Profiling the landscape of short tandem repeats in human immunity

Abstract

Tandem repeats (TRs) are highly polymorphic repetitive sequences found throughout the human genome. There are over 2 million TR loci, with many playing key roles in regulating gene expression and biological function. Despite their functional importance, our understanding of how TRs regulate gene expression have lagged behind that of other classes of genetic variation due to genotyping uncertainty and computational challenges. This PhD thesis aims to characterise the landscape of TR variation genome-wide and their effect on gene expression in circulating immune cells. Chapter 1 describes the causes and consequences of TR variation and discusses advances in sequencing technology and genotyping tools that enable genome-wide characterisation of TRs. Benchmarking and validation experiments are performed in Chapter 2 to evaluate the performance of short-read TR genotyping tools. Chapter 3 describes whole genome sequencing (WGS) analysis and quality control (QC) of the study cohort as well as QC of the TR genotypes. In Chapter 4, genome-wide single-cell expression quantitative trait TR loci (sc-eTR) discovery is performed using preliminary data from the TenK10K Phase 1 dataset, the largest collection of paired human WGS and single-cell RNA sequencing (scRNA-seq) data generated to date. In Chapter 5, the performance of fine-mapping tools is compared, and functional characterisation of candidate causal sc-eTRs is performed. Using the final dataset of 1,925 individuals from TenK10K Phase 1, Chapter 6 describes a genome-wide atlas of expression-modulating TRs across 28 immune cell types, including epigenetic characterisation and downstream fine-mapping and functional characterisation. Finally, Chapter 7 summarises the findings of the thesis and discusses future directions.

The discovery of immune cell type-specific sc-eTRs opens new avenues for understanding the genetic drivers of gene expression, immune function, and disease.