OFFBEAT: roles of unstudied genes in cellular quiescence and aging

Biological researchers concentrate their efforts on studying genes that are already known and function in established processes. While this focus on model genes is rewarding, we must also study genes whose functions remain uncharacterized. Progress with such unknown genes is astonishingly slow even in well-studied model organisms, presenting a limitation and challenge for research. We need to know what all parts do to fully understand how cells work.

I propose a concerted, cohesive effort to investigate the cellular functions of all 135 'priority unstudied' proteins that are widely conserved from fission yeast to humans but have not been directly studied in any organism. Our findings indicate that many of these proteins exert aging-related functions in non-dividing, quiescent cells. We will broadly characterize these unknown proteins in fission yeast by applying multi-dimensional approaches, both unbiased and targeted, including assays for metabolic profiles, genetic interactions, chronological lifespan, and bulk mapping of quantitative trait loci linked to cellular aging.

We will leverage these results with existing phenomics and other large-scale data for functional predictions using machine learning. We will actively disseminate the rich functional information and engage experts for specialized follow-on research. Using our predictions, we will apply targeted experiments in yeast to deeply characterize selected proteins with roles in cellular quiescence and aging, including any novel biological processes.

In complementary analyses, we will study conserved roles of aging-associated proteins in the short-lived turquoise killifish.

This project, OFFBEAT, breaks new ground by devoting resolute efforts to important but hitherto neglected proteins, a key blind spot for biological research. OFFBEAT offers vital groundwork to understand the roles of unknown proteins in quiescent cells and beyond, with the potential for discovering new aging biology.