Impact of age-relatd clonal haematopoiesis on immune receptor diversity

Supervisors

Objectives

This project aims to understand when and how the adaptive immune system exerts selective pressure on pre-malignant clones during ageing. By analysing large-scale genomic datasets from normal human tissues, we will investigate whether and where immune surveillance shapes the fitness landscape of somatic mutations across the body.

Methodology

The student will analyse large-scale sequencing datasets that capture somatic mutations in normal tissues (“norm-seq” datasets), including blood (e.g. UK Biobank, UKCTOCS) and other tissues from public datasets (e.g. those from Wellcome Sanger Institute studies). Using computational and statistical approaches from population genetics and immunogenomics, they will test for signatures of negative selection associated with immune recognition. The work will involve modelling, bioinformatic analysis, and integration of mutation, expression, and HLA-binding data to infer the timing and strength of immune surveillance across tissues.

Required Skills

Applicants should hold a degree in a scientific discipline with a strong quantitative component (e.g. physics, mathematics, computer science, bioinformatics, or quantitative biology) and have a keen interest in applying these skills to problems in cancer evolution and immunology. Experience with coding (e.g. Python or R) and data analysis will be advantageous.

Expected Results

The project will generate a comparative map of immune surveillance across human tissues and ages, identifying where adaptive immunity influences somatic evolution. The findings are expected to clarify the contexts in which immune selection operates, provide insight into tissue-specific cancer risk, and contribute to the development of early detection strategies.

Planned Secondments

CNRS (Walczak) in year 2 (2 months) to train on modelling of immune repertoires.
FLI (Valenzano) in year 3 (2 weeks) to learn about research on the genetics of ageing on a different model system.
UPF (Díez) in year 3 (2 weeks) to get exposed to research on a molecular virology laboratory.

Enrolment in doctoral programs

The student will be registered for a PhD at the University of Cambridge and based in the Early Cancer Institute.

References

Watson et al. (2020) Science — The evolutionary dynamics and fitness landscape of clonal haematopoiesis
Walkowiak et al. (2024) bioRxiv preprint — No evidence of immunosurveillance in mutation-hotspot driven clonal haematopoiesis
Watson et al. (2024) bioRxiv preprint — Evolutionary dynamics in the decades preceding acute myeloid leukaemia