Abstract
A new set of LGXSM recombinant inbred (RI) strains is presented. The RI strain panel consists of 18 remaining strains of the original 55 founding strains. Strain characterization is based on 506 polymorphic microsatellites and 4289 single nucleotide polymorphisms (SNPs) distributed across the genome. Average microsatellite intermarker distance is 4.80 ± 4.84 Mb or 2.91 ± 3.21 F2 cM. SNPs are more densely spaced at 0.57 ± 1.27 Mb. Ninety-five percent of all microsatellite intermarker intervals are separated by less than 15.00 Mb or 8.50 F2 cM, while 95% of the SNPs are less than 0.95 Mb apart. Strains show expected low levels of nonsyntenic association among loci and complete genomic independence. During inbreeding, the RI strains went through strong natural selection on the agouti locus on Chromosome 2, especially when the epistatically interacting tyrosinase locus on Chromosome 7 carried the wild-type allele. The LG/J and SM/J strains differ in a large number of biomedically important traits, and they and their intercross progeny have been used in multiple mapping studies. The LG×SM RI strain panel provides a powerful new resource for mapping the genetic bases of complex traits and should prove to be of great biomedical utility in modeling complex human diseases such as obesity and diabetes.
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Akada JK, Ogura K, Dailidiene D, Dailide G, Cheverud JM, et al. (2003) Heliobacter pylori tissue tropism: Mouse colonizing strains can target different gastric niches. Microbiology 149:1901–1909
Brinkmann B, Klintschar M, Neuhuber F, Hühne J, Rolf B (1998) Mutation rate in human microsatellites: Influence of the structure and length of the tandem repeat. Am J Hum Genet 62:1408–1415
Chai C (1956a) Analysis of quantitative inheritance of body size in mice. I. Hybridization and maternal influence. Genetics 41: 157–164
Chai C (1956b) Analysis of quantitative inheritance of body size in mice. II. Gene action and segregation. Genetics 41: 167–178
Chai C (1957) Analysis of quantitative inheritance of body size in mice. III. Dominance. Genetics 42: 601–607
Chai C (1961) Analysis of quantitative inheritance of body size in mice. IV. An attempt to isolate polygenes. Genet Res 2: 25–32
Chai C (1968) Analysis of quantitative inheritance of body size in mice. V. Effects of small numbers of polygenes on similar genetic backgrounds. Genet Res 11: 239–246
Cheverud JM, Routman EJ, Duarte FAM, Van Swinderen B, Cothran K, et al. (1996) Quantitative trait loci for murine growth. Genetics 142: 1305–1319
Cheverud JM, Routman EJ, Irschick DJ (1997) Pleiotropic effects of individual gene loci on mandibular morphology. Evolution 51: 2004–2014
Cheverud JM, Pletscher LS, Vaughn TT, Marshall B (1999a) Differential response to dietary fat in Large (LG/J) and Small (SM/J) inbred mouse strains. Physiol Genomics 1: 33–39
Cheverud JM, Vaughn TT, Pletscher LS, King-Ellison K, Bailiff J, et al. (1999b) Epistasis and the evolution of additive genetic variance in populations that pass through a bottleneck. Evolution 53: 1009–1018
Cheverud JM, Vaughn TT, Pletscher LS, Peripato AC, Adams ES, et al. (2001) Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice. Mamm Genome 12: 3–12
Cheverud JM, Ehrich TH, Hrbek T, Kenney JP, Pletscher LS, et al. (2004a) Quantitative trait loci for obesity and diabetes-related traits and their dietary responses to a high fat diet in the LGXSM recombinant inbred mouse strains. Diabetes 53: 3328–3336
Cheverud JM, Ehrich TH, Kenney JP, Pletscher LS, Semenkovich CF (2004b) Genetic evidence for discordance between obesity- and diabetes-related traits in the LGXSM recombinant inbred mouse strains. Diabetes 53: 2700–2708
Cheverud JM, Ehrich TH, Vaughn TT, Koreishi SF, Linsey RB, et al. (2004c) Pleiotropic effects on mandibular morphology II. Differential epistasis and genetic variation in morphological integration. J Exp Zool Mol Dev Evol 302: 424–435
Crow JF, Kimura M (1970) An Introduction to Population Genetics Theory (Burgess Publishing: Minneapolis)
Dietrich WF, Katz H, Lincoln SE (1992) A genetic map of the mouse suitable for typing in intraspecific crosses. Genetics 131: 423–447
