The effect of gene loss and the underlying genetic architecture on evolvability

Loss of gene function is surprisingly common throughout evolution, even though it often leads to lower fitness. Humans for example each carry about 100 loss-of-function variants, some of which underlie severe genetic disorders. Even though it is known that loss-of-function mutations can offer a quick evolutionary advantage during adaptation, it remains unclear how losing a gene influences evolutionary parameters such as the speed of adaptation (~adaptability) or the variability in the outcome of evolution. Additionally, it remains unclear if and how crucial architectural features of an organism's genetic network, such as modularity and connectivity, influence the adaptive process after gene loss. In this thesis, experimental evolution of budding yeast (Saccharomyces cerevisiae) was used to systematically explore the influence of genetic architecture on adaptation after gene loss and evaluate how gene loss affects evolvability. I systematically evaluated how yeast strains adapt after losing genes that are important for growth under oxidative stress, a trait involved in many disease phenotypes. By evolving, sequencing, and phenotyping over 200 yeast lineages, I found that gene loss can enhance an organism's capacity to evolve and adapt. Although gene loss often led to an immediate decrease in fitness, many mutants rapidly acquired suppressor mutations that restored fitness. Depending on the strain's genotype, some ultimately even attained higher fitness levels than similarly adapted wild-type cells. Further, cells with deletions in different modules of the genetic network followed distinct and predictable mutational trajectories. Finally, losing highly connected genes increased evolvability by facilitating the emergence of a more diverse array of phenotypes after adaptation. Together, these findings show that loss of specific parts of a genetic network can facilitate adaptation by opening alternative evolutionary paths.

Jaar van publicatie:2021

Toegankelijkheid:Open