Overview
Our lab is actively applying a new “systems” approach to studying the genetics of health and disease, incorporating new statistical methods for the investigation of complex disease-related traits in the mouse. We employ a combination of strategies using standard genotype and phenotype data obtained from mouse crosses together with data from high-throughput gene expression arrays to investigate the genetic basis of these complex traits. We have developed new methods that improve the power of gene expression analysis and have also developed methods to establish relational networks among traits using genetically randomized populations of mice.
Scientific report
Statistical Genetics
Genetics of complex traits
Our laboratory focuses on the development and application of methodology to study complex trait inheritance using inbred line crosses. We have been actively involved in studies of disease-related traits including cancer, diabetes, asthma, osteoporosis, gallstones, kidney disease and anemia. We have applied cutting-edge analysis methods, many developed in our own laboratory, to reveal the genetic mechanisms of complex trait inheritance. We have found growing evidence for the importance of epistatic gene-gene interactions in several traits. For example, our studies of animal behavior in a rat model of chronic depression have revealed an interesting maternally derived epigenetic effect that may have implications for familial patterns of depression observed in humans.
Recent methodological advances in statistical genetics include the development of a novel approach to combine information from multiple inbred-line crosses. This technique improves the power and precision of genetic mapping and, in some cases, can substantially narrow the field of candidate genes from hundreds to just a few. New developments in the information theory of crosses have important implications for efficient study designs. We have developed new methodology for the recombinant inbred diallel cross (RIX) and have presented a critical analysis of this design.
We released a new software package, J/qtl, that provides a graphical user interface to the popular quantitative trait locus (QTL) data analysis software package R/qtl, and have continued to contribute to the development of R/qtl. Our software package pseudomarker, for analysis of QTL data from inbred line crosses, has been modified to perform thousands of genome scan analyses in minutes. This unprecedented speed was achieved using sophisticated numerical computing techniques and will prove to be valuable for applications in mapping gene expression traits.
With an eye on the future of mouse genetics, we have undertaken the task of establishing more than 1,000 new inbred lines of mice for complex trait analysis. This project, known as the Collaborative Cross, is supported by The Ellison Medical Foundation, the Department of Energy and the Wellcome Trust. First-generation animals were raised at The Jackson Laboratory in the summer of 2005 and distributed to breeding centers in Oak Ridge, Tenn., Australia and Nairobi.
Gene expression analysis
We have continued to make groundbreaking progress in the area of gene expression microarray analysis. New methodology introduced this year includes "information borrowing" statistics that can leverage the information across many genes on a microarray to improve the power to detect differential expression. We have developed novel experimental design and analysis methods for three- and four-color microarray systems and have carried out a proof-of-concept experiment using the three-color designs.
Our microarray analysis software package R/maanova has been upgraded to incorporate these new analysis methods and is now able to process data from Affymetrix and other single-color systems. R/maanova is part of the Bioconductor software suite, and we are currently developing a user interface termed J/maanova.
Systems genetics
In 2005, we established the Center for Genome Dynamics (CGD), a consortium of investigators at The Jackson Laboratory and the University of North Carolina with a shared interest in the emerging field of systems biology. We refer to our work as "systems genetics." It embodies a holistic approach to understanding genetics from an evolutionary perspective. Our first major publication appeared in the journal PLoS Genetics, and it describes a genome-wide pattern of linkage disequilibrium observed in inbred mouse strains. This result implies that extensive functional organization is a feature of the mammalian genome and that networks of coadapted loci span the entire genome. These observations have profound implications for the nature of complex trait inheritance and the evolutionary processes that give rise to the most common and complex diseases.
Lab staff
Principal Investigator: Gary A. Churchill, Ph.D.
Research Scientist: Shirng-Wern (Sharon) Tsaih, Sc.D.
Research Programs Manager: Imogen Hurley, Ph.D.
Research Program Manager: Randy Von Smith, Ph.D.
Postdoctoral Fellows: Rachael Hageman, Ph.D., Peter Vedell, Ph.D., Ricardo Verdugo, Ph.D., Hyuna Yang, Ph.D.
Biostatistician I: Qian Li, B.S.
