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Integration of genomic, proteomic, and metabolomic analyses towards polygene discovery in mice selected for 3 to 6 week post weaning weight gain
Positional cloning of genes underlying QTL for complex traits has had little success. Mechanisms to select from large numbers of candidate genes within QTL regions are required. Our objective is to integrate proteomic and metabolomic analysis (sub-phenotyping) with QTL analysis, to facilitate a better understanding of the genetic architecture of complex traits in a mouse model selected for growth. The M16 line of mice is the result of selection for 3 to 6 wk weight gain for 27 generations. M16 mice have larger body weight, are hyperphagic and moderately obese, and exhibit NIDDM relative to the ICR base population. Protein levels in tissues (liver, brain, skeletal muscle, epididymal adipose, plasma) representing 8-wk-old males within M16 and ICR were analyzed with ∼900 different monoclonal antibodies in duplicate. Specific protein differences were confirmed in lines using Western blots. Differences verified in liver are PTEN, Insulin Receptor beta, elf-6, and Spot14. PTEN and Insulin Receptor beta regulate insulin metabolism, while Spot14 is involved in lipogenesis. Total lipid class analysis of plasma, liver, and epididymal adipose identified increased de novo synthesis of fatty acids along with accelerated activity in delta 5,6 desaturase/elongation pathways in M16 mice. A resource population (n = 1,183 mice) was created representing an F2 intercross of M16 and ICR and 80 microsatellite markers were genotyped for all individuals. This study successfully identified 131 Quantitative Trait Loci (QTL) for traits representing weight, fat, lean, bone, feed intake, blood glucose, insulin, leptin, triacylglyceride, phospholipid, free fatty acids, diacylglycerides, and cholesterol esters. QTL were identified on chromosomes 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 15, and 17. A merging of physiological and predisposition analyses will facilitate the placement of QTL effects within specific pathways, and may differentiate between QTL with direct (cis) or regulatory (trans) influences on energy-balance phenotypes. ^
Biology, Animal Physiology|Chemistry, Biochemistry
Allan, Mark F, "Integration of genomic, proteomic, and metabolomic analyses towards polygene discovery in mice selected for 3 to 6 week post weaning weight gain" (2003). ETD collection for University of Nebraska - Lincoln. AAI3116557.