Overview

My laboratory integrates quantitative genetics, bioinformatics and behavioral science to understand and identify the biological basis for the relationships among behavioral traits. We develop and apply cross-species genomic data integration, advanced computing methods, and novel high-precision mouse populations to find genes associated with a constellation of behavioral disorders. This integrative strategy enables us to relate mouse behavior to specific aspects of human disorders, to test the validity of behavioral classification schemes, and to find genes and genetic variants that influence behavior.

Scientific report

The underlying genetics of behavior

 

My research emphasizes the integration of genetic, genomic, and phenomic resources to improve the ways in which behavioral traits in mice are associated with complex underlying genetics and genomics. I integrate genetic and genomic findings in model organisms including the laboratory mouse with data on human behavioral disorders using novel computational tools and approaches developed in my laboratory. We devise ways to ensure that mouse models are relevant to the human clinical state to achieve greater precision in identifying the genetic, environmental, and life history contributions that shape behavior. To this end, my lab has developed GeneWeaver.org in close collaboration with computer scientists at the University of Tennessee and Baylor University. This system allows users to integrate heterogeneous phenotype-centered gene sets across species, tissues, and experimental platforms. This publicly available tool uses fast combinatorial algorithms to infer the latent ontology of behavior from the sets of genes and phenotypes developed using large empirical data sets. It provides a unique resource for investigators in many areas of biological science to integrate data that is typically lost to further analysis. The use of this system has led to the identification of several genes and polymorphisms underlying behavioral variation.

Other research efforts center on the use of genetic reference populations for the systems genetic analysis of behavior. Our earlier studies made use of the BXD Recombinant Inbred strains to understand the common genetic mediation of behavioral variability. These studies revealed underlying factors of behavior in laboratory mice, and the co-expressed genes associated with each behavior. We continue to analyze this tremendous wealth of data to understand the relations among behavioral traits and to identify novel candidate genes for complex behaviors, many of which are related to vulnerability to drug and alcohol use.

Behavioral variation in the widely used laboratory mouse strains has been historically limited. New high-diversity mouse resources exhibit an expanded behavioral repertoire and provide phenomenal opportunities for investigation of the genetics of behavior. My group performs genetic and behavioral characterization of the Collaborative Cross and Diversity Outbred populations, novel mouse resources which randomize the genetic diversity found among inbred mouse strains. My group at the Oak Ridge National Laboratory played a critical role in generating and characterizing this population, which has now given rise to the mature Collaborative Cross population at ORNL and the Diversity Outcross at The Jackson Laboratory. Our genetic analyses demonstrate the high precision and accuracy of these new populations for genetic research, which will enable the deep discovery of biological mechanisms of behavioral variation.

Lab staff

Principal Investigator: Elissa J. Chesler, Ph.D., Associate Professor

Associate Research Scientist: Jason Bubier, Ph.D.

Predoctoral Associate: Juliet Ndukum, Ph.D.; Price Dickson, Ph.D.

Research Assistants II: Troy Wilcox, B.S.

Research Assistant III: James Clark; Laura Anderson, M.S.

Laboratory Technician IV: Zachary Seavey

Visiting Investigator: Erich J. Baker, Ph.D., Baylor University

Research Administrative Assistant: Jessica CN Seavey, M.S.

Publication listings

2014

Bubier, JA, Jay J, Baker CL, Bergeson SE, Ohno H, Metten P, Crabbe JC, Chesler EJ. Identification of a QTL in Mus musculus for alcohol preference, withdrawal and Ap3m2 expression using integrative functional genomics and precision genetics. Genetics. PMCID: In press

Chesler EJ. 2014. Out of the bottleneck: the Diversity Outcross and Collaborative Cross mouse populations in behavioral genetics research. Mamm Genome. 2014 Feb;25(1-2):3-11. Epub

2013 Nov

Gatti DM, Svenson KL, Shabalin A, Wu L, Valdar W, Simecek P, Goodwin N, Cheng R, Pomp D, Palmer A, Chesler EJ, Broman KW, Churchill GA. 2014. Quantitative trait locus mapping methods for Diversity Outbred mice. Genetics. PMCID: In Press

Jay JJ, Chesler EJ. 2014. Performing integrative functional genomics analysis in GeneWeaver.org. Methods Mol Biol. 2014;1101:13-29.