Software Engineer: Keith Sheppard, M.S.
Interns: Aubrey Smith
Visiting Scientists: Karl Broman, Ph.D., Johns Hopkins University, Elissa Chesler, Ph.D., Oak Ridge National Laboratory, Cathy Laurie, Ph.D., University of Washington, Kenneth Manly, Ph.D., University of Buffalo, Michael Nachman, Ph.D., University of Arizona, Fernando Pardo Manuel de Villena, Ph.D., University of North Carolina, Frans Schalekamp
Research Administrative Assistant: Christina Gagliardi
Publication listings
(2005-present)
Ackert-Bicknell CL, Shockley KR, Horton LG, Lecka-Czernik B, Churchill GA, Rosen CJ. 2009. Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I. Endocrinology 150(3):1330-1340.
Brockmann GA, Tsaih SW, Neuschl C, Churchill GA, Li R. 2009. Genetic factors contributing to obesity and body weight can act through mechanisms affecting muscle weight, fat weight, or both. Physiol Genomics 36(2):114-126. PMC2636925
Llamas B, Verdugo RA, Churchill GA, Deschepper CF. 2009. Chromosome Y variants from different inbred mouse strains are linked to differences in the morphologic and molecular responses of cardiac cells to postpubertal testosterone. BMC Genomics 10:150. PMC2679052
Mackiewicz M, Zimmerman JE, Shockley KR, Churchill GA, Pack AI. 2009. What are microarrays teaching us about sleep? Trends Mol Med 15(2):79-87.
Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B. 2009. PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 106(2):232-246. PMC2631627
Ackert-Bicknell CL, Demissie S, Marφn de Evsikova C, Hsu YH, DeMambro VE, Karasik D, Cupples LA, Ordovas JM, Tucker KL, Cho K, Canalis E, Paigen B, Churchill GA, Forejt J, Beamer WG, Ferrari S, Bouxsein ML, Kiel DP, Rosen CJ. 2008. PPARG by dietary fat interaction influences bone mass in mice and humans. J Bone Miner Res 23(9):1398-1408.
Bailey JS, Grabowski-Boase L, Steffy BM, Wiltshire T, Churchill GA, Tarantino LM. 2008. Identification of QTL for locomotor activation and anxiety using closely-related inbred strains. Genes Brain Behav Epub ahead of print.
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.
Churchill GA, Doerge RW. 2008. Naive application of permutation testing leads to inflated type I error rates. Genetics 178(1):609-610.
Doorenbos C, Tsaih SW, Sheehan S, Ishimori N, Navis G, Churchill G, Dipetrillo K, Korstanje R. 2008. Quantitative trait loci for urinary albumin in crosses between C57BL/6J and A/J inbred mice in the presence and absence of Apoe. Genetics 179(1):693-699. PMC2390645
Iraqi FA, Churchill G, Mott R. 2008. The Collaborative Cross, developing a resource for mammalian systems genetics: A status report of the Wellcome Trust cohort. Mamm Genome 19(6):379-381.
Ishimori N, Stylianou IM, Korstanje R, Marion MA, Li R, Donahue LR, Rosen CJ, Beamer WG, Paigen B, Churchill GA. 2008. Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene. J Bone Miner Res 23(9):1529-1537.
Kumar KG, Byerley LO, Volaufova J, Drucker DJ, Churchill GA, Li R, York B, Zuberi A, Richards BK. 2008. Genetic variation in Glp1r expression influences the rate of gastric emptying in mice. Am J Physiol Regul Integr Comp Physiol 294(2):R362-R371.
Li R, Svenson KL, Donahue LR, Peters LL, Churchill GA. 2008. Relationships of dietary fat, body composition, and bone mineral density in inbred mouse strain panels. Physiol Genomics 33(1):26-32.
Mrug M, Zhou J, Woo Y, Cui X, Szalai AJ, Novak J, Churchill GA, Guay-Woodford LM. 2008. Overexpression of innate immune response genes in a model of recessive polycystic kidney disease. Kidney Int 73(1):63-76.
