| Abstrakt: |
Engineered gene-drive techniques for population modification and/or suppression have the potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Gene-drive systems with low threshold frequencies for invasion, such as homing-based gene drive, require initially few transgenic individuals to spread and are therefore easy to introduce. The self-propelled behavior of such drives presents a double-edged sword, however, as the low threshold can allow transgenic elements to expand beyond a target population. By contrast, systems where a high threshold frequency must be reached before alleles can spread—above a fitness valley—are less susceptible to spillover but require introduction at a high frequency. We model a proposed drive system, called "daisy quorum drive," that transitions over time from a low-threshold daisy-chain system (involving homing-based gene drive such as CRISPR-Cas9) to a high-threshold fitness-valley system (requiring a high frequency—a "quorum"—to spread). The daisy-chain construct temporarily lowers the high thresholds required for spread of the fitness-valley construct, facilitating use in a wide variety of species that are challenging to breed and release in large numbers. Because elements in the daisy chain only drive subsequent elements in the chain and not themselves and also carry deleterious alleles ("drive load"), the daisy chain is expected to exhaust itself, removing all CRISPR elements and leaving only the high-threshold fitness-valley construct, whose spread is more spatially restricted. Developing and analyzing both discrete patch and continuous space models, we explore how various attributes of daisy quorum drive affect the chance of modifying local population characteristics and the risk that transgenic elements expand beyond a target area. We also briefly explore daisy quorum drive when population suppression is the goal. We find that daisy quorum drive can provide a promising bridge between gene-drive and fitness-valley constructs, allowing spread from a low frequency in the short term and better containment in the long term, without requiring repeated introductions or persistence of CRISPR elements. Author summary: Gene drive based on CRISPR-Cas9 technology holds great promise for addressing many pressing environmental and humanitarian problems, ranging from reducing the incidence of disease to protecting species at risk. These potential benefits come with substantial concerns about engineered elements having unintended consequences and expanding beyond targeted populations. We model an alternative, called daisy quorum drive, where CRISPR-Cas9 elements are only present temporarily, as part of a daisy chain that drives a second construct to high frequency but that is counterselected and exhausts over time. This second construct carries out an intended genetic modification but is unfit at low frequencies. Thus, once drive has exhausted, a fitness valley is created where individuals carrying only wildtype alleles or the second construct have high fitness, but crosses between them do not. We show that this "fitness-valley construct", once established by drive, can persist and modify local populations, but its expansion to other populations is inhibited because the fitness-valley construct is unfit at low frequency. This design can be used when it is challenging to breed a species in the large numbers needed to establish a fitness-valley construct, while avoiding the long-term presence of gene drive elements. [ABSTRACT FROM AUTHOR] |
