PMC

Expected drive trajectories for ideal drives were simulated in a deterministic model of a single panmictic population with an initial release of drive/wild-type heterozygotes and assuming no fitness costs. a An ideal TARE drive increases in frequency less rapidly than an ideal homing drive. It has similar dynamics to an ideal Medea drive, but with slightly increased speed to fixation since both male and female drive individuals contribute to the disruption and subsequent removal of wild-type alleles. b A TARE drive is expected to show frequency-dependent dynamics, increasing in frequency more rapidly at moderate frequencies than at low frequencies. At high frequencies, however, the rate at which wild-type individuals are removed is slowed. Nevertheless, the drive should rapidly reach all individuals in a population (in the sense that most individuals should carry at least one copy of the drive) with a moderate initial release size. c Invasion threshold frequencies of drive heterozygotes as a function of the fitness cost of the drive in homozygotes. These thresholds represent unstable equilibria above which the drive increases in frequency and below which the drive is removed. With fitness costs, both TARE and Medea drives will not reach fixation, but instead reach an equilibrium frequency as shown, which is the same for both types of drives. Note that all individuals at equilibrium still have at least one copy of the drive allele. d Drive allele frequency dynamics when assuming a drive homozygote fitness equal to 75% that of wild-type individuals, which yields a threshold heterozygote release frequency of 25% (12.5% allele introduction frequency).

(Top) GDSs consist of an endonuclease that cuts a specific region of the chromosome. When those nucleases are engineered into the very site that they cut, a cell that is heterozygous for the drive allele will experience a cut on the opposite, wild-type chromosome. The cell will repair the cut by copying from the intact (drive-bearing) chromosome, converting the former heterozygote into a homozygote for the drive allele. However, as an alternative to homology-based repair, the cell may use error-prone nonhomologous mechanisms to make a resistant allele that is not susceptible to the endonuclease. It is the very action of the nuclease that increases the likelihood of generating a resistant allele. (Bottom) This doubling of the drive allele in heterozygotes, if invariant and not deleterious to heterozygotes, provides a powerful evolutionary advantage. Clear individuals are wild-type homozygotes, light blue are drive heterozygotes, and gray are drive homozygotes. Introduction of just a few heterozygotes into a purely wild-type population will result in the drive allele sweeping through the population. Even when drive homozygotes die—lethal gene drive—the drive allele sweeps until everyone in the final population carries the drive allele. If the drive operates in both sexes, the final population is entirely homozygous and dead. If the drive operates in just 1 sex, the final population is a state in which half the progeny are heterozygotes, whereas the other half are homozygotes and die. Introduction of resistance alleles, particularly those that are homozygous viable (black), will impede and even reverse the spread of gene drive alleles.

Standard and tethered homing drive comparison. Populations are shown at three different times after drive release. a A standard homing drive has no threshold frequency, and it can spread to a wild-type population after a small release. b A tethered homing drive cannot increase in frequency within a wild-type population since it lacks Cas9 for drive conversion. c A TARE drive can spread after a moderate release, followed by a tethered homing drive after a small release. d A sufficiently small introduction of TARE drive to a population will not allow the TARE drive to spread, which will in turn prevent spread of the tethered homing drive

Drive/wild-type heterozygotes were released into a population of 100,000 individuals at an initial frequency of 1%. The simulation was then conducted for 100 generations using the full model. The displayed results are the average from 20 simulations for each type of drive and number of gRNAs. (A) The maximum drive allele frequency reached at any time in the simulations. Note that the standard drive and gene disruption drive have nearly identical values. (B) Number of generations needed for the drive to reach at least 50% total allele frequency. Note that the suppression drive is only shown in (B). (C) Final frequency of resistance alleles after 100 generations. The displayed values are only for resistance alleles that preserve the function of the target gene. No resistance alleles were present in the standard drive and gene disruption drive when at least four gRNAs were present. (D) Final effector allele frequency in the population after 100 generations. This was the drive allele for most drive types, but for the gene disruption drive, it includes resistance alleles that disrupt the function of the target gene as well.