Liu EY, Morgan AP, Chesler EJ, Wang W, Churchill GA, Pardo-Manuel de Villena F. 2014. High-Resolution Sex-Specific Linkage Maps of the Mouse Reveal Polarized Distribution of Crossovers in Male Germline. Genetics. 2014 Feb 27. Epub ahead of print

Munger SC, Raghupathy N, Choi KB, Simons AK, Gatti DM, Hinerfeld DA, Svenson KL, Keller MP, Attie AD, Hibbs MA, Graber JH, Chesler EJ, and Churchill GA. 2014. RNA-seq alignment to individualized genomes improves transcript abundance estimates in multiparent populations. Genetics. PMCID: In Press

Recla JM, Robledo RF, Gatti DM, Bult CJ, Churchill GA, Chesler EJ. 2014. Precise genetic mapping and integrative bioinformatics in Diversity Outbred mice reveals Hydin as a novel pain gene. Mamm Genome. 2014 Jun;25(5-6):211-22. doi: 10.1007/s00335-014-9508-0. Epub 2014 Apr 5. PMCID: PMC4032469

Zhang Y, Phillips CA, Rogers GL, Baker EJ, Chesler EJ, Langston MA. 2014. On finding bicliques in bipartite graphs: a novel algorithm and its application to the integration of diverse biological data types. BMC Bioinformatics. 2014 Apr 15;15(1):110. Epub ahead of print

2013

Chesler EJ. 2013. Out of the bottleneck: the Diversity Outcross and Collaborative Cross mouse populations in behavioral genetics research. Mamm Genome.

DuBose CS, Chesler EJ, Goldowitz D, Hamre KM. 2013. Use of the expanded panel of BXD mice narrow QTL regions in ethanol-induced locomotor activation and motor incoordination. Alcohol Clin Exp Res 37(1):170-83.

Jay JJ, Chesler EJ. 2013. Performing integrative functional genomics analysis in GeneWeaver.org. Methods Mol Biol. 2014;1101:13-29

Logan RW, Robledo RF, Recla JM, Philip VM, Bubier JA, Jay JJ, Harwood C, Wilcox T, Gatti DM, Bult CJ, Churchill GA, Chesler EJ. High-precision genetic mapping of behavioral traits in the diversity outbred mouse population. Genes Brain Behav. 2013 Feb 21.

2012

Baker EJ, Jay JJ, Bubier JA, Langston MA, Chesler EJ. 2012. GeneWeaver: a web-based system for integrative functional genomics. Nucleic Acids Res 40(Database ):D1067-1076. PMCID: PMC3245070

Bubier JJ, Chesler EJ. 2012. Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse. Neurotherapeutics 9(2):338-348. PMCID: PMC3325414

Campbell JH, Foster CM, Vishnivetskaya T, Campbell AG, Yang ZK, Wymore A, Palumbo AV, Chesler EJ, Podar M. 2012. Host genetic and environmental effects on mouse intestinal microbiota. ISME J 6(11):2033-2044. PMCID: PMC3475380

Chesler EJ, Logan RW. 2012. Opportunities for bioinformatics in the classification of behavior and psychiatric disorders. Int Rev Neurobiol (104)183-211.

Chesler EJ, Plitt A, Fisher D, Hurd B, Lederle L, Bubier JA, Kiselycznyk C, Holmes A. 2012. Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J×129S1/SvImJ inbred mouse cross. Mamm Genome 23(5-6):305-321. PMCID: PMC3357470

Collaborative Cross Consortium. 2012. The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics 190(2):389-401. PMCID: PMC3276630

Dubose, CS, Chesler EJ, Goldowitz D, Hamre K. 2012. Use of the Expanded Panel of BXD Mice Narrow QTL Regions in Ethanol-Induced Locomotor Activation and Motor Incoordination. Alcohol Clin Exp Res 37(1):170-183. 