Ehrich TH, Kenney JP, Vaughn TT, Pletscher LS, Cheverud JM (2003a) Diet, obesity, and hyperglycemia in LG/J and SM/J mice. Obes Res 11: 1400–1410
Ehrich TH, Vaughn TT, Koreishi SF, Linsey RB, Pletscher LS, et al. (2003b) Pleiotropic effects on mandibular morphology I. Developmental morphological integration and differential dominance. J Exp Zool Mol Dev Evol 269: 58–79
Ehrich TH, Hrbek T, Kenney-Hunt JP, Pletscher LS, Wang B, et al. (2005) Fine-mapping gene-by-diet interactions on Chromosome 13 in a LG/J × SM/J murine model of obesity. Diabetes 54: 1863–1872
Eicher EM, Lee BK (1990) The NXSM recombinant inbred strains of mice: Genetic profile for 58 loci, including Mtv proviral loci. Genetics 125: 431–446
Falconer DS, Mackay TFC (1996) Introduction to Quantitative Genetics, 4th ed. (Essex, UK: Longman)
Festing MFW (1996) Origins and Characteristics of Inbred Strains of Mice. (New York: Oxford University Press)
Frankel WN, Lee BK, Stoye JP, Coffin JM, Eicher EM (1992) Characterization of the endogenous nonecotropic murine leukemia viruses of NZB/B1NJ and SM/J inbred strains. Mamm Genome 2: 110–122
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229
Goodale H (1938) A study of the inheritance of body weight in the albino mouse by selection. J Hered 29: 101–112
Haldane JBS, Waddington CH (1931) Inbreeding and linkage. Genetics 16: 357–374
Hanson WD (1959) The breakup of initial linkage blocks under selected mating systems. Genetics 44: 857–868
Kayser M, Sajantila A (2001) Mutations at Y-STR loci: implications for paternity testing and forensic analysis. Forensic Sci Int 118: 116–121
Kenney-Hunt JP, Vaughn TT, Pletscher LS, Peripato A, Routman E, et al. (2006) Quantitative trait loci for body size components. Mamm Genome 17, in press
Klingenberg CP, Leamy LJ, Routman EJ, Cheverud JM (2001) Genetic architecture of mandible shape in mice: Effects of quantitative trait loci analyzed by geometric morphometrics. Genetics 157: 785–802
Klingenberg CP, Leamy LJ, Cheverud JM (2004) Integration and modularity of quantitative trait locus effects on geometric shape in the mouse mandible. Genetics 166: 1909–1921
Kramer MG, Vaughn TT, Pletscher LS, King-Ellison K, Adams E, et al. (1998) Genetic variation in body weight gain and composition in the intercross of Large (LG/J) and Small (SM/J) inbred strains of mice. Genet Mol Biol 21: 211–218
Leamy LJ, Routman EJ, Cheverud JM (1997) A search for quantitative trait loci affecting asymmetry of mandibular characters in mice. Evolution 51: 957–969
Leamy LJ, Routman EJ, Cheverud JM (1998) Quantitative trait loci for fluctuating asymmetry of discrete skeletal characters in mice. Heredity 80: 509–518
Leamy LJ, Routman EJ, Cheverud JM (1999) Quantitative trait loci for early- and late-developing skull characters in mice: A test of the genetic independence model of morphological integration. Am Nat 153: 201–214
Leamy LJ, Routman EJ, Cheverud JM (2002) An epistatic genetic basis for fluctuating asymmetry of mandible size in mice. Evolution 56: 642–653
Leamy LJ, Workman MS, Routman EJ, Cheverud JM (2005) An epistatic genetic basis for fluctuating asymmetry of tooth size and shape in mice. Heredity 94: 316-325
Liu S-C, Kowalski S, Lan T-H, Feldmann K, Paterson A (1996) Genome-wide high-resolution mapping by recurrent intermating using Arabidopsis thaliana as a model. Genetics 142: 247–258
MacArthur J (1944) Genetics of body size and related characters. I. Selection of small and large races of the laboratory mouse. Am Nat 78: 42–157
Mezey J, Cheverud JM, Wagner GP (2000) Is the genotype–phenotype map modular? A statistical approach using mouse QTL data. Genetics 156: 305–311
Nishimura M, Hirayama N, Serikawa T, Kanehira K, Matsushima Y, et al. (1995) The SMXA: A new set of recombinant inbred strain of mice consisting of 26 substrains and their genetic profile. Mamm Genome 6: 850–587
Peripato AC, Cheverud JM (2002) Genetic influences on maternal care. Am Nat 160: s173–s185
Peripato AC, de Brito RA, Vaughn TT, Pletscher LS, Matioli SR, et al. (2002) Quantitative trait loci for maternal performance for offspring survival in mice. Genetics 162: 1341–1353
