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Gene-drives and Active Genetics
University of California, San Diego, USA
The genetic process often referred to as meiotic drive is a well-known phenomenon by which a genetic trait of some kind is inherited by progeny of an individual carrying that trait more often than by random chance (e.g., more than 50% of the time for diploid species). Biased inheritance of... read moresex chromosomes - or sex wars -, is a classic example of meiotic drive. Similarly, balanced translocations leading to drive of the more prevalent chromosome, a phenomenon that was proposed in the 1960s by Chris Curtis, could in principle be coupled to a desired genetic trait to spread that trait through a population. The modern concept of gene-drive systems mediated by DNA-repair mechanisms was introduced over a decade ago by Austin Burt who proposed exploiting the self-propagating ability of homing endonuclease genes (HEGs) to eliminate or reduce vector or pest populations of insects (e.g., mosquitoes carrying malarial parasites or viruses such as those causing Dengue fever, Chikungunya, or Zika). HEGs encode nucleases that cleave the genome of an organism at the location where the HEG gene resides. The use of HEGS is highly constrained, however, by the specific site that the HEG nuclease recognizes which for many organisms is not present in their native genomes. The recent advent of programmable endonucleases such as CRISPR-Cas9 offers more general and flexible approaches to creating a new generation of gene-drive systems. These gene editing systems permit drive elements to be integrated virtually anywhere in the host genome, supporting schemes to either immunize organisms against pathogens they might otherwise transmit to humans, or to reduce/eliminate such species from the environment as originally proposed and modelled mathematically for HEGs. In addition, because CRISPR-Cas9 is a two-component system, it is possible to create a variety of configurations of the various "active genetic" elements to produce conditional or reversible gene-drive systems.
In addition to uses for creating gene-drive systems, active genetic elements can also be used to greatly accelerate genetic manipulations in experimental laboratory settings. Applications of active genetics, which bypass typical Mendelian constraints such as independent chromosomal assortment and linkage of neighbouring traits, include assembly of complex genetic combinations of elements and allelic variants in animals and plants to enable a new generation of mammalian models to study human diseases, and aggregation of complex arrays of desired traits such as drought or pest resistance in crops for agriculture.
Associated with the great potential practical impacts of gene-drive systems for combating vector-borne diseases, insect pests and acceleration of new avenues of research by active genetic approaches, there are also important social implications of these new revolutionary technologies. Among the most issues are whether humans should modify the genetic make-up of wild populations to further goals of public health or other endeavors benefiting humanity. Another question is whether adequate control of gene-drive systems can be achieved and what longer term effects the use of such systems might bring about.
Speakers in the HST mini-series "Gene-drives and active genetics" examine each of these topic areas and experimental applications as well as their attendant social and ethical issues. These talks are aimed at a broad audience of research scientists, medical professionals, social scientists, ethicists and members of the engaged lay public to explain the scientific underpinnings of active genetics, to outline the great potential for this technology to advance health and the public good, and to thoughtfully examine the social and ethical implications of implementing these applications.