Orthologs of mouse obesity genes may be involved in human obesity, and have a significant impact on human health. The focus of this application is to identify a gene or genes on mouse chromosome 9 that influence adiposity. As a prelude to this work, we have conducted a genome scan using an F2 population derived from the B6 and 129 strains. A major finding from this genome scan was evidence for linkage of body weight (LOD score--3.8) and adiposity on chromosome 9 (LOD scores=3.2). The locus on chromosome 9 accounts for between 10 and 20% of the total trait variance, and has an additive mode of inheritance. There have been several studies, in addition to this genome scan, that have identified mouse chromosome 9 as an important area of linkage for obesity, yet no fine mapping of this region has been done. This goal will be met by the completion of four Specific Aims:
Specific Aim 1 : Fine mapping of chromosome 9 using 457 mice from the F2 intercross between B6 and 129 strains. A dense map will be created to refine the linkage peak.
Specific Aim 2 will be the creation of congenic and subcongenic lines of mice with the plus adiposity allele introgressed into the donor genetic background. Comparison of overlapping donor fragments will further refine the location of the trait locus, and restrict the number of candidate genes.
Specific Aim 3 will be an evaluation of candidate genes: first, genes that are polymorphic between the B6 and 129 strain will be identified by comparison of their sequences (Mouse Genome Sequencing Project and Celera). Then phenotype-genotype correlations among other inbred strains of mice will be conducted, followed by laboratory and in silico assays of the tissue distribution of gene expression, and gene expression differences between the B6 and 129 strains for selected tissues. The goal of Specific Aim 4 is to determine gene function of high-priority candidates using transgenic mouse construction, and subsequent phenotype analysis. Understanding the role of each molecule important in obesity will be a significant step towards the development of safe and effective therapeutics.
| Lin, Cailu; Fesi, Brad D; Marquis, Michael et al. (2015) Body Composition QTLs Identified in Intercross Populations Are Reproducible in Consomic Mouse Strains. PLoS One 10:e0141494 |
| Lin, Cailu; Theodorides, Maria L; McDaniel, Amanda H et al. (2013) QTL analysis of dietary obesity in C57BL/6byj X 129P3/J F2 mice: diet- and sex-dependent effects. PLoS One 8:e68776 |
| Jiang, Peihua; Josue, Jesusa; Li, Xia et al. (2012) Major taste loss in carnivorous mammals. Proc Natl Acad Sci U S A 109:4956-61 |
| Mennella, J A; Finkbeiner, S; Reed, D R (2012) The proof is in the pudding: children prefer lower fat but higher sugar than do mothers. Int J Obes (Lond) 36:1285-91 |
| Reed, Danielle R; Duke, Fujiko F; Ellis, Hillary K et al. (2011) Body fat distribution and organ weights of 14 common strains and a 22-strain consomic panel of rats. Physiol Behav 103:523-9 |
| Li, Xia; Bachmanov, Alexander A; Maehashi, Kenji et al. (2011) Sweet taste receptor gene variation and aspartame taste in primates and other species. Chem Senses 36:453-75 |
| Bachmanov, Alexander A; Bosak, Natalia P; Floriano, Wely B et al. (2011) Genetics of sweet taste preferences. Flavour Fragr J 26:286-294 |
| Tordoff, M G; Reed, D R; Shao, H (2008) Calcium taste preferences: genetic analysis and genome screen of C57BL/6J x PWK/PhJ hybrid mice. Genes Brain Behav 7:618-28 |
| Reed, Danielle R (2008) Animal models of gene-nutrient interactions. Obesity (Silver Spring) 16 Suppl 3:S23-7 |
| Reed, Danielle R; McDaniel, Amanda H; Avigdor, Mauricio et al. (2008) QTL for body composition on chromosome 7 detected using a chromosome substitution mouse strain. Obesity (Silver Spring) 16:483-7 |
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