Evolution of the Mouse H-2k Region: A Hot Spot of Mutation Associated with Genes Transcribed in Embryos and/or Germ Cells

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Active gene transcription is known to promote genetic change in neighboring DNA. We reasoned that the change would be readily heritable if transcription was occurring in germ cells or early embryonic cells before the germ cells are set aside. The H-2K region of the major histocompatibility complex (MHC) provides a good vehicle for testing this hypothesis because it is replete with such genes. We have compared the amount of polymorphism in 240 kb of DNA contiguous with H-2K and 150 kb of DNA flanking a homologous duplicated region in t-haplotypes and inbred strains. Using 90 probes and three restriction enzymes, we find a staggering difference in the amount of polymorphism in the H-2K region vs. the duplicated region (26% vs. 0%) of t-haplotypes. The disparity in the rate of divergence between the two regions indicates that the spatial distribution of genes and their expression pattern might be important factors in sequence evolution. Since t-haplotypes normally show extremely limited variability among themselves due to their recent divergence from a single ancestor, these results imply that the mutation rate in the H-2K region is unusually high. This is in apparent contradiction to the current view that the MHC loci have evolved at the same rate as other loci. The implications for the evolution of the H-2K gene are discussed.

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