The Genetics of Human Immune Response
Jimmie Ye, University of California, San Francisco
Interactions between genetic and environmental factors (GXE) are critical drivers of complex human diseases, but little is typically known about the mechanisms by which genetic variants affect specific responses to disease triggers. Immune responses, driven by interactions between immune cells and pathogens, offer a unique opportunity to systematically dissect this relationship. Here, we integrate principles of population genetics, functional genomic profiling and statistical genetic modeling to determine the effect of genetic variants on immune function. We isolated innate and adaptive immune cell types from over 500 healthy donors representing three ethnicities in the Boston metropolitan area over the course of three years. To assess the function of these cell types, we stimulated cells in vitro with ligands known to induce responses and measured gene expression using high throughput genomic approaches. When combined with a high density map of the genetic variation in this cohort, we designed computational strategies to identify genetic variants associated with gene expression response. Using our integrative analyses, we identified genomic regions associated with expression response, predicted single nucleotide polymorphisms causal for the observed association, and validated our predictions with extensive directed mutagenesis and biochemical assays. We also leveraged recently developed genome engineering techniques to modify a single base in the human genome predicted to affect immune response to flu infection and observed the expected outcome. This to our knowledge, represents one of the first experiments to unequivocally establish causality between a genetic variant and a molecular phenotype in humans. Finally, a number of genomic regions associated with variability in immune response are also near regions previously associated with autoimmune and infectious diseases, suggesting a contribution of these molecular events to disease processes. We demonstrated that gene-by-environment interactions are widespread in the human immune system, identified several variants affecting pathogen-sensing and their underlying molecular mechanisms, and charted a map annotating the function of hundreds of common genetic variants known to alter susceptibility to infectious and autoimmune diseases.