Ha TJ, Swanson DJ, Kirova R, Yeung J, Choi K, Tong Y, Chesler EJ, Goldowitz D. 2012. Genome-wide microarray comparison reveals downstream genes of Pax6 in the developing mouse cerebellum. Eur J Neurosci Oct; 36(7):2888-2898.

Haendel MA, Chesler EJ. 2012. Lost and found in behavioral informatics. Int Rev Neurobiol (103)1-18.

Jay JJ, Eblen JD, Zhang Y, Benson M, Perkins AD, Saxton AM, Voy BH, Chesler EJ, Langston MA. 2012. A systematic comparison of genome-scale clustering algorithms. BMC Bioinformatics Jun 25;13 Suppl 10:S7. PMCID: PMC3382433

Kelada SN, Aylor DL, Peck BCE, Ryan JF, Tavarez U, Buus RJ, Miller DR, Chesler EJ, Threadgill DW, Churchill GA, Pardo-Manuel de Villena F, Collins FS. 2012. Genetic analysis of hematological parameters in incipient lines of the Collaborative Cross. G3 (Bethesda) 2(2):157-165. PMCID: PMC3284323

Parsons MJ, Grimm C, Paya-Cano JL, Fernandes C, Lin L, Philip VM, Chesler EJ, Nietfeld W, Lehrach H, Schalkwyk LC. 2012. Genetic variation in hippocampal microRNA expression differences in C57BL/6 J X DBA/2 J (BXD) recombinant inbred mouse strains. BMC Genomics (13)476. PMCID: PMC3496628

Svenson KL, Gatti DM, Valdar W, Welsh CE, Cheng R, Chesler EJ, Palmer AA, McMillan L, Churchill GA. 2012. High-resolution genetic mapping using the mouse diversity outbred population. Mamm Genome 190(2):437-447. PMCID: PMC3276626

Thaisz J, Tsaih SW, Feng M, Philip VM, Zhang Y, Yanas L, Sheehan S, Xu L, Miller DR, Paigen B, Chesler EJ, Churchill GA, Dipetrillo K. 2012. Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations. Am J Physiol Renal Physiol 303(7):F972-981. PMCID: PMC3469684

2011

Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kelada SN, Collins FS, Yang IV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Liu EY, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, Pardo-Manuel de Villena F, Churchill GA. 2011. Genetic analysis of complex traits in the emerging collaborative cross. Genome Res 21(8):1213-1222. PMC3149489

Baker EJ, Jay JJ, Bubier JA, Langston MA, Chesler EJ. 2011. GeneWeaver: a web-based system for integrative functional genomics. Nucleic Acids Res. Nov 12 [Epub aheads of print].

Dickson PE, Rogers TD, Lester DB, Miller MM, Matta SG, Chesler EJ, Goldowitz D, Blaha CD, Mittleman G. 2011. Genotype-dependent effects of adolescent nicotine exposure on dopamine functional dynamics in the nucleus accumbens shell in male and female mice: a potential mechanism underlying the gateway effect of nicotine. Psychopharmacology 215(4):631-642.

Gelinas R, Chesler EJ, Vasconcelos D, Miller DR, Yuan Y, Wang K, Galas D. 2011 A genetic approach to the prediction of drug side effects: bleomycin induces concordant phenotypes in mice of the collaborative cross. Pharmacogenomics and Personalized Medicine (2011:4):35-45.

Kelada SN, Aylor D, Tavarez U, Kubalanza K, Carpenter D, Miller D, Chesler E, Churchill G, Villena FP, Schwartz DA, Collins FS . 2011. Identification of genetic loci in Mice that mediate allergen-induced airway hyperresponsiveness, inflammation, and serum IgG1 . Proc Am Thorac Soc 8(2):203.

