In our first grant period Center researchers laid the groundwork for a new generation of experimental approaches in systems genetics by developing novel genetic resources, high throughput measurement technologies, and new computational approaches to modeling biological systems. In the renewal period, we are capitalizing on these advances to launch an ambitious program to transform the way the laboratory mouse is used in biomedical research.
Novel Mouse Resources
Our previous work provided 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. Derived from the same set of eight progenitor strains, and hence sharing the same allelic compositions, the Collaborative Cross (CC) recombinant inbred strains provide reproducible genomes optimal for multiple testing, while Diversity Outbred (DO) mice provide high genetic mapping resolution. To these we have added additional genetic crosses using the same progenitor strains. Collectively, these mouse populations provide an integrating backbone for connecting multiple levels of genomic function, and for developing and validating predictive models of genetic and environmental effects.
Integrated research projects investigating dynamic processes
The Center’s research activities are built around a core set of experiments that were designed to yield data for analysis and systems-level modeling. The experiments all interrogate the same genetic material (a large, fixed universe of allelic variants) but use different strategies for combining alleles. The allelic variants derive from three different subspecies of mice that have evolved independently, with minimal admixture over the past 0.5 million years. This design allows us to address one of the most perplexing questions in genetics – how do novel phenotypes emerge when diverse genomes are interbred? This question has broad relevance for understanding the emergence of human diseases as well as addressing fundamental properties of genetic inheritance.
In order to lead the field, the Center must address questions about important biological processes that are bold and challenging, but not intractable. We are investigating four broad areas relating to dynamic functions that affect or involve whole genomes. These are epigenetic modification, recombination, gene expression, and metabolism. We are studying these areas to better understand how genetic variation on a genomic scale affects biological outcomes, which we call genome dynamics.