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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Karp, Robert W
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Monell Chemical Senses Center
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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
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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
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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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