Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems
Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems
19904B. S. Khatri and A. Burt, bioRxiv, 2021.12.23.473701. 2021-12-23 08:31:18.
Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising strategy to overcome resistance. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. If the fraction of functional end-joining mutants is rare, we show that standing variation dominates, via a qualitatively new phenomenon where weakly deleterious variants significantly amplify the probability of multi-site resistance. This means resistance can be probable even with many target sites in not very large populations. This result has broad application to resistance arising in multi-site evolutionary scenarios including the evolution of vaccine escape mutations in large populations.Competing Interest StatementThe authors have declared no competing interest.
