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Dr. Steven Munger
Associate Professor
The Jackson Laboratory
Bar Harbor, ME

The Stories That SNPs Tell: Genetic Diversity as a Tool for Biological Discovery

Abstract: The promise of “Precision Medicine” is to leverage genome sequencing data to tailor treatment strategies to each patient’s specific disease etiology and genetic background. However, enthusiasm for this worthwhile goal is tempered by that growing understanding that most common diseases are highly polygenic and pleiotropic, and many adult-onset diseases likely stem at least in part from insults to cell differentiation and organogenesis in utero.

This genetic and developmental complexity presents a steep challenge and points to the need for animal and cell models to fully dissect the complex molecular hierarchy and temporal dynamics linking genetic lesions to disease. My research program takes advantage of genetically diverse laboratory mice and stem cells, and applies genetic mapping approaches to large, multi-scale genomic datasets to decode how segregating genetic variation perturbs gene regulatory networks to influence ground state pluripotency, cell differentiation trajectories, and adult organ function.

In my seminar, I will present two vignettes that highlight the power of this integrated “systems genetics” approach to reveal new biological insights. First, we profiled quantitative liver transcriptomics and proteomics in a large population of adult outbred mice, and used genetic mapping and mediation analyses to show that most of the genetic variation affecting transcript abundance is buffered at the level of protein abundance by protein-protein interactions and stable binding in protein complexes. Second, we derived embryonic stem cell lines (ESCs) from the same population of mice, and combined multi-omics profiling and genetic mapping to trace well-known but previously uncharacterized strain differences in ESC derivation efficiency and ground state pluripotency to a single nucleotide variant in an enhancer region of the LIF receptor gene. Finally, I will show how we are extending this powerful stem cell panel and systems genetics approaches to the field of developmental toxicology.