An analysis of genetic variation in the beta-globin cluster of the house mouse.

House mouse haemoglobins are encoded by two unlinked clusters of alpha- and beta-globin genes. The beta-globin polypeptides arising from three well-defined distinct adult beta-globin alleles (s, d and p) can be distinguished electrophoretically. In wild populations these exist as a discrete s/d polymorphism in Europe and a d/p polymorphism in Asia. DNA restriction site haplotypes of these beta-globin genes were investigated. A unique s haplotype was found in all European subspecies and inbred mice, but the distinct d and p haplotypes of inbred mice are likely to be just a two sample subset from a much wider spectrum of the variable diffuse- like (d and p) DNA haplotypes found in wild mice. In English mice the discrete s and d adult haplotypes appear to extend to the embryonic and beta-related sequences. Restriction mapping, cloning and DNA heteroduplex analysis of the inbred adult beta-globin genes have shown that the differences between s, d and p haplotypes point to a remarkable DNA sequence divergence within a single species. The distinct pattern of variation between all three haplotypes consists of long invariant regions (involving both coding and flanking sequences) separated by a variable region(s) that has undergone major rearrangements and DNA sequence divergence. From these results and DNA sequencing data (assuming rodent DNA molecular evolution rates) a chronology of mouse evolution can be proposed. The adult beta-globin gene was duplicated and the two copies last corrected against each other about 10-35 MA. The s and diffuse-like haplotypes began to diverge about 2-4 MA and subsequently the diffuse-like haplotype appears to have diverged in its beta-minor gene component, after perhaps a localized gene correction around 1 MA. Three models of (i) bottleneck, (ii) allopatric and (iii) sympatric evolution have been proposed to explain the distinct pattern of DNA divergence and the maintenance of the beta-globin polymorphisms.