FEATURE ARTICLE
Genetic Strategies for Controlling Mosquito-Borne Diseases
Engineered genes that block the transmission of malaria and dengue can hitch a ride on selfish DNA and spread into wild populations
Fred Gould, Krisztian Magori, Yunxin Huang
A Two-Transgene Technique
The disinterest didn't last long. Soon after the first successful addition of foreign DNA to the fruit fly Drosophila melanogaster, biologists began to explore the potential for genetic manipulation of pest species. The growing sophistication of molecular biology has enabled them to make genetic changes with much greater precision than before. For example, Stephen Davis and his colleagues at the University of New South Wales in Australia developed a novel idea for a two-transgene system that uses underdominance to spread new genes into a population. They envisioned the creation of two distinct pieces of DNA, or constructs, that were spliced into different chromosomes. Each construct contained an on/off switch and a gene that encodes a biological toxin. The switch was "on" by default. Construct I also carried a gene that turns off the toxin production in construct II, and construct II had a gene that turns off toxin production from construct I. Thus, individuals with both constructs (or neither) survived. Having just one of them was lethal.
In this model, a cross between a wild-type strain and a strain that was homozygous for both constructs (meaning that each construct was present on both halves of a chromosome pair) would yield progeny heterozygous for both constructs. (In other words, they would carry only one copy of construct I and one copy of construct II.) This generation would survive. But many of the second generation would die because they inherited only one of the two constructs (similar to the effect seen in Serebrovskii's translocation model).
This engineered form of underdominance is superior to a translocation because it can enable the transgenes to spread even if the number of mutants released is less than 30 percent of the population (the exact proportion depends on how much of a fitness cost is associated with the transgene). Furthermore, because the engineered strains only differ from native strains by two inserted genes (instead of a full chromosome rearrangement), the transgenics should be more fit under field conditions. And as Curtis noted in the similar case of translocations, an anti-pathogen gene included in the constructs would also spread through the population. Having the anti-pathogen gene on both constructs provides a backup in the event that a random mutation disables one copy.
Theoretically, the chance of success would be even higher—and the number of engineered insects needed even lower—if the mutant strain were homozygous for two independent insertions of construct I and two independent insertions of construct II. Our research team has modeled the effects of different fitness costs and different numbers of transgenes and found that multiple insertions of a construct can be more efficient than a single insertion as long as the cost per insertion is below 10 percent. These models can predict how many lab-bred insects would be needed to eventually saturate a wild population, a number called the critical release size. It's about 15 percent when there are no fitness costs associated with multiple insertions—a tall challenge for molecular biologists. Even releasing enough engineered mosquitoes to make up 15 percent of a local population is a daunting task. When entomologists first used genetics to control pest insects in the late 1950s, they reared the insects in giant factories that could produce millions of bugs per week. These were costly operations. A transgenic mosquito program might be able to use fewer insects by releasing them during a seasonal dip in the population or after spraying pesticide to shrink the mosquito population temporarily.
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