Dissection of a QTL Hotspot on Mouse Distal Chromosome 1 that Modulates Neurobehavioral Phenotypes and Gene Expression

A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21–q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of ∼20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes.

[1]  E. Fisher,et al.  Paralogy mapping: identification of a region in the human MHC triplicated onto human chromosomes 1 and 9 allows the prediction and isolation of novel PBX and NOTCH loci. , 1996, Genomics.

[2]  G. Churchill,et al.  Evidence of a Large-Scale Functional Organization of Mammalian Chromosomes , 2005, PLoS biology.

[3]  Jianmin Cui,et al.  Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder , 2005, Nature Genetics.

[4]  Robert W. Williams,et al.  Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis , 2004, Mammalian Genome.

[5]  Robert W. Williams,et al.  Ethanol-Responsive Brain Region Expression Networks: Implications for Behavioral Responses to Acute Ethanol in DBA/2J versus C57BL/6J Mice , 2005, The Journal of Neuroscience.

[6]  Ben Lehner,et al.  A protein interaction framework for human mRNA degradation. , 2004, Genome research.

[7]  A. Galecki,et al.  Quantitative trait loci for insulin-like growth factor I, leptin, thyroxine, and corticosterone in genetically heterogeneous mice. , 2003, Physiological genomics.

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

[9]  J. Flint,et al.  Multiple Cross Mapping (MCM) markedly improves the localization of a QTL for ethanol‐induced activation , 2002, Genes, brain, and behavior.

[10]  Z. Guan,et al.  Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid , 2005, Brain Research.

[11]  N. Zanesi,et al.  Mapping of Melanoma Modifier Loci in RET Transgenic Mice , 2000, Japanese journal of cancer research : Gann.

[12]  J. Raff,et al.  Two distinct mechanisms localise cyclin B transcripts in syncytial Drosophila embryos. , 1990, Development.

[13]  R. Gibbs,et al.  Genomic segmental polymorphisms in inbred mouse strains , 2004, Nature Genetics.

[14]  Douglas A. Hosack,et al.  Identifying biological themes within lists of genes with EASE , 2003, Genome Biology.

[15]  M. Low,et al.  The mapping of quantitative trait loci underlying strain differences in locomotor activity between 129S6 and C57BL/6J mice , 2003, Mammalian Genome.

[16]  A. Arnold,et al.  Tissue-specific expression and regulation of sexually dimorphic genes in mice. , 2006, Genome research.

[17]  J. Calley,et al.  Cappuccino, a Drosophila maternal effect gene required for polarity of the egg and embryo, is related to the vertebrate limb deformity locus. , 1995, Genes & development.

[18]  A. Borrego,et al.  Co-localization of quantitative trait loci regulating resistance to Salmonella typhimurium infection and specific antibody production phenotypes. , 2002, Microbes and infection.

[19]  M. Sperling,et al.  Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility , 2004, Epilepsy Research.

[20]  G. Churchill,et al.  Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice , 1999, Mammalian Genome.

[21]  T. W. Moon,et al.  Detection of quantitative trait loci affecting caffeine metabolism by interval mapping in a genome-wide scan of C3H/HeJ x APN F(2) mice. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[22]  A. Malgaroli,et al.  Protein homeostasis in neurons and its pathological alterations , 2006, Current Opinion in Neurobiology.

[23]  T. Kinzy,et al.  Improper Organization of the Actin Cytoskeleton Affects Protein Synthesis at Initiation , 2006, Molecular and Cellular Biology.

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

[25]  E V Koonin,et al.  Prediction of the archaeal exosome and its connections with the proteasome and the translation and transcription machineries by a comparative-genomic approach. , 2001, Genome research.

[26]  Judith A. Blake,et al.  The Mouse Genome Database (MGD): from genes to mice—a community resource for mouse biology , 2004, Nucleic Acids Res..

[27]  C. S. Lai,et al.  Significance of Molecular Signaling for Protein Translation Control in Neurodegenerative Diseases , 2007, Neurosignals.

[28]  R. Giegé,et al.  tRNAs and tRNA mimics as cornerstones of aminoacyl-tRNA synthetase regulations. , 2005, Biochimie.

[29]  Katsuyuki Kazusa,et al.  Quantitative trait loci analysis of heat stress resistance of spermatocytes in the MRL/MpJ mouse , 2005, Mammalian Genome.

