A Mouse Model for Complex Human Diseases

Summary

Principal Investigator: James Cheverud
Abstract: We propose to continue the development and maintenance of the LGXSM Recombinant Inbred (Rl) strain set and the associated Advanced Intercross (Al) Line formed by the intercross of inbred mouse strains LG/J and SM/J. The RIs are a tool for preliminary gene mapping, after which the Al Line can be used for finemapping quantitative trait loci to sub-cM regions. Under prior support we have developed a set of 18 Rl lines formed from the intercross of LG/J and SM/J and brought the Al line to the 32nd generation of random mating. The Rl lines have been scored for over 500 polymorphic microsatellite markers and for 4290 polymorphic SNPs, a polymorphic SNPs every 600 kb. Embryos have been cryopreserved for each Rl lines. These lines and other populations formed from the intercross of LG/J and SM/J have allowed the mapping of a large array of phenotypes relevant to disease processes of interest across the NIH Institutes. Here, we propose to enhance the Rl strain set by developing another 50 Rl strains using the present Al line as the source population. The addition of these strains will greatly increase the power of the Rl strain set in gene mapping studies. The new strains will be even more useful than the earlier set in that they will have accumulated 16 times the amount of recombination expected in Rl lines formed from a F2 generation. Furthermore, we will be able to use our prior breeding experience to increase strain survival to 50% in the production of new strains by selecting against specific loci that, singly and in combination, result in strain loss. The new strains will be genetically characterized for 500 microsatellites and 4290 SNPs and archived by embryonic cryopreservation. Strain genotypes and phenotypes will be made available through our web site, the Mouse Phenome Project, and the WebQTL database. In our earlier breeding, we discovered strong selection against the agouti alleles carried by SM/J, especially in the presence of the wild-type tyrosinase allele from that strain. We will examine the genetic basis for strain loss by sequencing the structural genes at these two loci and closely linked loci. We will produce 2ble congenic strains that are SM/J across the genome, except at the agouti and tyrosinase regions. Backcrossing with SM/J will be used to narrow the QTL interval for strain loss and to produce a new strain, carrying the unusual phenotypes of SM/J without requiring enforced heterozygosity at the agouti locus.
Funding Period: 2009-09-24 - 2010-09-23
more information: NIH RePORT

Top Publications

  1. pmc The effect of dietary fat intake on hepatic gene expression in LG/J AND SM/J mice
    Charlyn G Partridge
    Department of Anatomy and Neurobiology, Washington University in St, Louis, St, Louis, MO, USA
    BMC Genomics 15:99. 2014
  2. pmc Fine-mapping of obesity-related quantitative trait loci in an F9/10 advanced intercross line
    Gloria L Fawcett
    Department of Anatomy and Neurobiology, Washington University in St Louis, St Louis, Missouri, USA
    Obesity (Silver Spring) 18:1383-92. 2010
  3. pmc Diet-dependent genetic and genomic imprinting effects on obesity in mice
    James M Cheverud
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA
    Obesity (Silver Spring) 19:160-70. 2011
  4. pmc A framework for detecting and characterizing genetic background-dependent imprinting effects
    Jason B Wolf
    Faculty of Life Sciences, University of Manchester, Manchester M139PT, UK
    Mamm Genome 20:681-98. 2009
  5. pmc Sex-specific quantitative trait loci linked to autoresuscitation failure in SWR/J mice
    B T Thach
    Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA
    Heredity (Edinb) 103:469-75. 2009
  6. pmc Genetic relationships between obesity and osteoporosis in LGXSM recombinant inbred mice
    Michael S Reich
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Genet Res (Camb) 90:433-44. 2008
  7. ncbi A search for quantitative trait loci exhibiting imprinting effects on mouse mandible size and shape
    L J Leamy
    Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
    Heredity (Edinb) 101:518-26. 2008
  8. pmc Genome-wide analysis reveals a complex pattern of genomic imprinting in mice
    Jason B Wolf
    Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
    PLoS Genet 4:e1000091. 2008
  9. pmc Functional mapping imprinted quantitative trait loci underlying developmental characteristics
    Yuehua Cui
    Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA
    Theor Biol Med Model 5:6. 2008
  10. ncbi Quantitative trait loci for body size components in mice
    Jane P Kenney-Hunt
    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Mamm Genome 17:526-37. 2006

