Abstract
An analysis of transcriptional variation in the liver using a panel of B.A chromosome substitution strains identified 4209 transcripts that are differentially expressed relative to the C57BL/6J background and 1010 transcripts that are differentially expressed between C57BL/6J and A/J strains. A subset of these strains (substituting Chromosomes 1, 6, and 15) was used to identify 386 additional differentially expressed transcripts in the kidney. Approximately 15% of differentially expressed transcripts are located on the substituted chromosome. These cis-QTL are codirectionally expressed with the donor strain A/J. By comparison, trans-regulated loci comprise 85% of differentially expressed transcripts, often show opposite direction of change compared with A/J, and can be regulated by multiple chromosome substitutions. Gene expression differences in this study provide evidence for transgressive segregation: Only 438 of 4209 QTL in liver were inside the parental range. By combining QTL data with known biological functions, we were able to identify physiologic pathways altered in multiple strains. In many cases the same pathways were altered by multiple distinct chromosome substitutions. Taken together, these results suggest that widespread epistatic background effects may result in complex and overlapping transcriptional relationships among different chromosome substitution strains. Transcriptional profiling of chromosome substitution strains reveals a complex genetic architecture of transcriptional regulation.
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Actor JK, Olsen M, Jagannath C, Hunter RL (1999) Relationship of survival, organism containment, and granuloma formation in acute murine tuberculosis. J Interferon Cytokine Res 19:1183–1193
Ashburner M., Ball CA, Blake JA, Botstein D, Butler H, et al. 2002) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature Genetics 25:25–29
Cerny J, McAlack RF, Sajid MA, Friedman H (1971) Genetic differences in the immunocyte response of mice to separate determinants on one bacterial antigen. Nat New Biol 230:247–248
Cervino AC, Li G, Edwards S, Zhu J, Laurie C, et al. (2005) Integrating QTL and high-density SNP analyses in mice to identify Isig2 as a susceptibility gene for plasma cholesterol levels. Genomics 86:505–517
Chesler EJ, Lu L, Shou S, Qu Y, Gu J, et al. (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37:233–242
Churchill GA (2004) Using ANOVA to analyze microarray data. Biotechniques 37:173–175
Cowley AW Jr, Roman RJ, Jacob HJ (2004) Application of chromosomal substitution techniques in gene-function discovery. J Physiol 554:46–55
Cui X, Hwang JT, Qui J, Blades NJ, Churchill GA (2005) Improved statistical tests for differential gene expression by shrinking variance components estimates. Biostatistics 6:59–75
Curtis HJ (1971) Genetic factors in aging. Adv Genet 16:305–324
Festing MF (1969) Inbred mice in research. Nature 221:716
Fleiszer D, Hilgers J, Skamene E (1988) Multigenic control of colon carcinogenesis in mice treated with 1,2-dimethylhydrazine. Curr Top Microbiol Immunol 137:243–249
Fortin A, Diez E, Rochefort D, Laroche L, Malo D, et al. (2001) Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74:21–35
Gautier L, Cope LM, Bolstad BM, Irizarry RA (2004) Affy–Analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20:307–315
Goodrick GL (1975) Life-span and the inheritance of longevity of inbred mice. J Gerontol 30:257–263
Hamet P, Pausova Z, Dumas P, Sun YL, Tremblay J, et al. (1998) Newborn and adult recombinant inbred strains: A tool to search for genetic determinants of target organ damage in hypertension. Kidney Int 53:1488–1492
Hoag WG (1963) Spontaneous cancer in mice. Ann N Y Acad Sci 108:805–831
Ho M, Post CM, Donahue LR, Lidov HGW, Bronson RT, et al. (2004) Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency. Hum Mol Genet 13:1999–2010
Hosack DA, Dennis G, Sherman BT, Lane HC, Lempicki RA (2003) Identifying biological themes within lists of genes with EASE. Gen Biol 4:R70
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, et al. (2003a) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, et al. (2003b) Summaries of Affymetrix GeneChip probe level data. Nucl Acids Res 31:e15
Kaye M, Kusy RP (1995) Genetic lineage, bone mass, and physical activity in mice. Bone 17:131–135
Kerr MK, Churchill GA (2001) Bootstrapping cluster analysis: assessing the reliability of conclusions from microarray experiments. Proc Natl Acad Sci U S A 98:8961–8965
Kerr MK, Martin M, Churchill GA (2000) Analysis of variance for gene expression microarray data. J Comput Biol 7:819–837
Lipoldova M, Svobodova M, Krulova M, Havelkova H, Badalova J, et al. (2000) Susceptibility to Leishmania major infection in mice: Multiple loci and heterogeneity of immunopathological phenotypes. Gene Immunity 1:170–206