[30]  Megan K. Mulligan,et al.  Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Walport,et al.  Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice. , 1998, Journal of immunology.

[32]  W. Berrettini,et al.  Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene , 2004, Mammalian Genome.

[33]  J. Keller,et al.  Interplay between protein synthesis and degradation in the CNS: physiological and pathological implications , 2007, Trends in Neurosciences.

[34]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[35]  G A Churchill,et al.  Quantitative Trait Loci for Femoral and Lumbar Vertebral Bone Mineral Density in C57BL/6J and C3H/HeJ Inbred Strains of Mice , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

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

[37]  David Higgins,et al.  Haplotype analysis in multiple crosses to identify a QTL gene. , 2004, Genome research.

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

[39]  G. de Haan,et al.  Identification of evolutionarily conserved, functional noncoding elements in the promoter region of the sodium channel gene SCN8A , 2007, Mammalian Genome.

[40]  Robert Hitzemann,et al.  Further Characterization and High-Resolution Mapping of Quantitative Trait Loci for Ethanol-Induced Locomotor Activity , 2001, Behavior genetics.

[41]  Maureen P. Boyle,et al.  Palmitoylation regulates plasma membrane–nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family , 2005, The Journal of cell biology.

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

[43]  Martin S. Taylor,et al.  A High-Resolution Single Nucleotide Polymorphism Genetic Map of the Mouse Genome , 2006, PLoS biology.

[44]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[45]  E. Lander,et al.  Detection of regulatory variation in mouse genes , 2002, Nature Genetics.

[46]  Matthew W. Hahn,et al.  The evolution of transcriptional regulation in eukaryotes. , 2003, Molecular biology and evolution.

[47]  Benjamin A. Taylor,et al.  Genotyping new BXD recombinant inbred mouse strains and comparison of BXD and consensus maps , 1999, Mammalian Genome.

[48]  B. Dudek,et al.  Quantitative trait loci analysis affecting contextual conditioning in mice , 1997, Nature Genetics.

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

[50]  M. Kilberg,et al.  ATF4 Is a Mediator of the Nutrient-sensing Response Pathway That Activates the Human Asparagine Synthetase Gene* , 2002, The Journal of Biological Chemistry.

[51]  W. Frankel,et al.  Multiple seizure susceptibility genes on chromosome 7 in SWXL-4 congenic mouse strains. , 2000, Genomics.

[52]  K. Sekikawa,et al.  A quantitative trait locus that accounts for glucose intolerance maps to chromosome 8 in hereditary obese KK-A(y) mice. , 2002, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[53]  Ivan Rusyn,et al.  Genome‐level analysis of genetic regulation of liver gene expression networks , 2007, Hepatology.

[54]  O. Bernard,et al.  The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. , 2005, Genes & development.

[55]  R. Simon,et al.  Activation of Bcl-2-Associated Death Protein and Counter-Response of Akt within Cell Populations during Seizure-Induced Neuronal Death , 2002, The Journal of Neuroscience.

[56]  J. Crabbe,et al.  Quantitative trait loci affecting risk for pentobarbital withdrawal map near alcohol withdrawal loci on mouse Chromosomes 1, 4, and 11 , 1999, Mammalian Genome.

[57]  P. Suzdak,et al.  (S)‐Carboxy‐3‐Hydroxyphenylglycine, an Antagonist of Metabotropic Glutamate Receptor (mGluR)1a and an Agonist of mGluR2, Protects Against Audiogenic Seizures in DBA/2 Mice , 1994, Journal of neurochemistry.

[58]  C. Amos,et al.  Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis. , 2002, Cancer research.

[59]  P. Leder,et al.  Formin-2, polyploidy, hypofertility and positioning of the meiotic spindle in mouse oocytes , 2002, Nature Cell Biology.

[60]  R. Rozmahel,et al.  Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[61]  A. Lusis,et al.  Genetic linkage of hyperglycemia, body weight and serum amyloid-P in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice. , 2006, Human molecular genetics.

[62]  Marcin Piechota,et al.  Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes , 2006, BMC Genomics.

[63]  Jonathan Flint,et al.  High-resolution mapping of quantitative trait loci for emotionality in selected strains of mice , 1999, Mammalian Genome.

