Coat color mutations in laboratory mice have provided important insights into the cellular and developmental processes underlying mammalian pigmentation and have served as models for human disease. Of particular relevance to human obesity, for example, are several dominant, coat-lightening mutations in the regulatory region of the Agouti gene. These mutations lead to ectopic expression of the Agouti protein and are associated with severe pleiotropic effects that include embryonic lethality, diabetes, hyperphagia, tumor susceptibility, and obesity in laboratory mice. Recent work suggests a similar link between variation in the human homologue of Agouti and obesity. Preliminary evidence indicates that a dominant mutation in the Agouti regulatory region is also responsible for light coat color in natural Peromyscus maniculatus (deer mouse) populations inhabiting the Sand Hills region of Nebraska; however, this phenotype (""""""""wide-band agouti"""""""") appears to be unaccompanied by major pleiotropic effects. Comparison of mutations occurring in natural and laboratory organisms, which show low and high degrees of pleiotropy respectively, may provide insight into the nature of Agouti regulation. Therefore, the broad goal of this research is to pinpoint the mutation(s) responsible for light coat color in two geographically separated populations of P. maniculatus. This goal will require successful completion of three specific research aims. First, phenotypic (banding patterns on individual dorsal hairs and spectrophotometric measurements) and neutral genetic variation (from SNP markers) will be measured for 260 individuals collected at multiple locations within and outside of the Sand Hills region of Nebraska. Second, Peromyscus BAG sequences containing the Agouti gene will be used to identify candidate regulatory regions by comparative sequence analysis and once candidate regions are identified, association studies will be conducted between nucleotide variation in Agouti and coat color phenotypes from wild populations. Third, P. maniculatus populations inhabiting the Tularosa Basin, New Mexico will be sampled and genotyped for candidate SNPs identified in the Nebraska populations to determine whether the same molecular mechanism is responsible for a similar phenotype in this geographically distant population. Relevance: This research is of direct relevance to the mission of NIH because it will identify and molecularly characterize Agouti mutations, which will inform current models of mammalian pigmentation and human obesity. ? ? ?
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