A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment

TLDR

CRISPR‑based gene drives can spread through wild populations by biasing inheritance above Mendelian 50 % and are proposed for vector‑borne disease control, crop pest management, and ecosystem conservation, yet they raise safety concerns about unintended gene propagation. The authors split the drive into separate Cas9 and gRNA alleles to create a trans‑complementing split‑gene‑drive (tGD) that promotes super‑Mendelian inheritance of the individual transgenes. This dual‑component design permits combinatorial transgene optimization, limits escape risks to controlled windows, and is used to probe inheritance biology, resistant allele formation, maternal effects, and impaired homology on efficiency. Mathematical modeling indicates that tGD spread could enhance current gene‑drive technologies for field population modification.

Abstract

Abstract CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split–gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small–molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.