Project description:The specific genes influencing the quantitative variation in macronutrient preference and food intake are virtually unknown. We refined a previously identified mouse chromosome 17 (MMU17) region harboring quantitative trait loci (QTL) with large effects on preferential macronutrient intake-carbohydrate (Mnic1), total kilcalories (Kcal2), and total food volume (Tfv1) using interval-specific congenic strains. These loci were isolated in the [C57BL/6J.CAST/EiJ-17.1-(D17Mit19-D17Mit50); B6.CAST-17.1] strain, developed by introgressing a ~40.1 Mb CAST MMU17 region into recipient B6 genome. In a diet selection paradigm (carbohydrate/protein vs. fat/protein), these B6.CAST-17.1 sub-congenic mice eat 30% more calories from the carbohydrate-rich diet, ~10% more total calories, and ~9% more total food volume per body weight. In the current study, this carbohydrate-preferring B6.CAST-17.1 subcongenic strain was crossed with the fat-preferring inbred B6 strain to generate a subcongenic-derived F2 mapping population; genotypes were determined using a high-density, custom SNP panel. The main outcome of this study is that genetic linkage analysis greatly reduced the 95% confidence interval (CI) for Mnic1 (encompassing Kcal2 and Tfv1) from 40.1 to 29.5 Mb and more precisely established the QTL boundaries. Specifically, the genetic architecture for Mnic1 (preferential carbohydrate intake) does not follow the same pattern as that for co-localized Kcal2/Tfv1 (total kcal and food volume, respectively), suggesting the presence of separate quantitative trait genes for these food intake traits. No genetic linkage for self-selected fat intake was detected, underscoring the carbohydrate-specific effects of this MMU17 locus. The Mnic1/Kcal2/Tfv1 QTL was further de-limited to a ~19.1 Mb interval, based on the absence of macronutrient diet selection phenotypes in subcongenic HQ17IIa mice that possess CAST MMU17 donor segment on a C57BL/6Jhg/hg background. A second key finding is the separation of two energy balance QTLs: Mnic1/Kcal2/Tfv1 for food intake and a newly discovered locus regulating short term body weight gain. The genes Decr2, Ppard and Agapt1 in the critical QTL interval were identified and prioritized using a combination of genome sequence analysis, and tag-based transcriptome sequencing to measure hypothalamic gene expression in non-recombinant F2 controls, possessing cast/cast and b6/b6 genotypes across the sub-congenic segment.

Project description:The specific genes influencing the quantitative variation in macronutrient preference and food intake are virtually unknown. We refined a previously identified mouse chromosome 17 (MMU17) region harboring quantitative trait loci (QTL) with large effects on preferential macronutrient intake-carbohydrate (Mnic1), total kilcalories (Kcal2), and total food volume (Tfv1) using interval-specific congenic strains. These loci were isolated in the [C57BL/6J.CAST/EiJ-17.1-(D17Mit19-D17Mit50); B6.CAST-17.1] strain, developed by introgressing a ~40.1 Mb CAST MMU17 region into recipient B6 genome. In a diet selection paradigm (carbohydrate/protein vs. fat/protein), these B6.CAST-17.1 sub-congenic mice eat 30% more calories from the carbohydrate-rich diet, ~10% more total calories, and ~9% more total food volume per body weight. In the current study, this carbohydrate-preferring B6.CAST-17.1 subcongenic strain was crossed with the fat-preferring inbred B6 strain to generate a subcongenic-derived F2 mapping population; genotypes were determined using a high-density, custom SNP panel. The main outcome of this study is that genetic linkage analysis greatly reduced the 95% confidence interval (CI) for Mnic1 (encompassing Kcal2 and Tfv1) from 40.1 to 29.5 Mb and more precisely established the QTL boundaries. Specifically, the genetic architecture for Mnic1 (preferential carbohydrate intake) does not follow the same pattern as that for co-localized Kcal2/Tfv1 (total kcal and food volume, respectively), suggesting the presence of separate quantitative trait genes for these food intake traits. No genetic linkage for self-selected fat intake was detected, underscoring the carbohydrate-specific effects of this MMU17 locus. The Mnic1/Kcal2/Tfv1 QTL was further de-limited to a ~19.1 Mb interval, based on the absence of macronutrient diet selection phenotypes in subcongenic HQ17IIa mice that possess CAST MMU17 donor segment on a C57BL/6Jhg/hg background. A second key finding is the separation of two energy balance QTLs: Mnic1/Kcal2/Tfv1 for food intake and a newly discovered locus regulating short term body weight gain. The genes Decr2, Ppard and Agapt1 in the critical QTL interval were identified and prioritized using a combination of genome sequence analysis, and tag-based transcriptome sequencing to measure hypothalamic gene expression in non-recombinant F2 controls, possessing cast/cast and b6/b6 genotypes across the sub-congenic segment. Global gene expression profiles in the hypothalamus were compared between non-recombinant subcongenic-derived F2 mice, possessing a genotype of cast/cast (n=12) or b6/b6 (n=12) across the Chr 17 subcongenic segment and b6/b6 across the rest of the genome. RNA was isolated from individual mice of each genotype that were selected for study. Specifically, twelve mice of each genotype that displayed the most divergent phenotypic values for self-selected carbohydrate and total kcal intake were chosen for gene expression analysis, i.e., cast/cast mice with the highest and b6/b6 mice with the lowest kcal intake from carbohydrate, or the 25% tails of the distribution. Tissues were harvested ~48 h after re-initiation of the carbohydrate/protein vs. fat/protein diets, following an extended wash-out period on chow diet after completion of the 10 d macronutrient selection test.

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Identification of Positional Candidate Genes for Body Weight and Adiposity in Subcongenic Mice

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