Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits.

Genetic loci that regulate inherited traits are routinely identified using quantitative trait locus (QTL) mapping methods. However, the genotype-phenotype associations do not provide information on the gene expression program through which the genetic loci regulate the traits. Transcription modules are 'self-consistent regulatory units' and are closely related to the modular components of gene regulatory network [Ihmels, J., Friedlander, G., Bergmann, S., Sarig, O., Ziv, Y. and Barkai, N. (2002) Revealing modular organization in the yeast transcriptional network. Nat. Genet., 31, 370-377; Segal, E., Shapira, M., Regev, A., Pe'er, D., Botstein, D., Koller, D. and Friedman, N. (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet., 34, 166-176]. We used genome-wide genotype and gene expression data of a genetic reference population that consists of mice of 32 recombinant inbred strains to identify the transcription modules and the genetic loci regulating them. Twenty-nine transcription modules defined by genetic variations were identified. Statistically significant associations between the transcription modules and 18 classical physiological and behavioral traits were found. Genome-wide interval mapping showed that major QTLs regulating the transcription modules are often co-localized with the QTLs regulating the associated classical traits. The association and the possible co-regulation of the classical trait and transcription module indicate that the transcription module may be involved in the gene pathways connecting the QTL and the classical trait. Our results show that a transcription module may associate with multiple seemingly unrelated classical traits and a classical trait may associate with different modules. Literature mining results provided strong independent evidences for the relations among genes of the transcription modules, genes in the regions of the QTLs regulating the transcription modules and the keywords representing the classical traits.

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

[2]  Yan Cui,et al.  Inferring gene transcriptional modulatory relations: a genetical genomics approach. , 2005, Human molecular genetics.

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

[4]  R. Schwartz,et al.  T-cell clonal anergy. , 1997, Cold Spring Harbor symposia on quantitative biology.

[5]  C. Haley,et al.  Genetical genomics in humans and model organisms. , 2005, Trends in genetics : TIG.

[6]  R. McCall,et al.  Evidence that two loci predominantly determine the difference in susceptibility to the high pressure neurologic syndrome type I seizure in mice. , 1981, Genetics.

[7]  John D. Storey,et al.  Genetic interactions between polymorphisms that affect gene expression in yeast , 2005, Nature.

[8]  D. I. Hawkins,et al.  100 Statistical Tests , 1994 .

[9]  D. Ledbetter,et al.  Clinical and molecular basis of classical lissencephaly: Mutations in the LIS1 gene (PAFAH1B1) , 2002, Human mutation.

[10]  Nengjun Yi,et al.  The Collaborative Cross, a community resource for the genetic analysis of complex traits , 2004, Nature Genetics.

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

[12]  Leonid Kruglyak,et al.  Local Regulatory Variation in Saccharomyces cerevisiae , 2005, PLoS genetics.

[13]  P. Scott,et al.  Differential requirement of CD28 for IL‐12 receptor expression and function in CD4+ and CD8+ T cells , 2001, European journal of immunology.

[14]  W. Rea,et al.  Modulation of behavioral sensitization to cocaine by NAALADase inhibition , 2000, Synapse.

[15]  Robert Plomin,et al.  Use of recombinant inbred strains to detect quantitative trait loci associated with behavior , 1991, Behavior genetics.

[16]  C. Haley,et al.  The genetic dissection of immune response using gene-expression studies and genome mapping. , 2005, Veterinary Immunology and Immunopathology.

[17]  A. Sharpe,et al.  CTLA-4 regulates induction of anergy in vivo. , 2001, Immunity.

[18]  J. Castle,et al.  An integrative genomics approach to infer causal associations between gene expression and disease , 2005, Nature Genetics.

[19]  E. Petretto,et al.  Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease , 2005, Nature Genetics.

[20]  G. Mcclearn,et al.  Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry. , 1999, Pharmacogenetics.

[21]  J. Sahel,et al.  Cellular localization of the vesicular inhibitory amino acid transporter in the mouse and human retina , 2002, The Journal of comparative neurology.

[22]  S. Tonegawa,et al.  The T cell receptor repertoire of intestinal intraepithelial gammadelta T lymphocytes is influenced by genes linked to the major histocompatibility complex and to the T cell receptor loci. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Fauci,et al.  Cloning and analysis of the promoter region of CCR5, a coreceptor for HIV-1 entry. , 1997, Journal of immunology.

[24]  R. Locksley,et al.  Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint 1 , 2003, The Journal of Immunology.

[25]  Yaniv Ziv,et al.  Revealing modular organization in the yeast transcriptional network , 2002, Nature Genetics.

[26]  Gopal Kanji,et al.  100 Statistical Tests , 1994 .

[27]  Jintao Wang,et al.  Genetic correlates of gene expression in recombinant inbred strains , 2007, Neuroinformatics.

[28]  J. Willott,et al.  Genetics of age-related hearing loss in mice. IV. Cochlear pathology and hearing loss in 25 BXD recombinant inbred mouse strains , 1998, Hearing Research.

[29]  R. Sederoff,et al.  Coordinated Genetic Regulation of Growth and Lignin Revealed by Quantitative Trait Locus Analysis of cDNA Microarray Data in an Interspecific Backcross of Eucalyptus1 , 2004, Plant Physiology.