Mathes WF, Aylor DL, Miller DR, Churchill GA, Chesler EJ, Pardo Manuel de Villena F, Threadgill DW, Pomp D. 2011. Architecture of energy balance traits in emerging lines of the Collaborative Cross. Am J Physiol Endocrinol Metab 300(6):E1124-1134. PMC3118585

Meehan TF, Carr CJ, Jay JJ, Bult CJ, Chesler EJ, Blake JA. 2011. Autism candidate genes via mouse phenomics. J Biomed Inform Mar 21:[Epub ahead of print].

Nair HK, Hain H, Quock RM, Philip VM, Chesler EJ, Belknap JK, Lariviere WR. 2011. Genomic loci and candidate genes underlying inflammatory nociception. Pain 152(3):599-606. PMC3039031

Philip VM, Sokoloff G, Ackert-Bicknell CL, Striz M, Branstetter L, Beckmann MA, Spence JS, Jackson BL, Galloway LD, Barker P, Wymore AM, Hunsicker PR, Durtschi DC, Shaw GS, Shinpock S, Manly KF, Miller DR, Donohue KD, Culiat CT, Churchill GA, Lariviere WR, Palmer AA, O'Hara BF, Voy BH, Chesler EJ. 2011. Genetic analysis in the Collaborative Cross breeding population. Genome Res 21(8):1223-1238. PMC3149490

2010

Chesler EJ, Baker EJ. 2010. The Importance of open-source integrative genomics to drug discovery. Curr Opin Drug Discov Devel 13(3):310-316.

Gatti DM, Zhao N, Chesler EJ, Bradford BU, Shabalin AA, Yordanova R, Lu L, Rusyn I. 2010. Sex-specific Gene Expression in BXD Mouse Liver. Physiol Genomics 42(3):456-468. PMCID: PMC2929887

Lynch RM, Naswa S, Rogers GL Jr, Kania SA, Das S, Chesler EJ, Saxton AM, Langston MA, Voy BH. 2010. Identifying genetic loci and spleen gene coexpression networks underlying immunophenotypes in BXD recombinant inbred mice. Physiol Genomics 41:244-253.

Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ. 2010. High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains. Genes Brain Behav 9(2):129-159. PMCID: PMC2855868

Spindler KR, Welton AR, Lim ES, Duvvuru S, Althaus IW, Imperiale JE, Daoud AI, Chelser EJ. 2010. The major locus for mouse adenovirus susceptibility maps to genes of the hematopoietic cell surface-expressed Ly6 family. J. Immunol 184(6):3055-3062. PMCID: PMC2832721

2009

Baker EJ, Jay JJ, Philip VM, Zhang, Y, Li Z, Kirova R, Langston MA, Chesler, EJ. 2009. Ontological discovery environment: a system for integrating gene-phenotype associations. Genomics 94(6):377-387. PMCID: PMC2783409

Borate BR, Chesler, EJ, Langston MA, Saxton AM, Voy BH. 2009. Comparison of threshold selection methods for microarray gene co-expression matrices. BMC Res Notes 2:240. PMCID: PMC2794870

Carneiro AM, Airey DC, Thompson B, Zhu CB, Lu L, Chesler EJ, Erikson KM, Blakely RD. 2009. Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes. Proc Natl Acad Sci USA 106(6):2047-2052. PMCID: PMC2632716

Saccone SF, Bierut LJ, Chesler EJ, Kalivas PW, Lerman C, Saccone NL, Uhl GR, Li CY, Philip VM, Edenberg HJ, Sherry ST, Feolo M, Moyzis RK, Rutter JL. 2009. Supplementing high-density SNP microarrays for additional coverage of disease-related genes: addiction as a paradigm. PLoS One 4(4):e5225. PMCID: PMC2668711

Song MJ, Lewis CK, Lance ER, Chesler EJ, Yordanova RK, Langston MA, Lodowsi KH, Bergeson SE. 2009. Reconstructing generalized logical networks of transcriptional regulation in mouse brain from temporal gene expression data. EURASIP J Bioinform Syst Biol epub:545176. PMCID: PMC2656965

