CRISPR Gene Drive Dynamics

Gene Drives

Gene drives are genetic systems that bias inheritance, spreading through populations even when they impose fitness costs. CRISPR-Cas9 homing drives work by converting heterozygotes (w/d) into drive homozygotes (d/d) during reproduction, creating super-Mendelian inheritance.

Homing Mechanism

In the germline of a w/d heterozygote, the Cas9 enzyme (encoded on the drive allele) cuts the wild-type chromosome at the target site. When the cell repairs this break using the drive allele as a template, the wild-type allele is converted to a drive allele. With efficiency e, this converts w/d individuals into d/d before gamete formation.

• Genotypes: Wild-type (w/w), heterozygote (w/d), drive homozygote (d/d)
• Fitness: Relative fitness 1, 1-hs, 1-s (where h is dominance coefficient)
• Homing: w/d → d/d conversion with efficiency e (0 to 1)
• Inheritance: Without homing (e=0), drives follow Mendelian rules. With perfect homing (e=1), all offspring of w/d × w/w matings are w/d instead of 50% w/w, 50% w/d.

Invasion Threshold

Unlike purely deleterious mutations, gene drives can invade populations from low frequency if their transmission advantage exceeds their fitness cost. The invasion threshold depends on both homing efficiency (e) and selection coefficient (s). Low-threshold drives (high e, low s) can spread from a single introduced individual.

Applications

• Malaria control: Drives targeting mosquito fertility or Plasmodium susceptibility genes could reduce disease transmission.
• Invasive species: Population suppression drives could control rodents, carp, or other invasive organisms.
• Agricultural pests: Drives could spread pesticide resistance or reduce crop damage.
• Conservation: Immunization drives could protect endangered species from pathogens.

Dynamics

The time series shows genotype frequencies over generations. Low-threshold drives show rapid spread, while high-threshold drives require sustained releases. The phase diagram plots drive frequency versus fitness cost, revealing stable equilibria and invasion boundaries. The threshold curve shows the minimum initial frequency needed for invasion as a function of drive parameters.

Caveats and Concerns

• Resistance alleles can evolve, preventing homing and halting drive spread.
• Drives can spread across species boundaries through hybridization.
• Ecological consequences of population suppression or modification are uncertain.
• Containment strategies (e.g., split drives, daisy chains) may reduce risks.