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
Strain Replacement
The idea of designing a gene that actively spreads through a pest population without conveying some fitness advantage is not new. A Soviet geneticist, Alexander S. Serebrovskii of Moscow University, and a British biologist, Frederic L. Vanderplank of the Tanganyika (Tanzania) Research Department, sowedthe intellectual seeds for this approach in the 1940s. The two men realized independently that in certain circumstances, competition between two interbreeding insect strains doesn't favor the fitter group. This dynamic involves the genetic property that scientists call underdominance, which can actually cause the strain with greater fitness to die out.
To explain underdominance, it's helpful first to know the terms dominant and recessive, which describe the inheritance of traits. Consider a case with two purebred parents from different, interbreeding strains: Many features of their offspring will favor one parent or the other. For example, suppose that parent A comes from a strain that produces 100 eggs and parent B comes from one that produces 50 eggs. If the offspring from the mating of A and B each generate 95 eggs, a biologist would typically say that the high-egg-production trait was dominant. If, instead, the offspring laid only 55 eggs, then a biologist would classify the trait as recessive. But if offspring from the A x B mating produced fewer eggs than either parent (here, fewer than 50), then egg production would be considered underdominant. In most crosses between strains, traits do not show underdominance, but sometimes a mating between distantly related strains yields offspring that don't survive or reproduce as well as either parent. (In other words, those offspring have a lower evolutionary fitness.)
Still, the idea that the less-fit strain B could outcompete the more-fit strain A doesn't seem to make sense according to basic Darwinian theory. But Vanderplank, Serebrovskii and others realized this is exactly what happens when two conditions are met: when the offspring of a mating are less fit than either parent (underdominance), and when the less-fit parental strain is more abundant. Under these conditions, adults of the less common strain A are more likely to find and mate with adults from the more common strain B, thereby producing less-fit offspring. For example, if strain A makes up 20 percent of the insects in a certain habitat and strain B makes up 80 percent, then (all else being equal) four out of five individuals from strain A will encounter a mate from strain B, but only one out of five individuals from strain B will make a match with a strain A mate. Plugging some numbers into this example: If an A x A cross results in offspring that produce 100 eggs, a B x B cross yields offspring that produce 50 eggs, and (bringing in underdominance) an A x B cross has offspring that produce 20 eggs, then the average egg production by female offspring from the A strain will be (0.80 x 20) + (0.20 x 100) = 36, and the average for strain B offspring would be (0.20 x 20) + (0.80 x 50) = 44. Even though strain A is more fit, strain B produces offspring with higher average fitness. Over time, strain B would replace strain A.
Vanderplank did exactly this experiment in the late 1940s with two sexually compatible species of tsetse flies, the insects that transmit the parasite that causes sleeping sickness. Mating the two species yielded offspring with low fitness. Working in an area that had been abandoned because of disease risk, Vanderplank released high numbers of one species into the habitat where the second was more fit. Over time, the first species outcompeted the second, sending its numbers plummeting. Within two years or so, the introduced species (which was not well adapted to the habitat) had largely died off, leaving the area free of sleeping sickness and enabling local people and cattle to inhabit the region.
Serebrovskii worked out the theory for a type of mutation called a balanced chromosomal translocation, in which a piece of one chromosome breaks off andbecomes attached to another chromosome. Serebrovskii calculated that even less-fit insects with the translocation could replace the wild-type—the normal, nonmutant strain with higher fitness—because some of the grandchildren of the cross between mutant and wild-type parents don't inherit a complete set of chromosomes (a lethal condition). Christopher F. Curtis at the London School of Hygiene & Tropical Medicine later pointed out that if the strain with the translocation carried a desirable gene (such as one that conferred malaria resistance) on the translocated chromosome, then the translocation would also sweep the desirable gene into the population. The scientists needed only to inundate the natural pest population with such a translocation.
Several research teams conducted lab and field-cage experiments in the 1970s to test Serebrovskii's and Curtis's theories. The teams made some progress with the translocation studies, but this line of investigation ultimately failed: Rearranging a mosquito's chromosomes left it unfit to survive in the field. The products of classical genetics proved too crude for the job, and interest in this approach waned.
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