Peripato AC, de Brito RA, Matioli SR, Pletscher LS, Vaughn TT, et al. (2004) Epistatis affecting litter size in mice. J Evol Biol 17: 593–602
Routman E, Cheverud J (1994) A rapid method of scoring simple sequence repeat polymorphisms with agarose gel electrophoresis. Mamm Genome 5: 187–188
Routman EJ, Cheverud JM (1995) Polymorphism for PCR-analyzed microsatellites between the inbred mouse strains LG and SM. Mamm Genome 6: 401–404
Routman EJ, Cheverud JM (1997) Gene effects on a quantitative trait: Two-locus epistatic effects measured at microsatellite markers and at estimated QTL. Evolution 51: 1654–1662
Sajantila A, Lukka M, Syvänen A-C (1999) Experimentally observed germline mutations at human micro- and minisatellite loci. Eur J Hum Genet 7: 263–266
Sokal RR, Rohlf FJ (1995) Biometry (W.H. Freeman and Co.: New York)
Stickney HL, Schmutz J, Woods IG, Holtzer CC, Dickson MC, et al. (2002) Rapid mapping of zebrafish mutations with SNPs and oligonucleotide microarrays. Genome Res 12: 1929–1934
Taylor BA (1989) Recombinant inbred strains. In Lyon ML, Searle AG (eds.), Genetic Variants and Strains of the Laboratory Mouse, 2nd ed. (Oxford, UK: Oxford University Press), pp 773–796
Templeton AR, Read B (1984) Factors eliminating inbreeding depression in a captive herd of Speke’s gazelle (Gazella spekei). Zoo Biol 3: 177–199
Vaughn TT, Pletscher LS, Peripato A, King-Ellison K, Adams E, et al. (1999) Mapping quantitative trait loci for murine growth: A closer look at genetic architecture. Genet Res 74: 313–322
Wade CM, Kulbokas EJ III, Kirby AW, Zody MC, Mullikin JC, et al. (2002) The mosaic structure of variation in the laboratory mouse genome. Nature 420: 574–578
Weber JL, Broman KW (2000) Genotyping for human whole-genome scans: past, present, and future. Adv Genet 42: 77–96
Weber JL, Wong CC (1993) Mutation of human short tandem repeats. Hum Mol Genet 2: 1123–1128
Williams RW, Gu J, Qi S, Lu L (2001) The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis. Genome Res 2: 1–18
Williams RW, Bennett B, Lu L, Gu J, DeFries JC, et al. (2004) Genetic structure of the L×S panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis. Mamm Genome 15: 637–647
Wolf JB, Vaughn TT, Pletscher LS, Cheverud JM (2002) Contribution of maternal effect QTL to genetic architecture of early growth in mice. Heredity 89: 300–310
Wolf JB, Leamy LJ, Routman EJ, Cheverud JM (2005) Epistatic pleiotropy and the genetic architecture of covariation within early- and late-developing skull trait complexes in mice. Genetics 171: 683-694
Workman MS, Leamy LJ, Routman EJ, Cheverud JM (2002) Analysis of QTL effects on the size and shape of mandibular molars in mice. Genetics 160: 1573–1586
Wu R, Wang Z, Zhao W, Cheverud JM (2004) A mechanistic model for the genetic machinery of ontogenetic growth. Genetics 168: 2383–2394
Zhao W, Ma C-X, Cheverud JM, Wu R (2004) A unifying statistical model for QTL mapping of genotype-sex interaction for developmental trajectories. Physiol Genet 19: 218–277
Acknowledgments
The authors thank all those who helped with the creation and maintenance of the RI mouse lines, and who over the years have worked with and cared for the mice. They also thank T. H. Ehrich and J. P. Kenney-Hunt for insightful comments and critical discussion. This study was supported by NIH grants RR015116 and DK055736 (to JMC).
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Appendices
Appendix 1
This appendix is a table with all microsatellite and SNP markers and their states for the 18 RI strains. It is available at http://www.thalamus.wustl.edu/cheverudlab/
Appendix 2
This appendix shows the analysis of heterozygosity in all 18 RI strains across all 19 autosomes and the X sex chromosome. It is available at http://www.thalamus.wustl.edu/cheverudlab/
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Hrbek, T., de Brito, R.A., Wang, B. et al. Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the intercross of SM/J and LG/J inbred mouse strains. Mamm Genome 17, 417–429 (2006). https://doi.org/10.1007/s00335-005-0038-7
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DOI: https://doi.org/10.1007/s00335-005-0038-7