Gary Churchill

..We anticipate a flood of new results to follow as our community begins to adopt and utilize these new genetic resource populations...

..To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors...

..Between-mouse variance reflects differences in transcript abundance between genetically identical mice...

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..We performed quantitative trait locus (QTL) analysis to identify genomic loci regulating PLTP activity in mice...

..Our analysis furthers the knowledge of the genetic control of lipoprotein levels and points to the importance of Hdlq10, which was detected repeatedly in multiple studies...

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..The divergent skeletal responses to rosiglitazone in this study suggest the existence of a strong genetic background effect...

..This study shows the power of statistical modeling to resolve linked QTLs and the use of haplotype analysis in narrowing the list of candidates...

..All the major HDL QTLs in our study had homologous counterparts in humans, implying that their underlying genes regulate HDL in humans...

..Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder...

..The gene expression data and phenotype data have been made publicly available as an online tool for exploring the effects of atherogenic diet in inbred mouse strains (http://cgd-array.jax.org/DietStrainSurvey)...

..With these QTL, we have identified chromosomal regions that affect lipoprotein profiles in these strains...

..According to standard nomenclature, the gallstone QTL on chromosome 9 is named Lith5...

..The identification of causal networks sheds light on the nature of genetic heterogeneity and pleiotropy in complex genetic systems...

..To identify loci controlling these traits, we performed quantitative trait loci (QTL) analysis...

..These findings suggest that dietary fat has a significant influence on BMD that is dependent on the alleles present for the PPARG gene...

..These results support the continued use of multiple cross-mapping and cross-species comparisons to further our understanding of the genetic basis of kidney disease...

..Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9...

..Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice...

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..We conclude that all three approaches are important and that focusing on a single approach such as mRNA expression may fail to identify a QTL gene...

..The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes...

..This involves the use of a partial RIX population derived from a large RI panel in which the available information is maximized by minimizing correlations among RIX progeny...

..We found a significant association between ANGPTL3 and atherosclerotic lesions (P < 0.05) in human. These results suggest that Angptl3 is involved in atherosclerosis susceptibility in both mouse and human...

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..0) around D9Mit206, 20 cM from the centromere. The interval on mouse Chromosome 17 contains several orthologous genes potentially associated with human alopecia areata...

..Data generated by this effort builds on the value of inbred mouse strains as a powerful tool for biomedical research...

..This combined approach provides valuable insights into the causes and consequences of renal disease...

..These analyses underscore the genetic complexity underlying these traits in normal populations and provide the basis for future studies to identify novel genes involved in the regulation of mammalian hematopoiesis...

..To identify loci controlling BMD, we conducted a QTL analysis in a (B6 x 129) F2 population of mice. We report on additional QTLs and also narrow one QTL by combining the data from multiple crosses and through haplotype analysis...

..85 versus 7.13. Thus, as shown in human erythrocytes, positively charged Hbs are associated with cell dehydration and increased CHCM in mouse erythrocytes...

..We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach...

..These analyses emphasize the genetic complexity underlying the regulation of erythroid peripheral blood traits in normal populations and suggest that genes not previously recognized as significantly impacting normal erythropoiesis exist...

..We demonstrate that utilization of the revised genetic map improves QTL mapping, partially due to the resolution of previously undetected errors in marker ordering along the chromosome...

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..This review summarizes those resources and provides practical guidelines for their use, particularly in the analysis of quantitative traits...

..Sex has no net effect on areal BMD, but after accounting for body mass difference females have higher areal BMD. Leptin is affected by relative fat mass and has no net effect on areal BMD. IGF-I has a direct effect on areal BMD...

..The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease...

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..The discussion focuses on two-color spotted cDNA microarrays, but many of the same issues apply to single-color gene-expression assays as well...

..0) interacting with Obq18 (chromosome 9, cM 65). Knowing the genes for these QTL will enhance our understanding of obesity and lipid metabolism...

..Moreover, combined-cross analysis can establish the allelic states of a QTL among a set of parental lines, thus providing critical information for narrowing QTL regions by haplotype analysis...

..The MPD as of February 2004 contains approximately 500 phenotypic parameters relevant to human health, voluntarily contributed by several dozen investigators and laboratories. AVAILABILITY: www.jax.org/phenome..

..Identification of the genes for these QTL should lead to a better understanding of the causes of essential hypertension...

..Our data substantiate the evidence that Gct1 on Chr 4 is a fundamental oncogene for granulosa cell tumorigenesis in mice and has identified additional interacting autosomal loci that support tumor development...

..The peak LOD score was obtained with a marker for Spnb1 encoding erythroid beta-spectrin, an obvious candidate gene...

..Overall, we detected eight QTLs for lipoprotein cholesterol concentrations on Chrs 1, 9, 12, and 17 (each two per chromosome), including a new QTL for non-HDL cholesterol, Nhdlq3, on Chr 17...

..3-cM region where the high allele strains shared a common haplotype. Bpq8 is concordant with known QTL in both rat and human, suggesting that the causal gene underlying Bpq8 may be conserved as a disease gene in human hypertension...