Stylianou IM, Affourtit JP, Shockley KR, Wilpan RY, Abdi FA, Bhardwaj S, Rollins J, Churchill GA, Paigen B. 2008. Applying gene expression, proteomics and single-nucleotide polymorphism analysis for complex trait gene identification. Genetics 178(3):1795-1805.
Szatkiewicz JP, Beane GL, Ding Y, Hutchins L, Pardo-Manuel de Villena F, Churchill GA. 2008. An imputed genotype resource for the laboratory mouse. Mamm Genome 19(3):199-208.
Yang H, Harrington CA, Vartanian K, Coldren CD, Hall R, Churchill GA. 2008. Randomization in laboratory procedure is key to obtaining reproducible microarray results. PLoS ONE 3(11):e3724. PMC2579585
Churchill GA. 2007. Recombinant inbred strain panels: a tool for systems genetics. Physiol Genomics 31(2):174-175.
Davidson CE, Li Q, Churchill GA, Osborne LR, McDermid HE. 2007. Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans. Physiol Genomics 31(2):244-251.
Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, Rasmussen KE, Jones LP, Assefnia S, Chandrasekharan S, Backlund MG, Yin Y, Khramtsov AI, Bastein R, Quackenbush J, Glazer RI, Brown PH, Green JE, Kopelovich L, Furth PA, Palazzo JP, Olopade OI, Bernard PS, Churchill GA, Van Dyke T, Perou CM. 2007. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76.
Kiernan AE, Li R, Hawes NL, Churchill GA, Gridley T. 2007. Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice. Genetics 177(1):307-311.
Lecka-Czernik B, Ackert-Bicknell C, Adamo ML, Marmolejos V, Churchill GA, Shockley KR, Reid IR, Grey A, Rosen CJ. 2007. Activation of Peroxisome Proliferator-activated Receptor Gamma (PPARgamma) by Rosiglitazone Suppresses Components of the IGF Regulatory System in vitro and in vivo. Endocrinology 148(2):903-911.
Mackiewicz M, Shockley KR, Romer MA, Galante RJ, Zimmerman JE, Naidoo N, Baldwin DA, Jensen ST, Churchill GA, Pack AI. 2007. Macromolecule biosynthesis: a key function of sleep. Physiol Genomics 31(3):441-457.
Nishihara E, Tsaih SW, Tsukahara C, Langley S, Sheehan S, Dipetrillo K, Kunita S, Yagami K, Churchill GA, Paigen B, Sugiyama F. 2007. Quantitative trait loci associated with blood pressure of metabolic syndrome in the progeny of NZO/HILtJ x C3H/HeJ intercrosses. Mamm Genome 18(8):573-583.
Peters LL, Robledo RF, Bult CJ, Churchill GA, Paigen BJ, Svenson KL. 2007. The mouse as a model for human biology: a resource guide for complex trait analysis. Nat Rev Genet 8(1):58-69.
Petkov PM, Graber JH, Churchill GA, DiPetrillo K, King BL, Paigen K. 2007. Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Biology 5(5):e127.
Satagopan JM, Sen S, Churchill GA. 2007. Sequential Quantitative Trait Locus Mapping in Experimental Crosses. Statistical Applications in Genetics and Molecular Biology 6:Article 12.
Schughart K, Churchill G. 2007. 6th annual meeting of the Complex Trait Consortium. Mamm Genome 18(10):683-685.
Sen S, Satagopan JM, Broman KW, Churchill GA. 2007. R/qtlDesign: inbred line cross experimental design. Mamm Genome 18:87-93.
Sheehan S, Tsaih SW, King BL, Stanton C, Churchill GA, Paigen B, DiPetrillo K. 2007. Genetic analysis of albuminuria in a cross between C57BL/6J and DBA/2J mice. Am J Physiol Renal Physiol 293(5):F1649-F1656.
Shockley KR, Rosen CJ, Churchill GA, Lecka-Czernik B. 2007. PPARgamma2 Regulates a Molecular Signature of Marrow Mesenchymal Stem Cells. PPAR Res 2007:81219.
Svenson KL, Von Smith R, Magnani PA, Suetin HR, Paigen B, Naggert JK, Li R, Churchill GA, Peters LL. 2007. Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations. J Appl Physiol 102(6):2369-2378.
