Genomic basis of variation in the transcriptional response to pathogens among primates - PROJECT SUMMARY An organism’s response to environmental perturbations is a complex process that is influenced by the interplay between genetic and environmental factors. However, despite playing a critical role in health and survival, the gene-by-environment interactions (GxE) shaping disease susceptibility remain poorly understood. Understanding the genomic mechanisms underlying GxE is therefore essential for understanding the consequences of genetic variation on genomic function and complex traits. The immune response to infectious agents is a GxE interaction with clear consequences for health and survival. Mounting an appropriate immune response is essential, but substantial genetic variation in immune function exists within and between species. This makes immune responses an ideal system to understand how genetic and environmental variation interact to shape genome function. Specifically, comparative studies leveraging genetic variation within and between species can help reveal the genomic mechanisms for GxE, while also shedding light on the molecular basis for differences in susceptibility to infectious disease. The research questions driving this proposal are: How does genetic variation, both within and between primate species, influence the gene expression response to immunological perturbations? What are the gene regulatory mechanisms that mediate the relationship between gene expression and genetic variation? Which genetic variants are causally connected to variation in the gene expression response? To answer these questions, I will characterize the transcriptomic response to immune stimuli in peripheral blood cells using a powerful, in vitro assay and single-cell sequencing. This project will identify GxE interactions that are cell type, stimuli, and species-specific. I will then profile chromatin accessibility to identify key regulatory elements involved in the response to immune perturbation and use experimental assays to causally link genetic variation to differences in the response. This project is therefore an ambitious, novel integration of functional and population genetic approaches to study how the genome responds to environmental perturbations. At its conclusion, this study will reveal how immune GxE interactions have evolved among primates, improving our understanding of genome function and the genetic basis for complex traits.
