The Experts below are selected from a list of 1053 Experts worldwide ranked by ideXlab platform
Evan G. Williams - One of the best experts on this subject based on the ideXlab platform.
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a platform for experimental precision medicine the extended BXD Mouse family
Cell systems, 2021Co-Authors: David G Ashbrook, Evan G. Williams, Danny Arends, Pjotr Prins, Megan K Mulligan, Suheeta Roy, Cathleen M Lutz, Alicia Valenzuela, Casey J Bohl, Jesse IngelsAbstract:The challenge of precision medicine is to model complex interactions among DNA variants, phenotypes, development, environments, and treatments. We address this challenge by expanding the BXD family of mice to 140 fully isogenic strains, creating a uniquely powerful model for precision medicine. This family segregates for 6 million common DNA variants-a level that exceeds many human populations. Because each member can be replicated, heritable traits can be mapped with high power and precision. Current BXD phenomes are unsurpassed in coverage and include much omics data and thousands of quantitative traits. BXDs can be extended by a single-generation cross to as many as 19,460 isogenic F1 progeny, and this extended BXD family is an effective platform for testing causal modeling and for predictive validation. BXDs are a unique core resource for the field of experimental precision medicine.
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diet modulates cecum bacterial diversity and physiological phenotypes across the BXD Mouse genetic reference population
PLOS ONE, 2019Co-Authors: Evan G. Williams, Robert W Williams, Maria Elisa Perezmunoz, Autumn M Mcknite, Johan Auwerx, Daniel A Peterson, Daniel C CiobanuAbstract:The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13–18% fat) and a high-fat diet (HFD, 45–60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)—an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7–19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21–89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites—knowledge that will help in the understanding of the causal sources of metabolic disorders.
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Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes
Cell systems, 2018Co-Authors: Pooja Jha, Molly T. Mcdevitt, Emina Halilbasic, Evan G. Williams, Pedro M. Quirós, Karim Gariani, Maroun Bou Sleiman, Rahul Gupta, Arne Ulbrich, Adam JochemAbstract:The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD Mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent Mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits.
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systems proteomics of liver mitochondria function
Science, 2016Co-Authors: Evan G. Williams, Pooja Jha, Sebastien Dubuis, Peter Blattmann, Carmen Argmann, Sander M Houten, Tiffany Amariuta, Witold Wolski, Nicola Zamboni, Ruedi AebersoldAbstract:Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD Mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis.
Adam Jochem - One of the best experts on this subject based on the ideXlab platform.
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Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes
Cell systems, 2018Co-Authors: Pooja Jha, Molly T. Mcdevitt, Emina Halilbasic, Evan G. Williams, Pedro M. Quirós, Karim Gariani, Maroun Bou Sleiman, Rahul Gupta, Arne Ulbrich, Adam JochemAbstract:The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD Mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent Mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits.
Robert W Williams - One of the best experts on this subject based on the ideXlab platform.
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diet modulates cecum bacterial diversity and physiological phenotypes across the BXD Mouse genetic reference population
PLOS ONE, 2019Co-Authors: Evan G. Williams, Robert W Williams, Maria Elisa Perezmunoz, Autumn M Mcknite, Johan Auwerx, Daniel A Peterson, Daniel C CiobanuAbstract:The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13–18% fat) and a high-fat diet (HFD, 45–60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)—an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7–19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21–89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites—knowledge that will help in the understanding of the causal sources of metabolic disorders.
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Genetic Analysis of the Neurosteroid Deoxycorticosterone and Its Relation to Alcohol Phenotypes: Identification of QTLs and Downstream Gene Regulation
2016Co-Authors: Patrizia Porcu, Soomin C Song, Jo Lynne Harenza, Xusheng Wang, Robert W Williams, Michael F Miles, Todd K. O’buckley, Leslie A MorrowAbstract:Background: Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3a,5a)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. Methodology/Principal Findings: To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)6DBA/2J (D2) (BXD) Mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p,0.0001) with a heritability of,0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p,0.0001) with heritability of,0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and
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genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes identification of qtls and downstream gene regulation
PLOS ONE, 2011Co-Authors: Patrizia Porcu, Todd K Obuckley, Soomin C Song, Jo Lynne Harenza, Xusheng Wang, Robert W Williams, Michael F Miles, Leslie A MorrowAbstract:Background Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. Methodology/Principal Findings To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) Mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Conclusions/Significance Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.
