Using CRISPR/Cas9 to study and evoke “molecular drive” in insects

“Gene drive” or “Molecular drive” are different names for adaptation of an organism to any changing environment. This topic is obviously very central to gene-environment interactions. Mendel in the 19th century observed consistent patterns of inheritance that corresponded to each descendant receiving one of the two maternal copies of a gene affecting (some given) trait, and one of the two paternal copies of this gene; in the typical scenario of genetic inheritance, both maternal copies of a gene have an equal probability of being inherited, as do both paternal copies. This represents random selection. However, inheritance does not always proceed randomly, and in some cases the odds of a particular copy (allele) of a gene being transmitted to the next generation can be heavily skewed. This is where molecular drive comes into play.

For example, “jumping genes”’, originally proposed by Nobel Laureate Barbara McClintock, are inherited in non-Mendelian pattern. Today, genetic-engineering approaches are being developed to manipulate the inheritance pattern of a gene copy such that it will spread through a population more rapidly than would be expected by normal Mendelian inheritance, generating what is called an “engineered gene drive”, leading to super-Mendelian inheritance. So far, gene drives have been mostly engineered in insects.

Authors [see attached article] describe a method for generating “molecular drive” in mice, indicating that this approach can be used in mammals (including humans?). Engineered molecular drives developed in insects might provide a way to alter mosquito populations

to decrease the probability that they transmit diseases — such as malaria or dengue fever (e.g. a gene drive that affects mosquito fertility could be used to specifically eliminate a species of malaria-transmitting mosquito, allowing its ecological niche to be filled by other mosquito species that do not harbor the malaria-causing parasite). Alternatively, gene drives can be designed to confer widespread, species-specific resistance to infection by this parasite (e.g. by using a gene drive to spread sequences that encode antimalarial antibodies so that mosquitoes are no longer infected by the parasite).

Authors used an active genetic element that encodes a “guide-RNA”, which was embedded in the mouse tyrosinase gene (Tyr), to evaluate (by coat color) whether targeted gene conversion can occur when CRISPR/Cas9 is active in the early embryo or in the developing germline. Although Cas9 efficiently induces double-stranded DNA breaks in the early embryo and male germline, these breaks are not corrected by homology-directed repair. By contrast, Cas9 expression — limited to the female germline — induced double-stranded breaks that are corrected by homology-directed repair, which copies the active genetic element from the donor to the receiver chromosome, and increased its rate of inheritance in the next generation. These data thus demonstrate the feasibility of CRISPR–Cas9-mediated systems that bias inheritance of desired alleles in mice. This technology has the potential to transform the use of rodent models (also cattle? pigs? horses?) in basic and biomedical research. The possiblities are endless…


Nature 7 Feb 2o19; 566: 105­­­-109 & 43-45 [News’N’Views editorial]

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