences are from the proximal promoter of the H2Aa, H2Ab, H2Eb, and H2K genes of 24 wild-derived inbred strains and a sample of the corresponding exon 2 sequences and of the RT1.Ba gene of six strains of laboratory rat. They reveal a high level of variation in the mouse MHC class II promoters (H2A and H2E), a low level in MHC class I (H2K), and none in the rat. The variation is pronounced in and around the cAMP response element, a major binding site for modulating promoter activity in response to external stimulation. This finding, together with the different levels of variation in MHC classes I and II, is suggestive of natural selection. However, selection operating via the MHC coding sequences must also contribute, as indicated by the minimal variation in both the MHC class II promoter and coding sequences of the rat. Furthermore CIITA (trans-activator of class II) of the mouse has been reported to have minimal variation in its promoter and none in its coding sequence. Taken together these data suggest that the regulatory and coding sequences undergo coselection. Each of the mouse class II promoters has a pattern of variation that appears to be basically dimorphic, with further variation added by recombination͞mutation. The dimorphic allelic lineages are in marginally detectable linkage disequilibrium with the exon 2 sequences, particularly in H2Aa, thus lending further support to the coevolution hypothesis.

Detecting natural selection on cis-regulatory DNA

“…They found an analog of p a /p s in regulatory regions to be greater than 1, and therefore evidence for balancing selection, in mouse but not man. Their result and further research into this and related regions (Mitchison and Roes 2002;Tan et al 2005), suggests that selection is acting to maintain both multiple protein variants and multiple expression patterns at histocompatibility loci.…”

Polymorphism in the bovine BOLA-DRB3 upstream regulatory regions detected through PCR-SSCP and DNA sequencing

“…Some of these polymorphisms were found in the regulatory motifs (i.e. X1, Y and CCAAT boxes), while others were observed among consensus boxes (Andersen et al, 1991;Pascale et al, 1993;Singal et al, 1993a;Reichstetter et al, 1994;Singal and Qiu, 1994;Cowell et al, 1998;Mitchinson and Roes, 2002). Polymorphisms found in conserved consensus sequences could affect DNA -protein interactions (Singal et al, 1993b;Emery et al, 1993).…”

Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice

“…In congenic inbred mice, MHC effects can be artificially amplified, because their background genes are highly homogenous. It is also known from studies on humans and mice that there are several background genes that either alone or in interaction with MHC genes can influence resistance and the outcome of disease (Vidal et al 1993;Vukusic et al 1995;Apanius et al 1997;Jepson et al 1997;Mitchison and Roes 2002;Greve et al 2004) and even overwhelm the MHC effects or change the resistance patterns (Apanius et al 1997). Therefore, our goal was to determine how MHC and MHC heterozygosity influence resistance on a wild background.…”