Genome‐level analysis of genetic regulation of liver gene expression networks

The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large‐scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single‐nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 37 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. Conclusion: The data are available through a public web‐based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross‐tissue, and cross‐species comparisons, as well as testing of a broad array of hypotheses. (HEPATOLOGY 2007.)

[1]  A. Elfarra,et al.  Oxidation of cysteine S-conjugates by rabbit liver microsomes and cDNA-expressed flavin-containing mono-oxygenases: studies with S-(1,2-dichlorovinyl)-L-cysteine, S-(1,2,2-trichlorovinyl)-L-cysteine, S-allyl-L-cysteine, and S-benzyl-L-cysteine. , 1997, Molecular pharmacology.

[2]  J. Huff,et al.  1,3-Butadiene: toxicity and carcinogenicity in laboratory animals and in humans. , 1992, Reviews of environmental contamination and toxicology.

[3]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[4]  L. Kruglyak,et al.  Genetics of global gene expression , 2006, Nature Reviews Genetics.

[5]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[6]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[7]  Robert W. Williams,et al.  A new set of BXD recombinant inbred lines from advanced intercross populations in mice , 2004, BMC Genetics.

[8]  R G Ulrich,et al.  Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. , 2001, Toxicology and applied pharmacology.

[9]  K. Morgan,et al.  Gene regulation of the serine proteinase inhibitors alpha1-antitrypsin and alpha1-antichymotrypsin. , 2002, Biochemical Society transactions.

[10]  C. Perou,et al.  A custom microarray platform for analysis of microRNA gene expression , 2004, Nature Methods.

[11]  E. Shephard,et al.  Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome , 1997, Nature Genetics.

[12]  B. Cooperman,et al.  Identification of Lysines within α1-Antichymotrypsin Important for DNA Binding. AN UNUSUAL COMBINATION OF DNA-BINDING ELEMENTS (*) , 1995, The Journal of Biological Chemistry.

[13]  K. Svenson,et al.  Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations. , 2007, Journal of applied physiology.

[14]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[15]  May D. Wang,et al.  GoMiner: a resource for biological interpretation of genomic and proteomic data , 2003, Genome Biology.

[16]  Kathleen F. Kerr,et al.  Standardizing global gene expression analysis between laboratories and across platforms , 2005, Nature Methods.

[17]  S. Hammond RNAi, microRNAs, and human disease , 2006, Cancer Chemotherapy and Pharmacology.

[18]  D. Rudnick,et al.  CONCISE REVIEW IN MECHANISMS OF DISEASE Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease , 2005 .

[19]  S. Janciauskiene Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles. , 2001, Biochimica et biophysica acta.

[20]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[21]  M. Farrall Quantitative genetic variation: a post-modern view. , 2004, Human molecular genetics.

[22]  Daniel E. Zak,et al.  PAINT: a promoter analysis and interaction network generation tool for gene regulatory network identification. , 2003, Omics : a journal of integrative biology.

[23]  Thomas R. Sutter,et al.  How replicable are mRNA expression QTL? , 2006, Mammalian Genome.

[24]  B. Paigen,et al.  Genetics of Variation in HDL Cholesterol in Humans and Mice , 2004 .

[25]  A. Widell,et al.  Serine protease inhibitors in patients with chronic viral hepatitis. , 1997, Journal of hepatology.

[26]  C. Klaassen,et al.  Metallothionein transgenic and knock-out mouse models in the study of cadmium toxicity. , 1998, The Journal of toxicological sciences.

[27]  K. Morgan,et al.  Gene regulation of the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin , 2001 .

[28]  W. Wurst,et al.  RNA interference in mice. , 2007, Handbook of experimental pharmacology.

[29]  Colin N. Dewey,et al.  Initial sequencing and comparative analysis of the mouse genome. , 2002 .

[30]  Rachel B. Brem,et al.  Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors , 2003, Nature Genetics.

[31]  Sam Griffiths-Jones,et al.  The microRNA Registry , 2004, Nucleic Acids Res..

[32]  S. Elledge,et al.  Dicer is essential for mouse development , 2003, Nature Genetics.

[33]  W. Toyofuku,et al.  Atherosclerosis and plasma and liver lipids in nine inbred strains of mice , 1993, Lipids.

[34]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[35]  T. Billiar,et al.  The role of nitric oxide in Kupffer cell-hepatocyte interactions. , 1995, Shock.

[36]  Mark J Daly,et al.  Genetic variation in laboratory mice , 2005, Nature Genetics.

[37]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[38]  K. Itagaki,et al.  Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[39]  Michael P Holt,et al.  Mechanisms of drug-induced liver injury , 2006, The AAPS Journal.