2008

Chesler EJ, Miller DR, Branstetter LR, Galloway LD, Jackson BL, Philip VM, Voy BH, Culiat CT, Threadgill DW, Williams RW, Churchill GA, Johnson DK, Manly KF. 2008. The collaborative cross at oak ridge national laboratory: developing a powerful resource for systems genetics. Mamm Genome 19(6):382-389. PMCID: PMC2745091

Matthews DB, Chesler EJ, Cook MN, Cockroft J, Philip VM, Goldowitz D. 2008. Genetic mapping of vocalization to a series of increasing acute footshocks using B6.A consomic and B6.D2 congenic mouse strains. Behav Genet 38(4):417-423. PMCID: PMC2504763

New J, Kendall W, Huang J, Chesler EJ. 2008. Dynamic visualization of coexpression in systems genetics data. IEEE Trans Vis Comput Graph 14(5):1081-1094.

Peirce JL, Broman KW, Lu L, Chesler EJ, Zhou G, Airey DC, Birmingham AE, Williams RW. 2008. Genome Reshuffling for Advanced Intercross Permutation (GRAIP): simulation and permutation for advanced intercross population analysis. PLoS One 3(4):e1977. PMCID: PMC2295257

2007

Cook MN, Dunning JP, Wiley RG, Chesler EJ, Johnson DK, Miller DR, Goldowitz D. 2007. Neurobehavioral mutants identified in an ENU-mutagenesis project. Mamm Genome 18(8):559-572.

Gatti D, Maki A, Chesler EJ, Kirova R, Kosyk O, Lu L, Manly KF, Williams RW,  Perkins A, Langston MA, Threadgill DW, Rusyn I. 2007. Genome-level analysis of genetic regulation of liver gene expression networks. Hepatology 46(2):548-557.

Mouse Phenotype Database Integration Consortium: Hancock JM, Adams NC, Aidinis V, Blake A, Bogue M, Brown SD, Chesler EJ, Davidson D, Duran C, Eppig JT, Gailus-Durner V, Gates H, Gkoutos GV, Greenaway S, Hrabe de Angelis M, Kollias G, Leblanc S, Lee k, Kengger C, Maier H, Mallon AM, Masuya H, Melvin DG, Muller W, Parkinson H, Proctor G, Reuveni E, Schofield P, Shukla A, Smith C, Toyoda T, Vasseur L, Wakana S, Walling A, White J, Wood J, Zouberakis M. 2007. Integration of mouse phenome data resources. Mamm Genome 18(3):157-163.

Rosen GD, Chesler EJ, Manly KF, Williams RW. 2007. An informatics approach to systems neurogenetics. Methods Mol Biol 401:287-303.

2006

Chesler EJ, Bystrykh L, de Haan G, Cooke MP, Su A, Manly KF, Williams RW. 2006. Reply to "Normalization procedures and detection of linkage signal in genetical-genomics experiments." Nat Genet 38(8):856-858.

Goldowitz D, Matthews DB, Hamre KM, Mittleman G, Chesler EJ, Becker HC, Lopez MF, Jones SR, Mathews TA, Miles MF, Kerns R, Grant KA. 2006. Progress in using mouse inbred strains,consomics, and mutants to identify genes related to stress, anxiety, and alcohol phenotypes. Alcohol Clin Exp Res 30(6):1066-1078.

Kempermann G, Chesler, EJ, Lu L, Williams RW, Gage FH. 2006. Natural variation and genetic covariance in adult hippocampal neurogenesis. Proc Natl Acad Sci USA 103(3):780-785.

Li H, Chen H, Bao L, Manly KF, Chesler EJ, Lu L, Wang J, Zhou M, Williams RW, Cui Y. 2006. Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits. Hum Mol Genet 15(3):481-492.

Voy BH, Scharff JA, Perkins AD, Saxton AM, Borate B, Chesler EJ, Branstetter LK, Langston MA. 2006. Extracting gene networks for low-dose radiation using graph theoretical algorithms. PLoS Comput Biol 2(7):e89.

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