Evolutionary dynamics of CRISPR gene drives

Abstract

The alteration of wild populations has been discussed as a solution to a number of humanity’s most pressing ecological and public health problems. Enabled by the recent revolution in genome editing, CRISPR gene drive systems—selfish genetic elements that can be engineered to spread through populations even if they confer no advantage to their host organism—are rapidly emerging as a promising approach. However, before real-world applications are considered, it is imperative to develop a clear understanding of the potential outcomes of drive release in nature. Toward this aim, in this dissertation, I mathematically study the evolutionary dynamics of CRISPR gene drive systems. In the first chapter, I demonstrate that the emergence of drive-resistant alleles could present a major challenge to existing proof-of principle constructs, and I show that an alternative design that selects against resistant alleles could potentially improve evolutionary stability. In the second chapter, I address the question of how likely it might be for a small accidental or unauthorized release of existing CRISPR gene drive organisms to result in significant spread through a wild population—despite the problem of resistance. The mathematical results in this chapter suggest that significant spread is highly likely following even small releases, and this has important implications for laboratory containment protocols and future design of field trials. Finally, in the third chapter, I study the dynamics of a new CRISPR-based gene drive system called “daisy-chain gene drive,” which aims to address the issue of accidental spread discussed in the previous chapter. The results suggest that daisy-chain gene drive constructs could act as “self-limiting” drive systems, with the potential to spread to high frequency in a local population with a comparatively low risk of spreading indefinitely through many linked populations.