Loyola University Chicago

Department of Biology

LG/J by SM/J Mouse Intercross Populations

We have performed numerous gene mapping experiments using the LG/J and SM/J mouse strains which vary for an incredible range of phenotypes. We presently hold 10 LGXSM Recombinant Inbred (RI) lines generated from the F 2 generation of our LG/J by SM/J intercross. These RI lines are very useful for initial gene mapping studies, especially for phenotypes that are difficult to measure. In addition to these original RI lines we also generated an Advanced Intercross (AI) line that has been randomly mated for 38 generations. The effective population size of this randomly-mated, closed colony is about 300, limiting the rate at which inbreeding accumulates. The AI line serves as a fine-mapping resource. With the large numbers of SNPs known to be polymorphic between LG/J and SM/J, it is possible to map QTLs to a sub-centi Morgan region with only a small number of positional candidate genes. The AI line has several benefits in relation to other means of fine-mapping, such as sub-congenics, in that it accumulates recombination throughout the genome rather than only in the congenic interval, making it generally useful for a wide range of characters and and genomic positions. We are now generating another set of RI lines formed from the F 34 generation of the AI line. Eighty-five strains were started in 2007 and the survivors should reach fully inbred status in 2012.

Animals of these strains are available from our laboratory. Please e-mail cheverud {at} wustl.edu for more information.

New Recombinant Lines: Update

We began the construction of new Lg/J x Sm/J inbred lines in April 2007 using 63 of the randomly bred families from the F34 generation of the Advanced Intercross Line (AIL). Initially there were 63 genetically distinct strains, and for 33 of these strains, two sets of siblings were separated in the P0 generation to act as additional strains, albeit genetically similar to their AIL sibling strains. Our mating experience has demonstrated that bad parenting behavior is associated at least partially with the Agouti locus on chromosome 2. Since coat color cannot be used to determine allele state in the Lg/J and Sm/J strains, we must genotype the mice to determine their status. All animals were genotyped in the F1 for three microsatellite loci (D2Mit22, D2Mit286, D2Mit409) surrounding the Agouti locus, and we selected for animals with large alleles on a minimum of two, but preferably all three of the loci to breed in the F1 generation.

As of July, 2008 almost 6,000 mice have been born for this experiment and the majority of strains are in the F5 or F6 generations. We have lost 7 strains completely (11.1% of the original genetically distinct strains), as well as 8 of the sib strains (8.1% of all strains), so that their genetically similar sib strain remains alive. We are maintaining 3 or 4 breeding pairs per strain and generation, and all breeding animals that contribute pups used as parents in the next generation are given a standard necropsy at death. Many of the strains are now fixed for the loci surrounding the Agouti locus and no longer require genotyping each generation. Forty-eight of the strains required genotyping during the F2 generation; this dropped to 34 in the F3 generation, 20 in the F4, and 6 in the F5. In the near future, we will check the genotypes of each strain to ensure that these loci remain fixed.

Grant Funding

Supported by NCRR grant RR015116

Publications on the Topic

Nikolskiy, I., D. F. Conrad, S. Chun, J. C. Fay, J. M. Cheverud, and H. A. Lawson. 2015. Using whole-genome sequences of the LG/J and SM/J inbred mouse strains to prioritize quantitative trait genes and nucleotides. BMC Genomics 16:415 (12 pg.).

Wang, J. R., F. Pardo-Manuel de Villena, H. A. Lawson, J. M. Cheverud, G. A. Churchill, and L. McMillan. 2012. Imputation of single-nucleotide polymorphisms in inbred mice using local phylogeny. Genetics 190:449-458.

Hrbek, T, Alves de Brito, R, Wang, B, Pletscher, L & Cheverud, J. (2006) 'Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the intercross of SM/J and LG/J inbred mouse strains', Mammalian Genome, vol. 17, pp. 417-429. doi:10.1007/s00335-005-0038-7 [pdf]

Ehrich, T, Hrbek, T, Kenney-Hunt, J, Pletscher, L Wang, B, Semenkovich, C & Cheverud, J. (2005) 'Fine-mapping gene by diet interactions on chromosome 13 in a LG/J´SM/J murine model of obesity', Diabetes, vol. 54, pp. 1863-1872. doi:10.2337/diabetes.54.6.1863 [pdf]

