The problem of identifying complex epistatic quantitative trait loci (QTL) across the entire genome continues to be a formidable challenge for geneticists. The complexity of genome-wide epistatic analysis results mainly from the number of QTL being unknown and the number of possible epistatic effects being huge. In this article, we use a composite model space approach to develop a Bayesian model selection framework for identifying epistatic QTL for complex traits in experimental crosses from two inbred lines. By placing a liberal constraint on the upper bound of the number of detectable QTL we restrict attention to models of fixed dimension, greatly simplifying calculations. Indicators specify which main and epistatic effects of putative QTL are included. We detail how to use prior knowledge to bound the number of detectable QTL and to specify prior distributions for indicators of genetic effects. We develop a computationally efficient Markov chain Monte Carlo (MCMC) algorithm using the Gibbs sampler and MetropolisHastings algorithm to explore the posterior distribution. We illustrate the proposed method by detecting new epistatic QTL for obesity in a backcross of CAST/Ei mice onto M16i. M ANY complex human diseases and traits of biotive corrections for multiple testing. Non-Bayesian model logical and/or economic importance are deterselection methods combine simultaneous search with a mined by multiple genetic and environmental influsequential procedure such as forward or stepwise selecences (Lynch and Walsh 1998). Mounting evidence tion and apply criteria such as P-values or modified Bayesuggests that interactions among genes (epistasis) play sian information criterion (BIC) to identify well-fitting an important role in the genetic control and evolumultiple-QTL models (Kao et al. 1999; Carlborg et al. tion of complex traits (Cheverud 2000; Carlborg and 2000;Reifsnyder et al. 2000; Bogdan et al. 2004). These Haley 2004). Mapping quantitative trait loci (QTL) is methods, although appealing in their simplicity and popa process of inferring the number of QTL, their genoularity, have several drawbacks, including: (1) the uncermic positions, and genetic effects given observed phenotainty about the model itself is ignored in the final intype and marker genotype data. From a statistical perference, (2) they involve a complex sequential testing spective, two key problems in QTL mapping are model strategy that includes a dynamically changing null hysearch and selection (e.g., Broman and ful and conceptually simple approach to mapping multiExtensions of this approach can allow for main and epiple QTL (Satagopan et al. 1996; Hoeschele 2001; Sen static effects at two or perhaps a few QTL at a time and and Churchill 2001). The Bayesian approach proemploy a multidimensional scan to detect QTL. Howceeds by setting up a likelihood function for the phenoever, such an approach neglects potential confoundtype and assigning prior distributions to all unknowns ing effects from additional QTL and requires prohibiin the prob...

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Conjugated linoleic acid (CLA) is a unique lipid that elicits dramatic reductions in adiposity in several animal models when included at < or = 1% of the diet. Despite a flurry of investigations, the precise mechanisms by which conjugated linoleic acid elicits its dramatic effects in adipose tissue and liver are still largely unknown. In vivo and in vitro analyses of physiological modifications imparted by conjugated linoleic acid on protein and gene expression suggest that conjugated linoleic acid exerts its de-lipidating effects by modulating energy expenditure, apoptosis, fatty acid oxidation, lipolysis, stromal vascular cell differentiation and lipogenesis. The purpose of this review shall be to examine the recent advances and insights into conjugated linoleic acid's effects on obesity and lipid metabolism, specifically focused on changes in gene expression and physiology of liver and adipose tissue.

