The long-term objective of this project is to identify and characterize the quantitative trait genes (QTGs) located on proximal mouse chromosome 17 (Chr17) that confer susceptibility and risk for the development of obesity. We have identified significant linkage for % body fat content on Chr17 using a mouse cross between C57BL/6N and 129P2 mouse strains. At this locus it is the C57BL allele that is associated with increased body fat. Linkage in this region on proximal Chr17 has been identified in numerous other mouse genetic crosses using different substrains of C57 mice, and the C57 allele is always the allele conferring increased risk for obesity. The physical location of the genes underlying this Chr17 QTL has been significantly narrowed by haplotype-based association analysis and bioinformatics. The best candidates for this trait on proximal Chr17 will be identified using a variety of molecular techniques including tiling arrays, sequencing, and expression analyses. Finally the role of specific candidates will be validated using phenotypes measured in null/null mice and the recombinant Quantitative Complementation (rQC) test. The functional role of validated QTGs will then be tested in wildtype, null/null and the mice produced in the rQC test by characterizing the molecular function, as well as the cellular and systems biology of the candidate QTG.
Identification of the genetic basis of disease risk will lead to the development of better treatments for obesity and obesity-related diseases and will lead to methods for tailoring treatment to individual patients based upon their genetic background.