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mapping the genetic architecture of complex traits in experimental populations
Bioinformatics, 2007Co-Authors: Jian Yang, Jun Zhu, Robert W WilliamsAbstract:Summary: Understanding how interactions among set of genes affect diverse phenotypes is having a greater impact on biomedical research, agriculture and evolutionary biology. Mapping and characterizing the isolated effects of single quantitative trait locus (QTL) is a first step, but we also need to assemble networks of QTLs and define non-additive interactions (epistasis) together with a host of potential environmental modulators. In this article, we present a full-QTL model with which to explore the genetic architecture of complex trait in multiple environments. Our model includes the effects of multiple QTLs, epistasis, QTL-by-environment interactions and epistasis-by-environment interactions. A new mapping strategy, including marker interval selection, detection of marker interval interactions and genome scans, is used to evaluate putative locations of multiple QTLs and their interactions. All the mapping procedures are performed in the framework of mixed linear model that are flexible to model environmental factors regardless of fix or random effects being assumed. An F-statistic based on Henderson method III is used for hypothesis tests. This method is less computationally greedy than corresponding likelihood ratio test. In each of the mapping procedures, permutation testing is exploited to control for genome-wide false positive rate, and model selection is used to reduce ghost peaks in F-statistic profile. Parameters of the full-QTL model are estimated using a Bayesian method via Gibbs sampling. Monte Carlo simulations help define the reliability and efficiency of the method. Two real-world phenotypes (BXD Mouse olfactory bulb weight data and rice yield data) are used as exemplars to demonstrate our methods. Availability: A software package is freely available at http://ibi.zju.edu.cn/software/qtlnetwork Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.
Leslie A Morrow - One of the best experts on this subject based on the ideXlab platform.
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Genetic Analysis of the Neurosteroid Deoxycorticosterone and Its Relation to Alcohol Phenotypes: Identification of QTLs and Downstream Gene Regulation
2016Co-Authors: Patrizia Porcu, Soomin C Song, Jo Lynne Harenza, Xusheng Wang, Robert W Williams, Michael F Miles, Todd K. O’buckley, Leslie A MorrowAbstract:Background: Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3a,5a)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. Methodology/Principal Findings: To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)6DBA/2J (D2) (BXD) Mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p,0.0001) with a heritability of,0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p,0.0001) with heritability of,0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and
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genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes identification of qtls and downstream gene regulation
PLOS ONE, 2011Co-Authors: Patrizia Porcu, Todd K Obuckley, Soomin C Song, Jo Lynne Harenza, Xusheng Wang, Robert W Williams, Michael F Miles, Leslie A MorrowAbstract:Background Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. Methodology/Principal Findings To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) Mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Conclusions/Significance Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.
Pooja Jha - One of the best experts on this subject based on the ideXlab platform.
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Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes
Cell systems, 2018Co-Authors: Pooja Jha, Molly T. Mcdevitt, Emina Halilbasic, Evan G. Williams, Pedro M. Quirós, Karim Gariani, Maroun Bou Sleiman, Rahul Gupta, Arne Ulbrich, Adam JochemAbstract:The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD Mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent Mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits.
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systems proteomics of liver mitochondria function
Science, 2016Co-Authors: Evan G. Williams, Pooja Jha, Sebastien Dubuis, Peter Blattmann, Carmen Argmann, Sander M Houten, Tiffany Amariuta, Witold Wolski, Nicola Zamboni, Ruedi AebersoldAbstract:Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD Mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis.
