Project Reference: TRG27-PAT-HM1

Project title: Comparative somatic evolution in the immune system across species

Project outline

Throughout life, immune cells accumulate mutations, and some of these mutations give a cell a growth or survival advantage, allowing it to expand into a detectable clone. This process of somatic selection is thought to shape immune ageing, contributing to the decline in immune function and the rise in autoimmunity and blood cancers seen with age. While recent studies have revealed a striking amount of mutation and selection in human immune cells, very little is know about selection in the immune cells of other species, and whether the same of different processes are under selection. This project asks whether the rules governing somatic evolution within the immune system are universal or species-specific, and what that can tell us about the biological basis of immune ageing.

To answer this, we will compare the landscape of selection in immune cells across species with contrasting lifespans and life histories. This requires a sequencing approach sensitive enough to detect mutations in cell populations that are highly polyclonal: NanoSeq, a duplex sequencing method with an extremely low error rate. The student will sort T, B, NK and myeloid cell populations from blood, generate exome-wide and targeted duplex sequencing data, and apply statistical driver-detection methods (e.g. dN/dS-based models) to identify genes and pathways under selection in each species. Comparative and phylogenetic analyses will then test whether the same genes are repeatedly selected across species, and whether the strength of selection scales with mutation rate or lifespan.

The project offers training in wet-lab methods (FACS, sequencing), computational biology, evolutionary genetics and immunology, and aims to reveal fundamental drivers of immune ageing, autoimmunity and blood cancer.

Principal Supervisor

Dr Heather Machado

Email address: hem48@cam.ac.uk

Department / Partner Institute: Pathology

Website: https://www.machado-lab.org/

BBSRC strategic theme

Bioscience for an integrated understanding of health