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
The Uses of Selfish DNA
Although the strategy of engineered underdominance might work in some cases, the true Holy Grail of genetic insect control would be a transgene that spreads through a population from only a few individuals. The first indication of the possibility of reaching this goal came from a transposon, or "jumping gene," a type of selfish DNA. The transposon encodes a protein that cuts the transposon DNA free of its place in a chromosome and then reinserts it in another random part of the genome. The cell's own DNA-repair machinery usually mends the hole at the original position by recreating the transposon sequence. At the end of the process, the host cell has two copies of the transposon instead of one. If this gene-hopping occurs in a cell that makes eggs or sperm, then the transposon stacks the odds that it will be passed on to future offspring. If the transposon doubles each generation (assuming for now that it doesn't harm the organism), then it will become increasingly common until all individuals in the population carry one or more copies.
This basic scenario occurred "naturally" in Drosophila melanogaster populations throughout most of the world in the past 60 years. Today, almost any fruit fly collected from an overripe banana, whether in New York City or Nairobi, contains a transposon called the P-element. Yet the descendants of fruit flies isolated in laboratories before 1950 lack this transposon. Scientists do not know the origin of the P-element but do know that it spreads rapidly when introduced into a naive laboratory population.
Several entomologists have noted that "loading" an anti-pathogen gene into a mosquito transposon could eventually confer disease resistance to an entire mosquito population as the transposon jumped from site to site through successive generations—even if the mosquitoes that bore these genes had lower fitness. However, this is not a sure-fire strategy (use of the word "could" instead of "would" in the previous sentence was deliberate). In one experiment with D. melanogaster in the laboratory of Margaret G. Kidwell at the University of Arizona, the transposon spread as predicted through the naive flies, but the loaded marker gene was lost. The investigators concluded that at some point during the experiment, one or more copies of the transposon must have "unloaded" the added gene. The cargo-free transposons seemed to replicate faster than their loaded counterparts and eventually displaced them. Clearly, scientists will need to stabilize the genetic composition of any transposon used for practical goals.
In addition to transposons, molecular biologists are studying several other types of selfish DNA that could spread a desired gene into a mosquito population. One Gates-funded project led by Austin Burt at Imperial College London focuses on a curious DNA sequence called a homing endonuclease gene (HEG). The HEG has the unique ability to copy itself from one chromosome to the identical site on the other chromosome in the pair. It accomplishes this feat by encoding a protein that recognizes the DNA sequences on either side of the HEG. When the protein, called a homing endonuclease, spots the same DNA pattern on the twin, or homologous, chromosome, it snips that sequence in two. The cell mends this double-strand break by using the HEG-containing chromosome as a template for patching the cut DNA. This repair incorporates the entire HEG sequence, and the cell becomes homozygous for the HEG. If the process of DNA cutting and repair happens in a cell that later forms sperm or eggs, then it's possible that nearly 100 percent of the offspring could inherit the HEG. And if the homing endonuclease genes are neither beneficial nor detrimental to the fitness of the organism, then they will eventually spread to the entire population even if they start at a very low frequency. HEGs exist naturally in fungi, plants, bacteria and bacteriophages, but not insects. A major challenge for Burt and his colleagues is to design an HEG that will function in an animal, a goal shared by biomedical scientists looking for a new tool for gene therapy.
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