Malkinson AM, Nesbitt MN, Skamene E (1985) Susceptibility to urethan-induced pulmonary adenomas between A/J and C57BL/6J mice: Use of AXB and BXA recombinant inbred lines indicating a three-locus genetic model. J Natl Cancer Inst 75:971–974
Marshall JD, Mu J-L, Cheah Y-C, Nesbitt MN, Frankel WN, et al. (1992) The AXB and BXA set of recombinant inbred mouse strains. Mamm Genome 3:669–680
Matesic LE, Niemitz EL, De Maio A, Reeves RH (2000) Quantitative trait loci modulate neutrophil infiltration in the liver during LPS-induced inflammation. FASEB J 14:2247–2254
Mills E, Kuhn CM, Feinglos MN, Surwit R (1993) Hypertension in CB57BL/6J mouse model of non-insulin-dependent diabetes mellitus. Am J Physiol 264:R73–78
Mosier DE (1986) Animal models for retrovirus-induced immunodeficiency disease. Immunol Invest 15:233–261
Mu J- L, Naggert JK, Nishina PM, Cheah Y-C, Paigen B (1993) Strain distribution pattern in AXB and BXA recombinant inbred strains for loci on murine chromosomes 10, 13, 17, and 18. Mamm Genome 4:148–152
Myers DD, Meier H, Huebner RJ (1970) Prevalence of murine C-type RNA virus group specific antigen in inbred strains of mice. Life Sci 9:1071–1080
Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225
Petkov PM, Ding Y, Cassell MA, Zhang W, Wagner G, et al. (2004) An efficient SNP system for mouse genome scanning and elucidating strain relationships. Genome Res 14:1806–1811
Plant JE, Blackwell JM, O’Brien AD, Bradley AD, Bradley DJ, et al. (1982) Are the Lsh and Ity disease resistance genes at one locus on mouse chromosome 1? Nature 297:510–511
Qiao JH, Fishbein MC, Demer LL, Lusis AJ (1995) Genetic determination of cartilaginous metaplasia in mouse aorta. Arterioscler Thromb Vasc Biol 15:2265–2272
Rebuffe-Scrive M, Surwit R, Feinglos M, Kuhn C, Rodin J (1993) Regional fat distribution and metabolism in a new mouse model (C57BL/6J) of non-insulin-dependent diabetes mellitus. Metabolism 42:1405–1409
Rinn JL, Snyder M (2005) Sexual dimorphism in mammalian gene expression. Trends Gen 21:298–305
Sadarangani C, Skamene E, Kongshaven PAL (1980) Cellular basis for genetically determined enhanced resistance of certain mouse strains to Listeriosis. Infect Immun 28:381–386
Shih DM, Gu L, Hama S, Xia YR, Navab M, et al. (1996) Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest 97:1630–1639
Silver LM (1995) Mouse Genetics (New York: Oxford University Press)
Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, et al. (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304:445–448
Stevenson MM, Kongshavn PA, Skamene E (1981) Genetic linkage of resistance to Listeria monocytogenes with macrophage inflammatory responses. J Immunol 127:402–407
Storer JB (1966) Longevity and gross pathology at death in 22 inbred strains of mice. J Gerontol 21:404–409
Storey JD (2002) A direct approach to false discovery rates. J R Stat Soc B 64:479–498
Sugiyama F, Churchill GA, Higgins DC, Johns C, Makaritis KP, et al. (2001) Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 71:70–77
Surwit RS, Feinglos MN, Rodin J, Sutherland A, Petro AE, et al. (1995) Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism 44:645–651
Tankersley CG, Fitzgerald RS, Kleeberger SR (1994) Differential control of ventilation among inbred strains of mice. Am J Physiol 267, R1371–R1377
Thaete LG, Nesbitt MN, Malkinson AM (1991) Lung adenoma structure among inbred strains of mice: the pulmonary adenoma histologic type (Pah) genes. Cancer Lett 61:15–20
Wade CM, Kulbokas AJ III, Kirby AW, Zody MC, Mullikin JC, et al. (2002) The mosaic structure of variation in the laboratory mouse genome. Nature 420:574–578
Walton JP, Frisina RD, Meierhans LR (1995) Sensorineural hearing loss alters recovery from short-term adaptation in the C57BL/6 mouse. Hear Res 88:19–26
Wills-Karp M, Ewart SL (1997) The genetics of allergen-induced airway hyperresponsiveness in mice. Am J Respir Crit Care Med 156:S89–96
Wu H, Kerr K, Churchill GA (2003) MAANOVA: A Software Package for the Analysis of Spotted cDNA Microarray Experiments. In The Analysis of Gene Expression Data: an Overview of Methods and Software, Parmigiani G, Garrett ES, Irizarry RA, Zeger AL (eds). (New York: Springer), pp 313–431
Yang GM, Kitagawa K, Matsushita K, Mabuchi T, Yagita Y, et al. (1997) C57BL/6 strain is most susceptible to cerebral ischemia following bilateral common carotid occlusion among seven mouse strains: Selective neuronal death in the murine transient forebrain ischemia. Brain Res 752:209–218
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This work was supported by the National Institutes of Health (NIH) grants HLB55001, GM070683, and HLB66611. The authors thank Jason Affourtit, Greg MacKenzie, and Yong H. Wu for their contributions to this study.
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Shockley, K., Churchill, G. Gene expression analysis of mouse chromosome substitution strains. Mamm Genome 17, 598–614 (2006). https://doi.org/10.1007/s00335-005-0176-y
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DOI: https://doi.org/10.1007/s00335-005-0176-y