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Functional genomic characterization of delipidation elicited by trans-10, cis-12-conjugated linoleic acid (t10c12-CLA) in a polygenic obese line of mice. Physiol Genomics 21: 351-361, 2005; doi: 10.1152/physiolgenomics.00244.2004.-Gene expression was measured during t10c12-CLA-induced body fat reduction in a polygenic obese line of mice. Adult mice (n ϭ 185) were allotted to a 2 ϫ 2 factorial experiment consisting of either nonobese (ICR-control) or obese (M16-selected) mice fed a 7% fat, purified diet containing either 1% linoleic acid (LA) or 1% t10c12-CLA. Body weight (BW) by day 14 was 12% lower in CLA-compared with LA-fed mice (P Ͻ 0.0001). By day 14, t10c12-CLA reduced weights of epididymal, mesenteric, and brown adipose tissues, as a percentage of BW, in both lines by 30, 27, and 58%, respectively, and increased liver weight/BW by 34% (P Ͻ 0.0001). Total RNA was isolated and pooled (4 pools per tissue per day) from epididymal adipose (days 5 and 14) of the obese mice to analyze gene expression profiles using Agilent mouse oligo microarray slides representing Ͼ20,000 genes. Numbers of genes differentially expressed by greater than or equal to twofold in epididymal adipose (days 5 and 14) were 29 and 125, respectively. It was concluded that, in adipose tissue, CLA increased expression of uncoupling proteins (1 and 2), carnitine palmitoyltransferase system, tumor necrosis factor-␣ (P Ͻ 0.05), and caspase-3 but decreased expression of peroxisome proliferator-activated receptor-␥, glucose transporter-4, perilipin, caveolin-1, adiponectin, resistin, and Bcl-2 (P Ͻ 0.01). In conclusion, this experiment has revealed candidate genes that will be useful in elucidating mechanisms of adipose delipidation. apoptosis; cell biology; gene expression; lipid metabolism; obesity OVER THE PAST 20 YR, the incidence of obesity has reached epidemic proportions. According to the 1999-2000 National Health and Nutrition Examination Survey, ϳ64% of United States adults Ն20 yr old are overweight or obese (http:// www.cdc.gov/nchs/products/pubs/pubd/hestats/obese/obse99. htm) (28). In 2003, Sturm (53) reported that extreme obesity [body mass index (BMI) Ն40] quadrupled between 1986 and 2000 from 1 in 200 adults to 1 in 50. Additionally, within the same time period, there was an increase by a factor of five of Americans with a BMI Ն50, from 1 in 2,000 to 1 in 400 (53). Internationally, the World Health Organization reported that from 1995 to 2000, the number of obese adults worldwide increased from 200 million to over 300 million adults (http://www.who.int/nut/obs.htm). In 2003, $75 billion (US dollars) was spent on medical treatment ascribed to obesity, one-half of which was paid for by Medicare and Medicaid (23).The rapid increase in the prevalence of obesity has attracted much attention to the delipidative effects of conjugated linoleic acid (CLA). Found naturally in ruminant products (such as beef and cheese), the CLA family consists of several conjugated and stereoisomeric variations of linoleic acid (cis, cis-⌬ 9,12 -octadecad...

A genetic framework was developed for the interpretation of statistical parameters estimated from a diallel experiment among a fixed set of lines. These included average direct genetic, average maternal genetic, general combining ability, reciprocal, and line and specific direct and maternal heterotic effects. The genetic model is based on direct and maternal additive and dominance genetic effects as would be expected in animal species. The model assumes that dominance is the underlying basis of heterosis. As an example, litter size at birth was analyzed from a 5 × 5 diallel cross with mice.

We investigated the genetic basis of several limb bone lengths and weights of organs in mice produced from a cross of the F1 between CAST/Ei (wild strain) and M16i (selected for rapid growth rate) back to M16i. From previous correlation studies, we hypothesized that quantitative trait loci (QTLs) would exhibit greater pleiotropy within than between the limb length and organ weight character sets. Using interval mapping procedures and significance testing at the chromosome-wise level, we discovered 14 putative QTLs affecting weight of the liver, spleen, heart, and/or kidney, 9 of which affected more than one organ; and 12 QTLs for limb lengths, all of which affected the length of two or more of the limb bones in these mice. As was hypothesized, most QTLs affected either organ weights or limb lengths independently of each other, although five QTLs were found that affected both sets of characters. The direction of the effect of these QTLs was almost always consistent within and between characters, with little evidence for antagonistic pleiotropy.