Genetic Design of Biological Time in Fish

ongoing

Every species experiences a unique pace-of-life, which determines the duration of its embryonic development, onset of puberty, and rate of aging. However, how these traits are scaled so differently between species is largely unknown. Here, I propose to develop the tools to systematically study how the pace of life is regulated in vertebrates. To date, progress in our understanding has been experimentally hindered by the relatively long lifespans of classical vertebrate models. To address this challenge, I recently pioneered a genetic platform for rapid exploration of aging in the naturally short-lived turquoise killifish. Killifish species display up to 10-fold differences in their lifespan, thus providing a “microcosm” of extreme life-history adaptations. Here, we will significantly advance the state of the art by transforming selected species into genetic models. Specifically, we will use unbiased chemical screens to explore the molecular switch that allows killifish development to be suspended for years, in a process called diapause. We will then use our findings to establish genetic control of diapause and the aging processes that co-evolved in this clade. Interrogation of the transcriptional networks in play will be made possible by developing a CRISPR screen platform for fish cells. Finally, we will explore the co-regulation of rapid puberty and compressed lifespan in killifish, by developing multiplexed and reversible genetic approaches. Aging is the primary risk factor for many human pathologies. Thus, developing a quantitative and mechanistic understanding of the pace of life could revolutionize the way we manipulate aging, treat related diseases, and even control complex traits. Identifying such new principles will also have a broader impact, such as affecting developmental rates in in-vitro fertilization. Furthermore, providing precision genome editing tools for fish, and accelerating the generation time will greatly impact commercial aquaculture.