Genome dynamics of tandem repeat expansions in lung disease

About the Project

Project Summary

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease affecting approximately 50 per 100,000 individuals in the UK. Despite recent therapeutic advances, prognosis remains poor, with a median survival of three years and limited treatment options. Genetic studies have revealed several risk loci, yet common genetic variants explain only about 19% of disease heritability. Additional genomic mechanisms, such as tandem repeats (TRs - highly variable DNA regions consisting of repeated short motifs) may account for a greater proportion of the unexplained variation in IPF susceptibility.

TRs are increasingly recognised as important regulators of gene expression, accounting for up to 15% of cis-heritability attributed to common variants. Expansions in TRs are known to underlie over 40 monogenic disorders, including Huntington’s disease, by mechanisms including altered gene regulation and somatic instability. However, their role in complex diseases such as IPF remains poorly understood.

Using genome-wide analyses of whole-genome sequencing data from large biobank cohorts, we have identified four significant TR associations with IPF. Three novel TR expansions were linked to disease susceptibility: within the SLC15A4 gene, near GPATCH2L, and in a non-coding RNA region, while a TR near NEK6 was associated with transplant-free survival. These findings show TR variation affects both IPF risk and clinical outcome.

How do these TRs influence IPF pathogenesis? In this project, you will examine (1) how these TR expansions alters epigenetic patterns, and (2) whether the TRs show somatic mutation or instability across different cell types. To achieve this, you will use bisulfite PCR and sequencing to measure DNA methylation changes surrounding the repeats, integrate Hi-C and RNA-seq data to assess chromatin architecture and gene expression effects, and perform ultra-deep DNA sequencing to detect somatic mutations.

Training Opportunities

This PhD offers broad, hands-on training in experimental and computational genomics. The student will develop expertise in bisulphite PCR and sequencing to study DNA methylation, and in analysing Hi-C and RNA-seq data to explore chromatin structure and gene expression. You will gain experience with ultra-deep sequencing technologies (Oxford Nanopore and Illumina) to detect somatic mutations, and in processing large-scale genomic datasets, including data from the 1000 Genomes Project. The project also provides opportunities for collaboration with the NUCLEUS genomics facility and external sequencing providers.

Outputs.

By integrating genomic, epigenetic, and transcriptomic data, this project will provide new insights into how tandem repeat expansions contribute to IPF development and progression. These insights will be published in international peer-reviewed journals, and the student will have the opportunity to present results at appropriate scientific conferences. This project on understanding the biological mechanisms underlying IPF may reveal novel therapeutic targets, so you will advance our knowledge about how to treat this devastating disease.

Apply at:
https://le.ac.uk/study/research-degrees/research-subjects/genetics

PhD entry requirements:https://le.ac.uk/study/research-degrees/entry-reqs

Supervisor contact details:
Prof Ed Hollox - ejh33@le.ac.uk
Dr Richard Badge - rmb19@le.ac.uk