Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-ChrA/J/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity. Twenty CSS intercrosses, one derived from each of the 19 autosomes and chromosome X, were used to determine the number and location of quantitative trait loci (QTLs) on individual chromosomes and localized six QTLs. However, analyses of mean body weight in intercross progeny versus C57BL/6J provided strong evidence that many QTLs discovered in the CSS surveys eluded detection in these CSS intercrosses. Studies of the temporal effects of these QTLs suggest that obesity resistance was dynamic, with QTLs acting at different ages or after different durations of diet exposure. Thus, these studies provide insight into the genetic architecture of complex traits such as resistance to diet-induced obesity in the C57BL/6J-ChrA/J/NaJ CSSs. Because some of the QTLs detected in the CSS intercrosses were not detected using a traditional C57BL/6J × A/J intercross, our results demonstrate that surveys of CSSs and congenic strains derived from them are useful complementary tools for analyzing complex traits.

Prepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. PPI is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients demonstrate PPI impairments. As a first step towards identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSS). We identified five CSSs with altered PPI compared to the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16, and -Y exhibited higher PPI compared to C57BL/6J. These data indicate that A/J chromosomes 4, 10, 11, 16, and Y harbor at least one QTL region that modulates PPI in these CSSs. QTLs for the acoustic startle response were identified on seven chromosomes. Like PPI, habituation of the startle response is also disrupted in schizophrenia, and in the present study CSS-7 and -8 exhibited deficits in startle habituation. Linkage analysis of an F2 intercross identified a highly significant QTL for PPI on chromosome 11 between positions 101.5Mb – 114.4Mb (peak LOD = 4.54). Future studies will map the specific genes contributing to these QTLs using congenic strains and other genomic approaches. Identification of genes that modulate PPI will provide insight into the neural mechanisms underlying sensorimotor gating, as well as the psychopathology of disorders characterized by gating deficits.

Background-Development of viral-induced chronic myocarditis is thought to involve both environmental and genetic factors. However, to date, no susceptibility genes have been identified. Methods and Results-We sought to identify loci that confer susceptibility to viral-induced chronic myocarditis with the use of chromosome substitution strain mice that are composed of 1 chromosome from the disease susceptible A/J strain on an otherwise resistant C57BL/6 background. By this method, we identified chromosome 17 to confer susceptibility. To further isolate the region of susceptibility, 8 strains of mice congenic for different portions of chromosome 17 were generated. Characterization of these strains identified at least 4 susceptibility loci on the chromosome. Three of these loci are located in the proximal 22.8 cM, whereas the fourth locus is located in the portion of the chromosome distal to 34.3 cM. Conclusions-We have identified 4 loci that confer susceptibility of viral-induced chronic myocarditis. Of these loci, 3 were distinct from the major histocompatibility complex locus and thus represent novel susceptibility loci. The close proximately of the 2 novel loci with susceptibility loci for other autoimmune diseases such as type 1 diabetes and chronic experimental autoimmune thyroiditis suggests the presence of global autoimmune susceptibility genes. (Circ Cardiovasc Genet. 2010;3:399-408.)