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..We provide guidelines to select an appropriate subset. We also demonstrate that information borrowing statistics have substantially increased power compared to the t-test in small experiments...

..Given the strong conservation of gene order among mammals, the domains and networks we find in mice probably characterize all mammals, including humans...

..We conclude that lack of randomization cannot be corrected by normalization or by analytical methods. Proper randomization is essential for successful microarray experiments...

..Genome scans of N2 backcross mice identified a significant modifier locus on chromosome 7, as well as a suggestive locus on chromosome 14. We also analyzed modifiers of an eye defect in Jag1del1 heterozygous mice from this same cross...

..Genes showing similar expression (coexpression) patterns are often clustered along the genome. The goal of this study is to characterize coexpression clustering in mammalian genomes and to investigate the underlying mechanisms...

..Transcriptional profiling of chromosome substitution strains reveals a complex genetic architecture of transcriptional regulation...

..We apply statistical tests to ensure that we are not just making up stories based on seeing patterns where there may be none...

..jax.org/staff/churchill/labsite/pubs/yong...

..The dependence of QTL effects on sex suggests an important role for the sex hormones in HDL regulation. We recommend that sex should be explicitly accounted for in future studies in the genetics of HDL regulation in both mice and humans...

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..We anticipate that this resource will continue to evolve as new genotype data become available for laboratory mouse strains. The data are available for bulk download or query at http://cgd.jax.org /...

..Gluteal adipose tissue had the highest mass gain but was sluggish in its metabolism. In HFD conditions, BAT functioned largely like WAT in its role as a depot for excess energy, whereas WAT played a role in thermogenesis...

..Thus FS provides a powerful and robust approach to test differential expression of genes that utilizes information not available in individual gene testing approaches and does not suffer from biases of the pooled variance approach...

..The data from these crosses further increase the ability to perform haplotype analyses that can lead to the identification of causal lipid genes...

..53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan...

..The array opens the door to the characterization of genetic diversity, copy-number variation, allele-specific gene expression and DNA methylation, and will extend the successes of human genome-wide association studies to the mouse...

..Haplotype patterns and a literature-driven approach were used to generate hypotheses regarding the identity of the genes and pathways underlying the QTL...

..With more than two conditions, analysis of variance (ANOVA) can be used, and the mixed ANOVA model is a general and powerful approach for microarray experiments with multiple factors and/or several sources of variation...

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..This locus also influences bone density and morphology, with more dramatic effects in cancellous bone than in cortical bone...

..These findings show the complexity of inheritance underlying susceptibility to colitis and illustrate why detection of human inflammatory bowel disease loci has proven to be so difficult...

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..These results provide new insight into the genetic basis of naturally occurring variation in nutrient intake phenotypes...

..AVAILABILITY: The package is freely available at http://www.biostat.jhsph.edu/~kbroman/qtl...

..Ultimately, identification of genes that regulate trabecular bone traits may yield important information regarding mechanisms that regulate mechanical integrity of the skeleton...

..We illustrate the proposed method by detecting new epistatic QTL for obesity in a backcross of CAST/Ei mice onto M16i...

..Therefore, the positional candidate gene, Kif12, fulfills the major criteria for QTL gene discovery established by the Complex Trait Consortium, and, thus, it is proposed that Kif12 is a cpk modifier gene...

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..Genetic analysis of an NZB/B1NJ x RF/J cross has identified QTLs for femur mechanical, geometric, and densitometric phenotypes. Most mechanical QTLs were associated with geometric QTLs, strongly suggesting common genetic regulation...

..This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs...

..We found suggestive evidence of linkage to the X chromosome, which would be viewed as strong evidence of linkage if the X chromosome was treated as an autosome. Our methods have been implemented in the package R/qtl...

..Software for performing power calculations for backcross and F(2) intercross incorporating selective genotyping and marker spacing is available from http://www.biostat.ucsf.edu/sen...

..We give examples of software usage in real-life settings. The software is available at http://www.biostat.ucsf.edu/sen/software.html ...

..The presence of these loci across species suggests that these QTL may represent universal genetic factors contributing to mood disorders...

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..These results enhance our understanding of complicated genetic factors of hypertension in metabolic diseases...

..However, in both contexts, other loci had greater effects on the behavior. Our results imply that environmental context's effects on decision-making vary depending on the category of behavior...

..CAST-17 mice. Moreover, congenic mice displayed an impaired gastric emptying response to exendin-(9-39). These results suggest that genetic variation in Glp1r contributes to the strain differences in gastric emptying rate...

..We examine settings under which the two-stage analytic approach provides sufficient power to detect the putative QTLs...

..It is our premise that experimental design and design-based analysis tools are essential to obtaining high quality expression information at a reasonable cost. ..

..Our strategy is based on the hypothesis that the common mouse strains are derived from a limited ancestral gene pool and thus QTLs detected in multiple crosses are likely to represent shared ancestral polymorphisms. ..

..Didactic sessions will be held in the mornings, while the afternoon and evening sessions will be reserved for hands-on training workshops and case analysis of on-going projects in complex trait analysis. ..

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