Background
Older age is a major risk factor for cancers, autoimmune disease, and mortality following infections. Consequently, older people require more care significantly adding to rising healthcare costs worldwide. Finding ways to promote healthy immune ageing will therefore improve quality of life and reduce pressure on healthcare systems.
Key to the pathology of the above diseases are T lymphocytes of the adaptive immune system, either via killing malignant or pathogen-infected cells, secreting paracrine signalling proteins like cytokines, or by dysregulated activation in the case of autoimmunity. Cells acquire somatic mutations throughout life, and memory T lymphocytes which provide durable immunity, accumulate more mutations than naïve T cells [1]. Memory T cells are long lived, and go through multiple rounds of cell division, during the clonal expansion of an immune response, and homeostatically to maintain durable immune memory against pathogens.
Somatic mutations are individually rare but accumulate at a steady rate in the DNA of T cells as a person ages. Pilot data suggests that pro-inflammatory pathways are affected by the number of mutations a person carries in their T cells. However, in healthy people, the different environmental exposures that cause mutations in T cells, and their impact on T cell function and immune ageing, has not been investigated. In tandem, cytotoxic chemotherapy has been shown to induce extensive somatic mutations in haematopoietic cells [2,3], suggesting T cells of cancer patients may be significantly compromised.
Aims
This EastBIO PhD studentship seeks to unravel the role that somatic mutations play in shaping the natural ageing immune system and in patients receiving chemotherapy. The student will leverage unpublished and publicly available single-cell RNA-sequencing data, and newly generated whole genome sequencing data. T cell function will be measured using high-throughput single live-cell fluorescence microscopy. These T cells will be clonally expanded for whole genome sequencing and somatic mutation analysis. In collaboration with the Taylor Lab in Edinburgh, mutational profiles of T cells will be compared between natural ageing and chemotherapy to pinpoint dysregulated T cell activation pathways and the mutagenic mechanisms contributing to ageing immune function decline.
Training outcomes
This studentship provides interdisciplinary training in genomics, bioinformatics, statistical analysis, and immunology through collaboration with the Taylor Lab (Edinburgh).
1. Machado HE, Mitchell E, Øbro NF, Kübler K, Davies M, Leongamornlert D, et al. Diverse mutational landscapes in human lymphocytes. Nature. 2022;608: 724–732. doi:10.1038/s41586-022-05072-7
2. Mitchell E, Pham MH, Clay A, Sanghvi R, Williams N, Pietsch S, et al. The long-term effects of chemotherapy on normal blood cells. Nat Genet. 2025;57: 1684–1694. doi:10.1038/s41588-025-02234-x
3. Uryu H, Saeki K, Haeno H, Kapadia CD, Furudate K, Nangalia J, et al. Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation. Nat Genet. 2025;57: 1695–1707. doi:10.1038/s41588-025-02235-w
BSc (Hons) 2:1 or equivalent
Informal inquiries please contact michael.morgan@abdn.ac.uk. Formal application must be through findAPhD.com: www.findaphd.com/phds/project/eastbio-somatic-mutation-as-drivers-of-ageing-immune-dysfunction/?p191634