In mice, many genomic regions contain variation that results in differences in adiposity (Reed 2003;2006;2007;2008). The goal of this research program is to find the gene or genes on mouse chromosome 9 that account for the quantitative trait locus Adip5, which is associated with increased weight of the gonadal adipose depot. Although several lines of evidence suggest that a gene or genetic variant here has the ability to regulate adiposity, the exact gene or DNA sequence that causes this effect is not known. The QTL Adip5 has features that make it a practical target for a positional cloning approach: it is not particularly susceptible to maternal effects or epistatic interactions, and it is associated with a distinct phenotype (gonadal depot weight). Furthermore, the experimental plan is designed to identify Adip5 if the locus is imprinted (i.e., if there are parent-of-origin effects). Within the current Adip5 confidence interval, there are several credible candidate genes (Bbs4, Cpy19a1, Crabp1, Cplx3, Il18, Lipc, Nedd4), as well as dozens of genes and noncoding RNA of unknown function. Using a chromosome 9 substitution strain developed in our laboratory for this purpose (CSS-9), we will backcross these mice to the host strain (C57BL/6ByJ;B6) and conduct a genome scan to reduce the confidence interval of Adip5 (CSS-9 X B6 N2 genome scan;
Aim 1). Based on the refined confidence interval provided by the genetic mapping information, we will parse this chromosome into small intervals through successive breeding cycles, and create microcongenic strains (<200 kb), one of which will contain the gene responsible for Adip5 (Aim 2). To identify the exact gene responsible for Adip5, we will genetically engineer one or more mouse strains with a segment of 129 DNA substituted into a B6 background by homologous recombination, and evaluate its effect on gonadal depot weight (Specific Aim 3). The long-range goal of this work is to develop an approach to systematically identify genes that contribute to normal variation in fatness among mice.

Public Health Relevance

Like people, mice vary in how naturally fat they are when fed a standard diet, under standard conditions. By interbreeding mice, we can examine the pattern of genes and alleles that fat mice share with each other and which they do not share with lean mice. By finding influential DNA variation in one specific region (on mouse chromosome 9), we hope to learn how this variation contributes to obesity in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058797-13
Application #
8497672
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Karp, Robert W
Project Start
2000-03-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$307,565
Indirect Cost
$101,854
Name
Monell Chemical Senses Center
Department
Type
DUNS #
088812565
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Reed, Danielle R; Lawler, Maureen P; Tordoff, Michael G (2008) Reduced body weight is a common effect of gene knockout in mice. BMC Genet 9:4
Shao, Hongguang; Reed, Danielle R; Tordoff, Michael G (2007) Genetic loci affecting body weight and fatness in a C57BL/6J x PWK/PhJ mouse intercross. Mamm Genome 18:839-51
Tordoff, Michael G; Bachmanov, Alexander A; Reed, Danielle R (2007) Forty mouse strain survey of water and sodium intake. Physiol Behav 91:620-31

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