EVOLUTIONARY HISTORY OF THE MOUSE T COMPLEX--A MOLECULAR GENETICS APPROACH

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The t complex, a 20 cM region encompassing the proximal half of Chr 17 in house mice, offers unique opportunities for studying the origin and evolution of gene complexes, especially those that act as genetic parasites in the genome by preferentially transmitting themselves to the presumed detriment of the host. Additionally, the t complex harbors genes which influence mating behavior and aggression in mice, making it a model system for testing behavioral genetic hypotheses. Our previous work showed that many complete t haplotypes and many haplotypes in wild mice are combinations of t-specific and wild-type alleles. These wild- type alleles were confined to the distal portion of the t complex, suggesting that the nature of the chromosomal rearrangements and therefore the consequences of recombination differ between the proximal and distal portions of the complex. We propose to test several aspects of a hypothesis proposed to account for the origin and evolution of the t complex and to exploit the "mosaic" haplotypes to investigate several of these questions. The first goal involves estimating the relative ages of the four discrete portions of the complex through restriction fragment and sequence analysis of selected alleles, testing whether exceptional loci are confined to the distal portion of the t complex, and characterizing partial t haplotypes in wild mice. The second goal involves identifying functional genes within the t complex which may contribute to the critical phenotypes conferred by t haplotypes, i.e., transmission ratio distortion, male sterility, and embryonic lethality. This will be accomplished by selective cloning of t segments, examining transcription profiles of candidate genes, and identifying candidate genes in Mus spretus, a wild mouse species that has a gene arrangement on Chr 17 that is similar to part of the t complex. The third goal is to define the gene(s) within the t complex that are responsible for the well-defined mating behavior and aggression of mice harboring the t complex. This will be achieved through a combination of molecular analysis of semi-natural mouse populations, mapping recombination breakpoints in congenic laboratory mice, and the isolation of region- specific cloned segments from a congenic mouse library. All three goals are interrelated in that pursuing them will help to build a cohesive model of how the accumulation of specific mutations in Chr 17 genes helped to shape a genomic region that has propagated itself over the last 2 million years to the extent that over 25% of wild mice worldwide now possess this chromosomal variant.