[40]  D. Perlmutter,et al.  Pathogenesis of Chronic Liver Injury and Hepatocellular Carcinoma in Alpha-1-Antitrypsin Deficiency , 2006, Pediatric Research.

[41]  G. Hannon RNA interference : RNA , 2002 .

[42]  Andrew I Su,et al.  Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics' , 2005, Nature Genetics.

[43]  Eric S. Lander,et al.  Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse , 2000, Nature Genetics.

[44]  P. Coughlin,et al.  A review and comparison of the murine alpha1-antitrypsin and alpha1-antichymotrypsin multigene clusters with the human clade A serpins. , 2003, Genomics.

[45]  J. Cashman,et al.  Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans. , 1995, Chemico-biological interactions.

[46]  Janan T. Eppig,et al.  A mouse phenome project , 2000, Mammalian Genome.

[47]  H. Morse Origins of inbred mice. , 1978 .

[48]  Robert W. Williams,et al.  Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function , 2005, Nature Genetics.

[49]  Paul B Watkins,et al.  Drug‐induced liver injury: Summary of a single topic clinical research conference , 2006, Hepatology.

[50]  John D. Storey A direct approach to false discovery rates , 2002 .

[51]  Phillip D. Zamore,et al.  RNA Interference , 2000, Science.

[52]  M. Lyon,et al.  Genetic variants and strains of the laboratory mouse , 1989 .

[53]  E. Lander,et al.  Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. , 1989, Genetics.

[54]  Ivan Rusyn,et al.  Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[55]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[56]  David J. Arenillas,et al.  oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes , 2005, Nucleic acids research.

[57]  J. Treadwell Integrative strategies to identify candidate genes in rodent models of human alcoholism. , 2006, Genome.

[58]  R. Deitrich,et al.  Voluntary alcohol consumption in BXD recombinant inbred mice: relationship to alcohol metabolism. , 1996, Alcoholism, clinical and experimental research.

[59]  Michael A. Langston,et al.  Extracting Gene Networks for Low-Dose Radiation Using Graph Theoretical Algorithms , 2006, PLoS Comput. Biol..

[60]  Manjunatha Jagalur,et al.  Causal inference of regulator-target pairs by gene mapping of expression phenotypes , 2005, BMC Genomics.

[61]  D. Ziegler Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. , 1993, Annual review of pharmacology and toxicology.

[62]  J. Whisstock,et al.  The Murine Orthologue of Human Antichymotrypsin , 2005, Journal of Biological Chemistry.

[63]  G. -. Lee,et al.  Identification of hepatocarcinogen-resistance genes in DBA/2 mice. , 1995, Genetics.

[64]  E. Schadt Exploiting naturally occurring DNA variation and molecular profiling data to dissect disease and drug response traits. , 2005, Current opinion in biotechnology.

[65]  D. Nebert,et al.  The murine aromatic hydrocarbon responsiveness locus: a comparison of receptor levels and several inducible enzyme activities among recombinant inbred lines. , 1986, Journal of biochemical toxicology.

[66]  P. Coughlin,et al.  A review and comparison of the murine α1-antitrypsin and α1-antichymotrypsin multigene clusters with the human clade A serpins , 2003 .

[67]  Ligang Wu,et al.  PolymiRTS Database: linking polymorphisms in microRNA target sites with complex traits , 2006, Nucleic Acids Res..

[68]  R. Crebelli,et al.  Genetic toxicology of 1,1,2-trichloroethylene. , 1989, Mutation research.

[69]  J. Lindon,et al.  Pharmaco-metabonomic phenotyping and personalized drug treatment , 2006, Nature.

[70]  M. Festing Recombinant Inbred Strains , 1979 .

[71]  P. Brouckaert,et al.  Identification of a locus on distal mouse chromosome 12 that controls resistance to tumor necrosis factor-induced lethal shock. , 1999, Genomics.

[72]  P. L. Broadhurst Recombinant Inbred Strains , 1978 .

[73]  Albert-László Barabási,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002 .

[74]  J. Crabbe,et al.  Mapping of quantitative trait loci underlying ethanol metabolism in BXD recombinant inbred mouse strains. , 2002, Alcoholism, clinical and experimental research.

[75]  E. Schadt,et al.  Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility. , 2005, Diabetes.

[76]  E. Hodgson,et al.  Gender differences in hepatic expression of flavin-containing monooxygenase isoforms (FMO1, FMO3, and FMO5) in mice. , 1995, Journal of biochemical toxicology.

[77]  Eric E Schadt,et al.  Cis-acting expression quantitative trait loci in mice. , 2005, Genome research.

[78]  Margaret C. Green,et al.  Genetic variants and strains of the laboratory mouse , 1981 .