Prevalence and evolutionary origins of autoimmune susceptibility alleles in natural mouse populations

The evolutionary origin of genetic diversity in the SLAM/CD2 gene cluster, implicated in autoimmune lupus susceptibility in

mice, was investigated by sequence analysis of exons from six members of the cluster in 48 wild mouse samples derived from

the global mouse population. A total of 80 coding region SNPs were identified among the six genes analyzed, indicating that

this gene cluster is highly polymorphic in natural mouse populations. Phylogenetic analyses of these allelic sequences revealed

clustering of alleles derived from multiple Mus species and subspecies, indicating alleles at several SLAM/CD2 loci were

present in ancestral Mus populations prior to speciation and have persisted as polymorphisms for more than 1 million years.

Analyses of nonsynonymous/synonymous ratios using likelihood codon substitution models identified several segments in

Cd229, Cd48 and Cd84 that were impacted by positive diversifying selective pressures. These findings support

the interpretation that selection favoring the generation and retention of functional polymorphisms has played a role in the

evolutionary origin of genetic polymorphisms that are predisposing to autoimmunity.