Mack Pilot Project Summary

Gene regulatory variation is known to play an important role in variation in complex traits, but linking regulatory loci to organismal traits remains highly challenging. In this project proposal, we will investigate the gene regulatory basis of a classic complex trait of both ecological and biomedical importance: body mass variation. Utilizing wild-derived mouse strains from divergent climates, we will examine the genetic basis of body size and metabolic adaptation through a novel integration of genetic crosses, sequencing data, and computational approaches.

In Aim 1, we will use allele-specific measures of expression and chromatin activity to characterize the global landscape of cis-regulatory divergence associated with metabolic differentiation. By combining these allele-specific measures with polygenic tests for selection, we expect to be able to identify pathways underlying divergent metabolic phenotypes between mouse strains. We will then use single-cell RNA-seq to identify changes in cell-type-specific gene expression, cell proportions, and to reconstruct gene regulatory networks involved in metabolism. In Aim 2, we will investigate the adaptive significance and genetic basis of gene-by-environment interactions in metabolic variation. The role of environmental variation in metabolic variation will be examined by (1) comparing population-specific responses in metabolic traits and gene expression to food deprivation (i.e., gene-by-environment interactions) and (2) identifying context-specific gene regulatory divergence using F1 hybrids. In summary, this research will identify genes and pathways associated with metabolic and body mass differences, with implications for the genetic basis of human metabolic disorders. This project proposal will produce results that will be used for a future NIH R01 or a MIRA grant. Sequencing for this project will be performed at one of COBRE’s Core Labs, the KU Genome Sequencing Core.