[64]  P. Lasko,et al.  Translational regulation and RNA localization in Drosophila oocytes and embryos. , 2001, Annual review of genetics.

[65]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[66]  N. Woo,et al.  Distinct Role of Long 3′ UTR BDNF mRNA in Spine Morphology and Synaptic Plasticity in Hippocampal Neurons , 2008, Cell.

[67]  S. Paul,et al.  Mapping Quantitative Trait Loci for Open-Field Behavior in Mice , 1997, Behavior genetics.

[68]  C. Haley,et al.  Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines , 2000, Mammalian Genome.

[69]  Lydia Ng,et al.  Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain , 2008, BMC Bioinformatics.

[70]  C. Freitag,et al.  Rgs 2 gene polymorphisms as modulators of anxiety in humans? , 2006, Journal of Neural Transmission.

[71]  G. Duyk,et al.  A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse. , 2002, Genetics.

[72]  P. Scambler,et al.  Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. , 2005, Human molecular genetics.

[73]  W. Berrettini,et al.  Analysis of a Quantitative Trait Locus for Seizure Susceptibility in Mice Using Bacterial Artificial Chromosome‐Mediated Gene Transfer , 2007, Epilepsia.

[74]  A. Copp,et al.  Paralogous sm22alpha (Tagln) genes map to mouse chromosomes 1 and 9: further evidence for a paralogous relationship. , 1998, Genomics.

[75]  Jin P. Szatkiewicz,et al.  The Recombinational Anatomy of a Mouse Chromosome , 2008, PLoS genetics.

[76]  R. Simon,et al.  Death‐associated protein kinase expression in human temporal lobe epilepsy , 2004, Annals of neurology.

[77]  J. Sikela,et al.  A strategy for the integration of QTL, gene expression, and sequence analyses , 2003, Mammalian Genome.

[78]  Kelsey C. Martin,et al.  Identification of Process-Localized mRNAs from Cultured Rodent Hippocampal Neurons , 2006, The Journal of Neuroscience.

[79]  J. Crabbe,et al.  Genomewide Search for Epistasis in a Complex Trait: Pentobarbital Withdrawal Convulsions in Mice , 2001, Behavior genetics.

[80]  A. Galecki,et al.  Genetic polymorphisms in mouse genes regulating age-sensitive and age-stable T cell subsets , 2003, Genes and Immunity.

[81]  K. Sekikawa,et al.  Quantitative Trait Locus Analysis of Plasma Cholesterol and Triglyceride Levels in KK × RR F2 Mice , 2003, Biochemical Genetics.

[82]  J. Crabbe.  Quantitative trait locus gene mapping: a new method for locating alcohol response genes , 1996, Addiction biology.

[83]  J. Eberwine,et al.  Analysis of Subcellularly Localized mRNAs Using in Situ Hybridization, mRNA Amplification, and Expression Profiling , 2002, Neurochemical Research.

[84]  P. Leder,et al.  Formin-2, a novel formin homology protein of the cappuccino subfamily, is highly expressed in the developing and adult central nervous system , 2000, Mechanisms of Development.

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

[86]  R. A. Hunt,et al.  Snapin interacts with the N-terminus of regulator of G protein signaling 7. , 2003, Biochemical and biophysical research communications.

[87]  K. Sekikawa,et al.  Quantitative trait loci that regulate plasma lipid concentration in hereditary obese KK and KK-Ay mice. , 1999, Biochimica et biophysica acta.

[88]  T. Schikorski,et al.  Horseradish peroxidase cDNA as a marker for electron microscopy in neurons , 2007, Journal of Neuroscience Methods.

[89]  J. Defries,et al.  Response to 30 generations of selection for open-field activity in laboratory mice , 1978, Behavior genetics.

[90]  Daesoo Kim,et al.  Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice , 2004, The Journal of Neuroscience.

[91]  B. Dudek,et al.  Genetic analysis of the psychomotor stimulant effect of ethanol , 2003, Genes, brain, and behavior.

[92]  M. Kiebler,et al.  Staufen2 isoforms localize to the somatodendritic domain of neurons and interact with different organelles. , 2002, Journal of cell science.

