Abstract
There is growing awareness that complex interactions among multiple genes and environmental factors play an important role in controlling obesity traits. The BSB mouse, which is produced by the backcross of (lean C57BL/6J x lean Mus spretus) x C57BL/6J, provides an excellent model of epistatic obesity. To evaluate potential epistatic interactions among six chromosomal regions previously determined to influence obesity phenotypes, we performed novel Bayesian analyses on the basis of both epistatic and nonepistatic models for four obesity traits: percentage of body fat, adiposity index, total fat mass, and body weight, and also for plasma total cholesterol. The epistatic analysis detected at least one more QTL than the nonepistatic analysis did for all obesity traits. These obesity traits were variously influenced by QTL on chromosomes 2, 7, 12, 15, and 16. Interaction between genes on chromosomes 2 and 12 was present for all obesity traits, accounting for 3-4.8% of the phenotypic variation. Chromosome 12 was found to have weak main effects on all obesity traits. Several different epistatic interactions were also detected for percentage of body fat, adiposity index, and total fat mass. Chromosomes 6 and 12 have not only main effects but also strong epistatic effects on plasma total cholesterol. Our results emphasize the importance of modeling epistasis for discovery of obesity genes.
Full Text
The Full Text of this article is available as a PDF (175.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bell G. E., Stern J. S. Evaluation of body composition of young obese and lean Zucker rats. Growth. 1977 Mar;41(1):63–80. [PubMed] [Google Scholar]
- Brockmann G. A., Kratzsch J., Haley C. S., Renne U., Schwerin M., Karle S. Single QTL effects, epistasis, and pleiotropy account for two-thirds of the phenotypic F(2) variance of growth and obesity in DU6i x DBA/2 mice. Genome Res. 2000 Dec;10(12):1941–1957. doi: 10.1101/gr.gr1499r. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Castellani L. W., Navab M., Van Lenten B. J., Hedrick C. C., Hama S. Y., Goto A. M., Fogelman A. M., Lusis A. J. Overexpression of apolipoprotein AII in transgenic mice converts high density lipoproteins to proinflammatory particles. J Clin Invest. 1997 Jul 15;100(2):464–474. doi: 10.1172/JCI119554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cheverud J. M., Vaughn T. T., Pletscher L. S., Peripato A. C., Adams E. S., Erikson C. F., King-Ellison K. J. Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice. Mamm Genome. 2001 Jan;12(1):3–12. doi: 10.1007/s003350010218. [DOI] [PubMed] [Google Scholar]
- Coleman D. L., Hummel K. P. The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia. 1973 Aug;9(4):287–293. doi: 10.1007/BF01221856. [DOI] [PubMed] [Google Scholar]
- Cordell Heather J. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet. 2002 Oct 1;11(20):2463–2468. doi: 10.1093/hmg/11.20.2463. [DOI] [PubMed] [Google Scholar]
- Corva P. M., Horvat S., Medrano J. F. Quantitative trait loci affecting growth in high growth (hg) mice. Mamm Genome. 2001 Apr;12(4):284–290. doi: 10.1007/s003350010275. [DOI] [PubMed] [Google Scholar]
- Dong Chuanhui, Wang Shuang, Li Wei-Dong, Li Ding, Zhao Hongyu, Price R. Arlen. Interacting genetic loci on chromosomes 20 and 10 influence extreme human obesity. Am J Hum Genet. 2002 Dec 11;72(1):115–124. doi: 10.1086/345648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Farahani Poupak, Fisler Janis S., Wong Howard, Diament Adam L., Yi Nengjun, Warden Craig H. Reciprocal hemizygosity analysis of mouse hepatic lipase reveals influence on obesity. Obes Res. 2004 Feb;12(2):292–305. doi: 10.1038/oby.2004.37. [DOI] [PubMed] [Google Scholar]
- Fisler J. S., Warden C. H., Pace M. J., Lusis A. J. BSB: a new mouse model of multigenic obesity. Obes Res. 1993 Jul;1(4):271–280. doi: 10.1002/j.1550-8528.1993.tb00621.x. [DOI] [PubMed] [Google Scholar]
- Harris R. B., Mitchell T. D., Yan X., Simpson J. S., Redmann S. M., Jr Metabolic responses to leptin in obese db/db mice are strain dependent. Am J Physiol Regul Integr Comp Physiol. 2001 Jul;281(1):R115–R132. doi: 10.1152/ajpregu.2001.281.1.R115. [DOI] [PubMed] [Google Scholar]
- Hofmann W. E., Liu X., Bearden C. M., Harper M. E., Kozak L. P. Effects of genetic background on thermoregulation and fatty acid-induced uncoupling of mitochondria in UCP1-deficient mice. J Biol Chem. 2001 Jan 24;276(15):12460–12465. doi: 10.1074/jbc.M100466200. [DOI] [PubMed] [Google Scholar]
- Hummel K. P., Coleman D. L., Lane P. W. The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL-KsJ and C57BL-6J strains. Biochem Genet. 1972 Aug;7(1):1–13. doi: 10.1007/BF00487005. [DOI] [PubMed] [Google Scholar]
- Lander E. S., Botstein D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989 Jan;121(1):185–199. doi: 10.1093/genetics/121.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore Jason H. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered. 2003;56(1-3):73–82. doi: 10.1159/000073735. [DOI] [PubMed] [Google Scholar]
- Satagopan J. M., Yandell B. S., Newton M. A., Osborn T. C. A bayesian approach to detect quantitative trait loci using Markov chain Monte Carlo. Genetics. 1996 Oct;144(2):805–816. doi: 10.1093/genetics/144.2.805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Segal N. L., Allison D. B. Twins and virtual twins: bases of relative body weight revisited. Int J Obes Relat Metab Disord. 2002 Apr;26(4):437–441. doi: 10.1038/sj.ijo.0801941. [DOI] [PubMed] [Google Scholar]
- Sillanpä M. J., Arjas E. Bayesian mapping of multiple quantitative trait loci from incomplete inbred line cross data. Genetics. 1998 Mar;148(3):1373–1388. doi: 10.1093/genetics/148.3.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vaughn T. T., Pletscher L. S., Peripato A., King-Ellison K., Adams E., Erikson C., Cheverud J. M. Mapping quantitative trait loci for murine growth: a closer look at genetic architecture. Genet Res. 1999 Dec;74(3):313–322. doi: 10.1017/s0016672399004103. [DOI] [PubMed] [Google Scholar]
- Warden C. H., Fisler J. S., Shoemaker S. M., Wen P. Z., Svenson K. L., Pace M. J., Lusis A. J. Identification of four chromosomal loci determining obesity in a multifactorial mouse model. J Clin Invest. 1995 Apr;95(4):1545–1552. doi: 10.1172/JCI117827. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Warnick G. R., Remaley A. T. Measurement of cholesterol in plasma and other body fluids. Curr Atheroscler Rep. 2001 Sep;3(5):404–411. doi: 10.1007/s11883-001-0079-7. [DOI] [PubMed] [Google Scholar]
- Yi Nengjun, Xu Shizhong. Mapping quantitative trait loci with epistatic effects. Genet Res. 2002 Apr;79(2):185–198. doi: 10.1017/s0016672301005511. [DOI] [PubMed] [Google Scholar]