The International Stem Cell Initiative. 2007. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25(7):803-816.
Yang H, Bell TA, Churchill GA, Pardo-Manuel de Villena F. 2007. On the subspecific origin of the laboratory mouse. Nat Genet 39(9):1100-1107.
Yang H, Churchill G. 2007. Estimating p-values in small microarray experiments. Bioinformatics 23(1):38-43.
Baum AE, Solberg LC, Churchill GA, Ahmadiyegh N, Takahashi JS, Redei EE. 2006. Test-and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality. Behav Brain Res 169:220-230.
Broman KW, Sen S, Owens SE, Manichaikul A, Southard-Smith EM, Churchill GA. 2006. The X chromosome in quantitative trait locus mapping. Genetics 174:2151-2158.
Churchill GA. 2006. The genetics of gene expression. Mamm Genome 17:465.
Cui X, Affourtit J, Shockley KR, Woo Y, Churchill GA. 2006. Inheritance patterns of transcript levels in F1 hybrid mice. Genetics 174(2):627-637.
Graber JH, Churchill GA, Dipetrillo KJ, King BL, Petkov PM, Paigen K. 2006. Patterns and mechanisms of genome organization in the mouse. J Exp Zool 305A(9):683-688.
Ishimori N, Li R, Walsh KA, Korstanje R, Rollins JA, Petkov P, Pletcher MT, Wiltshire T, Donahue LR, Rosen CJ, Beamer WG, Churchill GA, Paigen B. 2006. Quantitative trait loci that determine BMD in C57BL/6J and 129S1/SvImJ inbred mice. J Bone Miner Res 21(1):105-12.
Li R, Tsaih S-W, Shockley K, Stylianou IM, Wergedal J, Paigen B, Churchill GA. 2006. Structural model analysis of multiple quantitative traits. PLoS Genetics 2(7):e114.
Peters LL, Lambert AJ, Zhang W, Churchill GA, Brugnara C, Platt OS. 2006. Quantitative trait loci for baseline erythroid traits. Mamm Genome 17:298-309.
Reifsnyder PC, Li R, Silveira PA, Churchill G, Serreze DV, Leiter EH. 2006. Conditioning the genome identifies additional diabetes resistance loci in Type 1 diabetes-resistant NOR/Lt mice. Genes Immun 7:184.
Shockley KR, Churchill GA. 2006. Gene expression analysis of mouse chromosome substitution strains. Mamm Genome 17:598-614.
Solberg LC, Baum AE, Ahmadiyeh N, Shimomura K, Li R, Turek FW, Takahashi JS, Churchill GA, Redei EE. 2006. Genetic analysis of the stress-responsive adrenocortical axis. Physiol Genomics 27(3):362-369.
Stylianou IM, Korstanje R, Li R, Sheehan S, Paigen B, Churchill GA. 2006. Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci. Mamm Genome 17:22-36.
Stylianou IM, Tsaih SW, Dipetrillo K, Ishimori N, Li R, Paigen B, Churchill G. 2006. Complex genetic architecture revealed by analysis of high-density lipoprotein cholesterol in chromosome substitution strains and f2 crosses. Genetics 174(2):999-1007.
Wergedal JE, Ackert-Bicknell CL, Tsaih S-W, Sheng M H-C, Li R, Mohan S, Beamer WG, Churchill GA, Baylink DJ. 2006. Femur mechanical properties in the F2 Progeny of an NZB/B1NJ x RF/J cross are regulated predominantly by genetic loci that regulate bone geometry. J Bone Miner Res 21(8):1256-1266.
Wittenburg H, Lyons MA, Li R, Kurtz U, Wang X, Mossner J, Churchill GA, Carey MC, Paigen B. 2006. QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains. J Lipid Res 47:1780-1790.
Zimmerman JE, Rizzo W, Shockley KR, Raizen DM, Naidoo N, Mackiewicz M, Churchill GA, Pack AI. 2006. Multiple mechanisms limit the duration of wakefulness in Drosophila brain. Physiol Genomics 27(3):337-350.
