Project Summary/Abstract: The long-term objective of this project is to identify polymorphisms in genes that confer susceptibility and risk for the development of obesity and type 2 diabetes in mouse models of these diseases, and to determine if polymorphisms in the same genes, or genes in the same pathway, confer risk in human populations. A genetic linkage analysis for body fat composition and response to a glucose tolerance test has been completed in a subset of mice from a very large genetic cross between C57BL/6N and 129P2 inbred mouse strains that produced ~5000 mice. Significant linkage findings on five different chromosomes for body fat and glucose tolerance were observed. The project will use additional linkage analyses, bioinformatics analyses, and haplotype mapping in the entire mapping population to identify candidate genes. Evaluation of candidate genes to confirm a role in the development of these traits will be completed by testing mice with knockouts of the candidates and with a variety of genetic and molecular techniques. The specific aims of this project are: 1) to genotype and complete a linkage analysis in a large (~5,000 mouse) N2F1 intercross between C57BL/6N and 129P2 mice to identify QTLs controlling body fat, body weight, and glucose tolerance;2) to narrow the QTL critical intervals and identify candidate genes using several methods including combining data from related projects that used similar strain pairs, bioinformatics, haplotype and congenic analysis;3) to evaluate positional candidate genes in one linkage region using molecular techniques and characterizing phenotypes using null mutants.