Oxygen‐Directed Laboratory Evolution and Conserved Mechanisms Underlying Hypoxia Tolerance

Abstract

Oxygen is essential for metazoan life on earth. In this work, we have taken advantage of Drosophila melanogaster as a genetic model system to dissect mechanisms of genomic adaptation to extreme oxygen conditions. We conducted a ~15‐year laboratory evolution experiment over >290 generations by chronically exposing multiple fly populations to normal, decreasing, or increasing O2 levels to determine the effect of selection pressure on their genomes, and to understand the mechanisms of adaptation to O2 imbalance. We have obtained Drosophila melanogaster populations and strains that can tolerate and perpetually survive environments containing extremely low (<4%) or high (>90%) level of O2, which are lethal for naïve controls. A time series of whole genome sequencing (WGS) analysis of multiple generations of the Low (L‐O2) and high (H‐O2) populations and normoxia control (N‐populations) demonstrated clear genomic changes along evolution between environments and generations. Furthermore, four genomic regions in the H‐O2 populations and five genomic regions in the L‐O2 populations were identified, which contain selection sweeps generated by selections with low or high oxygen condition. A total of 433 candidate genes and 215 candidate genes were identified in the selection sweeps in the L‐O2 populations and H‐O2 populations, respectively. This suggested a number of evolutionarily conserved mechanisms (e.g., the Notch signaling pathway) that may play a role in regulating adaptation to the extreme oxygen conditions. We believe that these mechanisms have a strong potential to be translated into humans and serve as novel targets for developing therapeutic strategies to prevent and treat hypoxia‐related diseases and oxidative stress‐induced injuries.