Our work is centered on advancing systems genetics approaches to study the genetic and environmental factors shaping dynamic, genome-wide processes of epigenetic modification, recombination, gene expression, and metabolism in a mammalian model system. Our approach is based on our previous work providing a detailed molecular understanding of the evolutionary origins of the laboratory mouse, which in turn led to the adoption of two novel populations of mice with extensive genomic diversity. The Collaborative Cross recombinant inbred strains provide a fixed number of reproducible genomes optimal for multiple testing, while Diversity Outbred mice provide high genetic mapping resolution and an endless supply of unique genomes. These populations share the same allelic compositions and are derived from the same set of eight progenitor strains. Together these mouse populations provide an integrating framework for connecting the multiple domains of genomic function we study, as well as complementary approaches for developing and validating predictive models of genetic and environmental effects. By pioneering the application of these resources, our Center aims to establish high community standards and new approaches for systems genetics studies. The Center for Genome Dynamics will engage a group of scientists with diverse specialties in computational, statistical, and biological domains in a common collaborative work environment. The Center will provide mentorship for career development of new faculty and postdoctoral associates. Our unique education program will engage high school and undergraduate students in challenging computational biology research. Our projects are designed to enhance our capabilities for discovering genetic and environmental causes of phenotypic diversity and for elucidating the molecular mechanisms underlying human health and disease. Using the premier mammalian model organism combined with high throughput molecular phenotyping technologies, physiological profiling, and computational modeling, we will develop predictive modeling and validation strategies that test the premises of personalized medicine. Our goal, using a variety of disease phenotypes, is to improve prediction and intervention strategies for complex diseases, with broad implication for multiple areas of human disease.

Public Health Relevance

Differences in disease susceptibility and outcome are linked with variation in an individual's genetic makeup and environment. The Center for Genome Dynamics will use novel mouse populations, animal measurements and computational methods to identify genetic and environmental factors, and probe their role in diseases. Our innovative outreach programs will immerse students in this interdisciplinary approach to research. Center resources and training will be available to the scientific community, accelerating efforts to improve prediction, prevention and intervention strategies for multiple human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
3P50GM076468-07S1
Application #
8424925
Study Section
Special Emphasis Panel (ZGM1-CBCB-2 (SB))
Program Officer
Eckstrand, Irene A
Project Start
2006-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$19,408
Indirect Cost
$8,608
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Chesler, Elissa J; Gatti, Daniel M; Morgan, Andrew P et al. (2016) Diversity Outbred Mice at 21: Maintaining Allelic Variation in the Face of Selection. G3 (Bethesda) 6:3893-3902
Korstanje, Ron; Deutsch, Konstantin; Bolanos-Palmieri, Patricia et al. (2016) Loss of Kynurenine 3-Mono-oxygenase Causes Proteinuria. J Am Soc Nephrol 27:3271-3277
Morgan, Andrew P; Holt, J Matthew; McMullan, Rachel C et al. (2016) The Evolutionary Fates of a Large Segmental Duplication in Mouse. Genetics 204:267-85
Chick, Joel M; Munger, Steven C; Simecek, Petr et al. (2016) Defining the consequences of genetic variation on a proteome-wide scale. Nature 534:500-5
Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj et al. (2016) Genetic Architectures of Quantitative Variation in RNA Editing Pathways. Genetics 202:787-98
Morgan, Andrew P; Didion, John P; Doran, Anthony G et al. (2016) Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers. G3 (Bethesda) 6:4211-4216
Tyler, Anna L; Donahue, Leah Rae; Churchill, Gary A et al. (2016) Weak Epistasis Generally Stabilizes Phenotypes in a Mouse Intercross. PLoS Genet 12:e1005805
Parvanov, Emil D; Tian, Hui; Billings, Timothy et al. (2016) PRDM9 interactions with other proteins provide a link between recombination hotspots and the chromosomal axis in meiosis. Mol Biol Cell :
Walker, Michael; Billings, Timothy; Baker, Christopher L et al. (2015) Affinity-seq detects genome-wide PRDM9 binding sites and reveals the impact of prior chromatin modifications on mammalian recombination hotspot usage. Epigenetics Chromatin 8:31
Bogue, Molly A; Churchill, Gary A; Chesler, Elissa J (2015) Collaborative Cross and Diversity Outbred data resources in the Mouse Phenome Database. Mamm Genome 26:511-20

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