Research Focus

The genetic origins of most developmental disorders and diseases are complex and remain poorly understood. Rather than a single deleterious mutation, genetic susceptibility to common diseases is conferred by many variants that individually assert subtle effects but in certain combinations perturb cellular networks sufficiently to bias them to a disordered/diseased state. Classic single-gene experimental approaches fail to elucidate these interactions, but new integrative genomic and genetic approaches from the emerging field of “Systems Genetics” hold considerable promise.

The Munger lab combines experimental and computational methods with advanced mouse mapping populations to solve these complex genetic puzzles.

We examine the natural genetic variation driving individual differences in 1) susceptibility to sex reversal during primary sex determination of the gonad, 2) disease severity in a mouse model of Cornelia de Lange Syndrome, and 3) transcript and protein expression in the adult liver. We apply our genetic and genomics toolkit to predict causal variants and genetic interactions underlying phenotypic variability, validate these predictions at the bench with functional genomics methods, and ultimately seek to extend these results to inform patient diagnosis and treatment.

Highlighted Abstract

The Diversity Outbred (DO) population is a heterogeneous stock derived from the same eight founder strains as the Collaborative Cross (CC) inbred strains. Genetically heterogeneous DO mice display a broad range of phenotypes. Natural levels of heterozygosity provide genetic buffering and, as a result, DO mice are robust and breed well. Genetic mapping analysis in the DO presents new challenges and opportunities. Specialized algorithms are required to reconstruct haplotypes from high-density SNP array data. The eight founder haplotypes can be combined into 36 possible diplotypes, which must be accommodated in QTL mapping analysis. Population structure of the DO must be taken into account here. Estimated allele effects of eight founder haplotypes provide information that is not available in two-parent crosses and can dramatically reduce the number of candidate loci. Allele effects can also distinguish chance colocation of QTL from pleiotropy, which provides a basis for establishing causality in expression QTL studies. We recommended sample sizes of 200-800 mice for QTL mapping studies, larger than for traditional crosses. The CC inbred strains provide a resource for independent validation of DO mapping results. Genetic heterogeneity of the DO can provide a powerful advantage in our ability to generalize conclusions to other genetically diverse populations. Genetic diversity can also help to avoid the pitfall of identifying an idiosyncratic reaction that occurs only in a limited genetic context. Informatics tools and data resources associated with the CC, the DO, and their founder strains are developing rapidly. We anticipate a flood of new results to follow as our community begins to adopt and utilize these new genetic resource populations.

The Munger Lab

Principal Investigator: Steven Munger, Ph.D.

Research Focus

Open Positions

Selected Publications

Highlighted Abstract

Improved methods, expanded capabilities: Analyzing cells one at a time

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Revealing cellular traits, one cell at a time

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A thorough characterization of structural variants in human genomes