[93]  Kazuo Suzuki,et al.  Genetic Dissection of Vasculitis, Myeloperoxidase-Specific Antineutrophil Cytoplasmic Autoantibody Production, and Related Traits in Spontaneous Crescentic Glomerulonephritis-Forming/Kinjoh Mice1 , 2006, The Journal of Immunology.

[94]  M. Walport,et al.  Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice. , 2000, Arthritis and rheumatism.

[95]  Alberto de la Fuente,et al.  Discovery of meaningful associations in genomic data using partial correlation coefficients , 2004, Bioinform..

[96]  S. Eddy,et al.  tRNAscan-SE: a program for improved detection of transfer RNA genes in genomic sequence. , 1997, Nucleic acids research.

[97]  A. C. Collins,et al.  A simple genetic basis for a complex psychological trait in laboratory mice , 1995, Science.

[98]  Ralf Dahm,et al.  Dendritic Localization of the Translational Repressor Pumilio 2 and Its Contribution to Dendritic Stress Granules , 2006, The Journal of Neuroscience.

[99]  L. Wodicka,et al.  Regional and strain-specific gene expression mapping in the adult mouse brain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[100]  R. Gerlai.  Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? , 1996, Trends in Neurosciences.

[101]  Allen,et al.  Genetics of graft‐versus‐host disease, I. A locus on Chromosome 1 influences development of acute graft‐versus‐host disease in a major histocompatibility complex mismatched murine model , 1999, Immunology.

[102]  M. Emi,et al.  Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred , 2002, Journal of Human Genetics.

[103]  M. Ichikawa,et al.  RGS7 and RGS8 Differentially Accelerate G Protein-mediated Modulation of K+ Currents* , 1999, The Journal of Biological Chemistry.

[104]  B. McEwen,et al.  Differential expression of suppressors of cytokine signaling-1, -2, and -3 in the rat hippocampus after seizure: implications for neuromodulation by gp130 cytokines , 2003, Neuroscience.

[105]  L. Whitehouse,et al.  Detection of quantitative trait loci affecting caffeine metabolism by interval mapping in a genome-wide scan of C3H/HeJ x APN F(2) mice. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[106]  J. Crabbe,et al.  Mapping murine loci for physical dependence on ethanol , 2002, Psychopharmacology.

[107]  Robert W. Williams,et al.  Complex genetics of interactions of alcohol and CNS function and behavior. , 2005, Alcoholism, clinical and experimental research.

[108]  O. Steward,et al.  Compartmentalized Synthesis and Degradation of Proteins in Neurons , 2003, Neuron.

[109]  P. Cahan,et al.  A High-Resolution Map of Segmental DNA Copy Number Variation in the Mouse Genome , 2006, PLoS genetics.

[110]  J. Lassalle,et al.  Two QTLs Located on Chromosomes 1 and 5 Modulate Different Aspects of the Performance of Mice of the B × D Ty RI Strain Series in the Morris Navigation Task , 2002, Behavior genetics.

[111]  Andrew P Morris,et al.  Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice , 2004, Nature Genetics.

[112]  R. Hitzemann,et al.  Detection and Mapping of Quantitative Trait Loci for Haloperidol-Induced Catalepsy in a C57BL/6J×DBA/2J F2 Intercross , 1999, Behavior genetics.

[113]  Samuel F. Berkovic,et al.  Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B , 1998, Nature Genetics.

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

[115]  C. Harrington,et al.  On the integration of alcohol-related quantitative trait loci and gene expression analyses. , 2004, Alcoholism, clinical and experimental research.

[116]  Douglas C. Wallace,et al.  Radicals r'aging , 1998, Nature Genetics.

[117]  D. Airey,et al.  Genetic Control of the Mouse Cerebellum: Identification of Quantitative Trait Loci Modulating Size and Architecture , 2001, The Journal of Neuroscience.

[118]  N. Schork,et al.  Mapping murine loci for seizure response to kainic acid , 1997, Mammalian Genome.

[119]  Lu Lu,et al.  The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis , 2001, Genome Biology.

[120]  B. Fredholm,et al.  Adenosine A1 receptors are crucial in keeping an epileptic focus localized , 2006, Experimental Neurology.

[121]  Tao Pan,et al.  Tissue-Specific Differences in Human Transfer RNA Expression , 2006, PLoS genetics.