Context matters:the power of single-cell analyses in identifying context-dependent effects on gene expression in blood immune cells

Abstract

The human immune system is a complex system that we still do not fully understand. No two humans react in the same way to attacks by bacteria, viruses or fungi. Factors such as genetics, the type of pathogen or previous exposure to the pathogen may explain this diversity in response. Single-cell RNA sequencing (scRNA-seq) is a new technique that enables us to study the gene expression of each cell individually, allowing us to study immune diversity in much greater detail. This increased resolution helps us discern how disease-associated genetic variants actually contribute to disease. In this thesis, I studied the relation between disease-associated genetic variants and gene expression levels in the context of different cell types and pathogen exposures in order to gain insight into the working mechanisms of these variants. For many variants we learnt in which cell types and under which pathogen exposures they affect gene expression, and we were even able to identify changes in gene co-expression, suggesting that disease-associated variants change how our genes interact with each other. With the single-cell field being so new, much of my work was showing the feasibility of using scRNA-seq to study the interplay between genetics and gene expression. To set up future research, we created guidelines for these analyses and established a consortium that brings together many major scientists in the field to enable large-scale studies across an even wider variety of contexts. This final work helps inform current and future large-scale scRNA-seq research