Ackerman KG, Huang H, Grasemann H, Puma C, Singer JB, Hill AE, Lander E, Nadeau JH, Churchill GA, Drazen JM, Beier DR. 2005. Interacting genetic loci cause airway hyperresponsiveness. Physiol Genomics 21:105-111.
Ahmadiyeh N, Churchill GA, Solberg LC, Baum AE, Shimomura K, Takahashi JS, Redei EE. 2005. Lineage is an epigenetic modifier of QTL influencing behavioral coping with stress. Behav Genet 35(2):189-198.
Baum AE, Solberg LC, Kopp P, Ahmadiyeh N, Churchill G, Takahashi JS, Jameson JL, Redei EE. 2005. Quantitative trait loci associated with elevated thyroid-stimulating hormone in the Wistar-Kyoto rat. Endocrinology 146:870-878.
Beamer WG, Shultz KL, Donahue LR, Churchill GA, Sen S, Wergedal JR, Baylink DJ, Rosen CJ. 2005. Quantitative trait loci for femoral and lumbar vertebral bone mineral density in C57BL/6J and C3h/HeJ inbred strains of mice. J Bone Miner Res 20(9):1701-1712, discussion 1700.
Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM. 2005. Gonadal sex reversal in mutant Dax1 XY mice: a failure to up-regulate Sox9 in pre-Sertoli cells. Development 132:3045-3054.
Cui X, Hwang JT, Qiu J, Blades NJ, Churchill GA. 2005. Improved statistical tests for differential gene expression by shrinking variance components estimates. Biostatistics 6:59-75.
Dorward AM, Shultz KL, Horton LG, Li R, Churchill GA, Beamer WG. 2005. Distal Chr 4 harbors a genetic locus (Gct1) fundamental for spontaneous ovarian granulosa cell tumorigenesis in a mouse model. Cancer Res 65(4):1259-1264.
Li R, Lyons MA, Wittenburg H, Paigen BJ, Churchill GA. 2005. Combining data from multiple inbred line crosses improve the power and resolution of quantitative trait loci mapping. Genetics 169(3):1699-1709.
Lyons MA, Korstanje R, Li R, Sheehan SM, Walsh KA, Rollins JA, Carey MC, Paigen B, Churchill GA. 2005. Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM. Mamm Genome 16(3):152-163.
Mrug M, Li R, Cui X, Schoeb TR, Churchill GA, Guay-Woodford LM. 2005. Kinesin Family Member 12 is a candidate polycystic kidney disease modifer in the cpk mouse. J Am Soc Nephrol 16:905-916.
Peters LL, Zhang W, Lambert AJ, Brugnara C, Churchill GA, Platt OS. 2005. Quantitative trait loci for baseline white blood cell count, platelet count, and mean platelet volume. Mamm Genome 16(10):749-763.
Petkov PM, Graber JH, Churchill GA, Dipetrillo K, King BL, Paigen K. 2005. Evidence of a large-scale functional organization of mammalian chromosomes. PLoS Genet 1(3):e33.
Reifsnyder PC, Li R, Silveira PA, Churchill G, Serreze DV, Leiter EH. 2005. Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice. Genes and Immunity 6:528-538.
Sen S, Satagopan JM, Churchill GA. 2005. Quantitative trait locus study design from an information perspective. Genetics 170:447-464.
Tsaih SW, Lu L, Airey DC, Williams RW, Churchill GA. 2005. Quantitative trait mapping in a diallel cross of recombinant inbred lines. Mamm Genome 16(5):344-355.
Wittenburg H, Lyons MA, Li R, Kurtz U, Mossner J, Churchill GA, Carey MC, Paigen B. 2005. Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome 16(7):495-504.
Woo Y, Krueger W, Kaur A, Churchill G. 2005. Experimental design for three-color and four-color gene expression microarrays. Bioinformatics 21(1):i459-i467.
Yi N, Yandell BS, Churchill GA, Allison DB, Eisen EJ, Pomp D. 2005. Bayesian model selection for genome-wide epistatic quantitative trait loci analysis. Genetics 170(3):1333-1344.
