Complex Signatures of Selection and Gene Conversion in the Duplicated Globin Genes of House Mice

Results of electrophoretic surveys have suggested that hemoglobin polymorphism may be maintained by balancing selection in natural populations of house mice, Mus musculus. Here we report a survey of nucleotide variation in the adult globin genes of house mice from South America. We surveyed nucleotide polymorphism in two closely linked a-globin paralogs and two closely linked b-globin paralogs to test whether patterns of variation are consistent with a model of long-term balancing selection. Surprisingly high levels of nucleotide polymorphism at the two b-globin paralogs were attributable to the segregation of two highly divergent haplotypes, Hbb s (which carries two identical b-globin paralogs) and Hbb d (which carries two functionally divergent b-globin paralogs). Interparalog gene conversion on the Hbb s haplotype has produced a highly unusual situation in which the two paralogs are more similar to one another than either one is to its allelic counterpart on the Hbb d haplotype. Levels of nucleotide polymorphism and linkage disequilibrium at the two b-globin paralogs suggest a complex history of diversity-enhancing selection that may be responsible for long-term maintenance of alternative protein alleles. The alternative two-locus b-globin haplotypes are associated with pronounced differences in intraerythrocyte glutathione and nitric oxide metabolism, suggesting a possible mechanism for selection on hemoglobin function.