Inherently confinable split-drive systems in Drosophila.
Gerard TerradasAnna B BuchmanJared B BennettIsaiah ShrinerJohn Macky MarshallOmar S AkbariEthan BierPublished in: Nature communications (2021)
CRISPR-based gene-drive systems, which copy themselves via gene conversion mediated by the homology-directed repair (HDR) pathway, have the potential to revolutionize vector control. However, mutant alleles generated by the competing non-homologous end-joining (NHEJ) pathway, resistant to Cas9 cleavage, can interrupt the spread of gene-drive elements. We hypothesized that drives targeting genes essential for viability or reproduction also carrying recoded sequences that restore endogenous gene functionality should benefit from dominantly-acting maternal clearance of NHEJ alleles combined with recessive Mendelian culling processes. Here, we test split gene-drive (sGD) systems in Drosophila melanogaster that are inserted into essential genes required for viability (rab5, rab11, prosalpha2) or fertility (spo11). In single generation crosses, sGDs copy with variable efficiencies and display sex-biased transmission. In multigenerational cage trials, sGDs follow distinct drive trajectories reflecting their differential tendencies to induce target chromosome damage and/or lethal/sterile mosaic Cas9-dependent phenotypes, leading to inherently confinable drive outcomes.
Keyphrases
- genome wide
- genome wide identification
- copy number
- dna methylation
- genome editing
- genome wide analysis
- type diabetes
- transcription factor
- dna repair
- dna damage
- oxidative stress
- adipose tissue
- pregnant women
- autism spectrum disorder
- metabolic syndrome
- young adults
- skeletal muscle
- climate change
- muscular dystrophy
- pregnancy outcomes