[30]  C. Molony,et al.  Genetic analysis of genome-wide variation in human gene expression , 2004, Nature.

[31]  C. Haley,et al.  A simple regression method for mapping quantitative trait loci in line crosses using flanking markers , 1992, Heredity.

[32]  Margit Burmeister,et al.  Genetical genomics: combining genetics with gene expression analysis. , 2005, Human molecular genetics.

[33]  P. Solenberg,et al.  Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice. , 2001, Immunity.

[34]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[35]  J. Nap,et al.  Genetical genomics: the added value from segregation. , 2001, Trends in genetics : TIG.

[36]  F. O. Risinger.  Genetic analyses of ethanol-induced hyperglycemia. , 2003, Alcoholism, clinical and experimental research.

[37]  Sven Bergmann,et al.  Iterative signature algorithm for the analysis of large-scale gene expression data. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[38]  Hao Chen,et al.  Content-rich biological network constructed by mining PubMed abstracts , 2004, BMC Bioinformatics.

[39]  J. Zhu,et al.  An integrative genomics approach to the reconstruction of gene networks in segregating populations , 2004, Cytogenetic and Genome Research.

[40]  E E Schadt,et al.  Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits , 2005, Nature Genetics.

[41]  S. Bergmann,et al.  Similarities and Differences in Genome-Wide Expression Data of Six Organisms , 2003, PLoS biology.

[42]  Ned S. Wingreen,et al.  Finding regulatory modules through large-scale gene-expression data analysis , 2003, Bioinform..

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

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

[45]  Ceri H. Davies,et al.  Loss of Hippocampal Serine Protease BSP1/Neuropsin Predisposes to Global Seizure Activity , 2001, The Journal of Neuroscience.

[46]  N. Bing,et al.  Genetical Genomics Analysis of a Yeast Segregant Population for Transcription Network Inference , 2005, Genetics.

[47]  M. Todtenkopf,et al.  Differential distribution of parvalbumin immunoreactive neurons in the striatum of cocaine sensitized rats , 2004, Neuroscience.

[48]  D. Pe’er,et al.  Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data , 2003, Nature Genetics.

[49]  D. Koller,et al.  A module map showing conditional activity of expression modules in cancer , 2004, Nature Genetics.

[50]  R. Wise.  Neural mechanisms of the reinforcing action of cocaine. , 1984, NIDA research monograph.

[51]  Robert Hitzemann,et al.  On the Relationships of High-Frequency Hearing Loss and Cochlear Pathology to the Acoustic Startle Response (ASR) and Prepulse Inhibition of the ASR in the BXD Recombinant Inbred Series , 1999, Behavior genetics.

[52]  Wei Wang,et al.  A Role for Nuclear Factor I in the Intrinsic Control of Cerebellar Granule Neuron Gene Expression* , 2004, Journal of Biological Chemistry.

[53]  J. Crabbe,et al.  Use of recombinant inbred strains to assess vulnerability to drug abuse at the genetic level. , 1991, Journal of addictive diseases.

[54]  Stéphane Pasteau,et al.  Proliferation of chicken neuroretina cells induced by v-src, in vitro, depends on activation of the E2F transcription factor , 1997, Oncogene.

[55]  O. Reiner,et al.  Platelet‐activating factor (PAF) acetylhydrolase activity, LIS1 expression, and seizures , 1999, Journal of neuroscience research.

[56]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  S. Sealfon,et al.  Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor* , 2003, Journal of Biological Chemistry.

[58]  Rachel B. Brem,et al.  The landscape of genetic complexity across 5,700 gene expression traits in yeast. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[59]  J. Marshall,et al.  Further characterization of preproenkephalin mRNA-containing cells in the rodent globus pallidus , 2002, Neuroscience.

[60]  G. Rousseau,et al.  An E2F-dependent late-serum-response promoter in a gene that controls glycolysis. , 1995, Oncogene.

[61]  Roded Sharan,et al.  Revealing modularity and organization in the yeast molecular network by integrated analysis of highly heterogeneous genomewide data. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[63]  John D. Storey,et al.  Multiple Locus Linkage Analysis of Genomewide Expression in Yeast , 2005, PLoS biology.

[64]  J. Allison,et al.  CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones , 1992, Nature.

[65]  E. Schadt,et al.  Genetic inheritance of gene expression in human cell lines. , 2004, American journal of human genetics.

[66]  L. McIntyre,et al.  Combining mapping and arraying: An approach to candidate gene identification , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[67]  Lu Lu,et al.  WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior , 2004, Nature Neuroscience.

[68]  N. Ohan,et al.  The transcription factor E2F1 promotes dopamine‐evoked neuronal apoptosis by a mechanism independent of transcriptional activation , 2001, Journal of neurochemistry.

[69]  M. Lynch,et al.  Genetics and Analysis of Quantitative Traits , 1996 .

[70]  J. Crabbe,et al.  Provisional mapping of quantitative trait loci for chronic ethanol withdrawal severity in BXD recombinant inbred mice. , 1998, The Journal of pharmacology and experimental therapeutics.