Scientific Experts

Detail Information

Publications14

  1. pmc The effect of dietary fat intake on hepatic gene expression in LG/J AND SM/J mice
    Charlyn G Partridge
    Department of Anatomy and Neurobiology, Washington University in St, Louis, St, Louis, MO, USA
    BMC Genomics 15:99. 2014
    ..LG/J and SM/J are known to differ in their responses to a high-fat diet for a variety of obesity- and diabetes-related traits, with the SM/J strain exhibiting a stronger phenotypic response to diet...
  2. pmc Fine-mapping of obesity-related quantitative trait loci in an F9/10 advanced intercross line
    Gloria L Fawcett
    Department of Anatomy and Neurobiology, Washington University in St Louis, St Louis, Missouri, USA
    Obesity (Silver Spring) 18:1383-92. 2010
    ..We also present further characterization of the pleiotropic and epistatic interactions underlying these obesity-related traits...
  3. pmc Diet-dependent genetic and genomic imprinting effects on obesity in mice
    James M Cheverud
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA
    Obesity (Silver Spring) 19:160-70. 2011
    ..Nearly every locus interacted with sex and/or diet in important ways demonstrating that gene effects are primarily context dependent, changing depending on sex and/or diet...
  4. pmc A framework for detecting and characterizing genetic background-dependent imprinting effects
    Jason B Wolf
    Faculty of Life Sciences, University of Manchester, Manchester M139PT, UK
    Mamm Genome 20:681-98. 2009
    ..Our application of the model to a genome scan supports this assertion by identifying pairs of loci that show reciprocal changes in their imprinting status as the background provided by the other locus changes...
  5. pmc Sex-specific quantitative trait loci linked to autoresuscitation failure in SWR/J mice
    B T Thach
    Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA
    Heredity (Edinb) 103:469-75. 2009
    ..These results establish a genetic basis for AR failure phenotype in mice, with relevance to Sudden Infant Death Syndrome...
  6. pmc Genetic relationships between obesity and osteoporosis in LGXSM recombinant inbred mice
    Michael S Reich
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA
    Genet Res (Camb) 90:433-44. 2008
    ..Our results support the use of the LG/J-by-SM/J mouse intercross populations as models for normal, complex genetic variation in obesity, bone properties and their interrelationship...
  7. ncbi A search for quantitative trait loci exhibiting imprinting effects on mouse mandible size and shape
    L J Leamy
    Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA
    Heredity (Edinb) 101:518-26. 2008
    ..We concluded that genomic imprinting has a negligible effect on these specific morphometric traits, and that maternal genetic effects may account for many of the previously reported instances of apparent genomic imprinting...
  8. pmc Genome-wide analysis reveals a complex pattern of genomic imprinting in mice
    Jason B Wolf
    Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
    PLoS Genet 4:e1000091. 2008
    ..Our findings also show that the imprinting pattern of a locus can be variable over ontogenetic time and, in contrast to current views, may often be stronger at later stages in life...
  9. pmc Functional mapping imprinted quantitative trait loci underlying developmental characteristics
    Yuehua Cui
    Department of Statistics and Probability, Michigan State University, East Lansing, MI 48824, USA
    Theor Biol Med Model 5:6. 2008
    ..For a developmental character such as growth, current approach is less efficient in dissecting the dynamic genetic effect of imprinted genes during individual ontology...
  10. ncbi Quantitative trait loci for body size components in mice
    Jane P Kenney-Hunt
    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Mamm Genome 17:526-37. 2006
    ..Antagonistic pleiotropy, in which a locus has opposite effects on different characteristics, is uncommon...
  11. ncbi Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the inter-cross of SM/J and LG/J inbred mouse strains
    Tomas Hrbek
    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, Missouri 63110, USA
    Mamm Genome 17:417-29. 2006
    ..The LGxSM 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...
  12. ncbi Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines
    Thomas H Ehrich
    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Genet Res 85:211-22. 2005
    ..Therefore, genetic effects for these traits are different depending on the environment an animal is exposed to...
  13. ncbi Fine-mapping gene-by-diet interactions on chromosome 13 in a LG/J x SM/J murine model of obesity
    Thomas H Ehrich
    Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA
    Diabetes 54:1863-72. 2005
    ..The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains...
  14. ncbi Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains
    Joseph P Jarvis
    Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA
    J Lipid Res 46:1692-702. 2005
    ..We also found an interaction affecting adult phenotype between the effects of maternal care between RI strain mothers and C57BL/6J mothers and a later environmental factor (dietary fat intake) for some age-specific weights...