UNKAGE: understanding the role of conserved UNKnown genes in AGEing

Ageing is the primary risk factor for most diseases, but we are far from a complete knowledge of all its determinants. The fission yeast, Schizosaccharomyces pombe, is a simple model in ageing research, with the chronological lifespan (CLS) of non-dividing cells mimicking the ageing of post-mitotic, quiescent cells in mammals. Recent large-scale screens uncovered novel S. pombe genes affecting the CLS, including those that are conserved from yeast to human but whose functions remain completely unknown. I propose an integrated approach to unravel the roles of conserved unknown genes during proliferation and ageing. I will: 1) identify the genetic interactors of the unknown genes, both during vegetative growth and chronological ageing; 2) experimentally evolve deletion mutants of these genes to identify other mutations that prolong their lifespan; 3) integrate results from Aims 1 and 2 and characterize molecular mechanisms linking unknown genes to ageing. For Aim 1, I will generate all combinations of double-deletion mutants of unknown query genes with all other non-essential genes and measure their colony size and CLS to construct genetic interaction networks relevant to proliferation and ageing, respectively. For Aim 2, I will adaptively evolve a subset of short-lived deletion mutants to select for longer-lived cells. Genome sequencing of the evolved populations will map suppressor mutations that rescue the initial phenotype. For Aim 3, I will perform cellular and proteomic approaches following-up on the results of Aims 1-2. This work will shed light on the role of hitherto unstudied genes that are highly conserved across phylogenetically distant taxa, with the potential to discover novel biological mechanisms controlling ageing. This knowledge will provide a valuable basis to understand conserved ageing-related processes in human cells and may guide future research and the development of measures to delay diseases of ageing.