Churchill, G, Airey, D, Allayee, H, Angel, J, Attie, A, Beatty, J, Beavis, W, Belknap, J, Bennett, B, Berrettini, W, Bleich, A, Bogue, M, Broman, K, Buck, K, Buckler, E, Burmeister, M, Chesler, E, Cheverud, J, Clapcote, S, Cook, M, Cox, R, Crabbe, J, Crusio, W, Darvasi, A, Deschepper, C, Doerge, R, Farber, C, Forejt, J, Gaile, D, Garlow, S, Geiger, H, Gershenfeld, H, Gordon, T, Gu, J, Gu, W, de Haan, G, Hayes, N, Heller, C, Himmelbauer, H, Hitzemann, R, Hunter, K, Hsu, H, Iraqi, F, Ivandic, B, Jacob, H, Jansen, R, Jepsen, K, Johnson, D, Johnson, T, Kempermann, G, Kendziorski, C, Kotb, M, Kooy, R, Llamas, B, Lammert, F, Lassalle, J, Lowenstein, P, Lu, L, Lusis, A, Manly, K, Marcucio, R, Matthews D, Medrano, J, Miller, D, Mittleman, G, Mock, B, Mogil, J, Montagutelli, X, Morahan, G, Morris, D, Mott, R, Nadeau, J, Nagase, H, Nowakowski, R, O'Hara, B, Osadchuk, A, Page, G, Paigen, B, Paigen, K, Palmer, A, Pan, H, Peltonen-Palotie, L, Perice, J, Pomp, D, Pravenec, M, Prows, D, Qi, Z, Reeves, R, Roder, J, Rosen, G, Schadt, Schalkwyk, L, Seltzer, Z, Shimomura, K, Shou, S, Sillanpää, M, Siracusa, L, Snoeck, H, Spearow, J, Svenson, K, Tarantino, L, Threadgill, D, Toth, L, Valdar, W, Pardo-Manuel de Villena, F, Warden, C, Whatley, S, Williams, R, Wiltshire, T, Yi, N, Zhang, D, Zhang, M & Zou, F. (2004) 'The Collaborative Cross, a community resource for the genetic analysis of complex traits', Nature Genetics, vol. 36, pp. 1133-1137. doi:10.1038/ng1104-1133 [pdf]

Flaherty, L, Abiola, O, Angel, J, Avner, P, Bachmanov, A, Belknap, J, Bennett, B, Blankenhorn, E, Blizard, D, Bolivar, V, Brockmann, G, Buck, K, Bureau, J, Casley, W, Chesler, E, Cheverud, J, Churchill, G, Cook, M, Crabbe, J, Crusio, W, Darvasi, A, de Haan, G, Demant, P, Doerge, R, Elliott, R, Farber, C, Flint, J, Gershenfeld, H, Gibson, J, Gu, W, Himmelbauer, H, Hitzemann, R, Hsu, H, Hunter, K, Iraqi, F, Jansen, R, Johnson, T, Jones, B, Kempermann, G, Lammert, F, Lu, L, Manly, K, Matthews, D, Medrano, J, Mehrabian, M, Mittleman, G, Mock, B, Mogil, J, Montagutelli, X, Morahan, G, Mountz, J, Nagase, H, Nowakowski, R, O'Hara, B, Osadchuk, A, PAigen, B, Palmer, A, Peirce, J, Pomp, D, Rosemann, M, Rosen, G, Schalkwyk, L, Seltzer, Z, Settle, S, Shimomura, K, Shou, S, Sikela, J, Siracusa, L, Spearow, J, Teuscher, C, Threadgill, D, Toth, L, Toye, A, Vadasz, C, Van Zant, G, Wakeland, E, Williams, R, Zhang, H & Zou, F. (2003) 'The nature and identification of quantitatie trait loci: a community's view', Nature Reviews: Genetics, vol. 4, pp. 911-916. doi:10.1038/nrg1206 [pdf]

Akada, J, Ogura, K, Dailidiene, D, Dailede, Cheverud, J & Berg, D. (2003) 'Heliobacter pylori tissue tropism: Mouse colonizing strains can target different gastric niches', Microbiology, vol. 149, pp. 1901-1909. doi:10.1099/mic.0.26129-0 [pdf]