MRC Integrative Epidemiology Unit (IEU) Seminar Series

Title: Mapping genetic effects on gene expression at the cellular level: macrophages, neurons and microglia

Abstract: The majority of common human trait associated genetic variation appears to alter gene expression rather than protein structure. Despite substantial progress in mapping expression quantitative trait loci (eQTLs), there are significant gaps in our resources to interrogate the function of human noncoding genetic variation. I will present two related pieces of work from our group. In the first project, I will show how we use in vitro model systems based on human induced pluripotent stem cells from hundreds of individuals to map eQTLs across scores of stimulated cell states, and in “pooled” designs, where cell lines from multiple individuals are grown together and profiled using single cell RNA-seq. Our results demonstrate that, even within a single cell type, there is abundant regulatory variation, with a detectable eQTL for almost every gene in the genome.  In the second project, I will present the first human eQTL map in primary human microglia, a key cell type for Alzheimer’s disease (AD). I will show how profiling these cells using bulk and single cell RNA-seq pinpoint candidate causal genes and variants for a range of AD loci, and how transcriptional heterogeneity in microglia varies between clinical pathologies, brain regions, and cellular states. 

Biography: Daniel Gaffney's research focusses on identifying genetic changes that alter cell phenotypes and functions. His research combines a mixture of computational and experimental techniques to map and characterise genetic variants that alter cellular traits. Daniel earned his PhD in evolutionary genetics from Edinburgh University in 2006 under the supervision of Dr Peter Keightley. His graduate research used computational methods to study variation in the mutation rate and natural selection in noncoding DNA. From 2006 to 2008 he pursued a postdoc with Dr Jacek Majewski in McGill University and Genome Quebec Genome Centre, where he worked on the evolution of transcriptional regulation and alternative splicing in mammals. From 2008 until 2011 he worked on population genetic variation in gene expression and regulation with Dr Jonathan Pritchard at the University of Chicago. In July 2011 Daniel started as a Career Development Fellowship Group Leader at the Wellcome Trust Sanger Institute and was promoted to Group Leader in October 2015. The long-term goal of the group is to understand the molecular and cellular consequences of genetic changes in gene regulatory regions. His research combines statistical genetics with high-throughput experimental techniques in human cells to address these questions. Much of the group's recent research has been focussed on using human induced pluripotent stem cells (hIPSCs) and cells derived from hIPSCs as model systems to map and characterise human noncoding genetic changes.

All welcome