Project Reference: TRG27-SAN-AN1

Project title: Determinants of somatic evolution and tissue resilience in the human oesophagus

Project outline

Cells in the epithelial lining of the human oesophagus acquire somatic mutations and epigenetic alterations throughout life. Despite the resulting mosaic of genetically distinct cell populations (clonal mosaicism), most individuals maintain normal tissue function. This project will determine how genetic background, ageing and chronic tissue stress shape somatic evolution and epithelial resilience. We will study non-neoplastic oesophageal tissue from diverse UK and Brazilian cohorts. Healthy samples, including older donors without oesophageal neoplasia, will define trajectories of preserved tissue health. Oesophageal diseases involving chronic inflammation or altered mechanics will provide perturbations of epithelial homeostasis rather than clinical endpoints. Genome-wide DNA methylation profiling will be combined with deep nanorate sequencing (NanoSeq), an ultra-accurate duplex method for detecting somatic mutations. Spatially preserving approaches will reconstruct epithelial landscapes and clonal relationships, allowing somatic mutations and DNA methylation patterns to be mapped anatomically. Analyses will quantify mutation burdens and signatures, infer clone-size distributions, identify positively selected driver mutations, and investigate whether evolutionary constraints limit somatic clone expansion. Integrative models will determine how these features vary with age, genetic ancestry and tissue environment, and identify DNA methylation patterns associated with clonal expansion and the maintenance of normal oesophageal tissue organisation. Findings will be validated in independent cohorts and, where feasible, using oesophageal epitheloids in vitro. By comparing healthy ageing with challenges to tissue homeostasis, the project will reveal how oesophageal tissue remains functional despite accumulating molecular damage.

Principal Supervisor

Dr Ayesha Noorani

Email address: an11@sanger.ac.uk

Department / Partner Institute: Sanger Institute

Website: https://www.sanger.ac.uk/external_person/noorani-ayesha/

BBSRC strategic theme

Understanding the rules of life