driving out insect-borne pathogens

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© 2007 Nature Publishing Group DOI: 10.1038/nrg2112 URLs Entrez Myd88 http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=gene&cm d=Retrieve&dopt=full_ report&list_uids=35956 Bruce Hay’s laboratory: http:// www.its.caltech.edu/~haylab TECHNOLOGY Driving out insect-borne pathogens A potential way to tackle pathogens such as malaria and dengue is to use transgenic insect vectors that are refractory to parasite transmission. However, there is a question mark over whether these modified vectors could successfully infiltrate the wild population. Using the fruitfly as a model, a recent study shows how this could be achieved: the authors have created a transgene that drives its own spread throughout an insect population. To have a chance of taking over a population, transgenic vectors must have a fitness advantage over unmodified insects. Chen and colleagues showed how such an advantage can be generated in a Drosophila melanogaster population. They made a transgene carrying a ‘toxin’ that is expressed specifically in the female germ line, consisting of two microRNAs (miRNAs) that silence Myd88, a gene that is essential for embryonic development. The transgene also includes an ‘antidote’ — a version of Myd88 that is expressed in embryos and is immune to the effects of the miRNAs. The authors confirmed that when a trans- genic female lays eggs, offspring that lack the transgene die as embryos — owing to a lack of Myd88 expression — whereas transgenic offspring survive. The authors generated fly popula- tions that contained the transgene at a 25% allele frequency to test whether it could drive itself throughout the insect population. Flies that lacked the transgene consistently disappeared after 10–12 generations, demonstrat- ing successful population replacement. For a transgenic vector to reduce disease, the gene that encodes the effector function — the means of making the insect refractory to pathogen transmission — would need to be tightly linked to the genes that mediate drive. This would be essential to prevent them from being separated by chromosomal rear- rangements, which would ultimately lead to the loss of the effector gene from the population. The transgene that was used in this study lacks an effector, so the authors instead looked at whether separation of the toxin and antidote could be prevented. This could indeed be achieved, by placing the toxin within an intron of the antidote, in the opposite orientation. When females that were homozygous for this transgene were crossed with males that lacked the transgene, embryonic survival was reduced to about 20% (as compared with the expected 100% survival), perhaps owing to inef- ficient antidote splicing. However, population replacement would still be expected to occur with this transgene, although at a slower rate. There is some way to go before this strategy could be put to use; for example, suitable maternal- and zygote-specific genes and promoters must be identified in mosquitoes to engineer the driver functions. However, this study provides a proof- of-principle that one potentially serious obstacle to such an approach can be overcome. Louisa Flintoft ORIGINAL RESEARCH PAPER Chen, C.-H. et al. A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 29 March 2007 (doi: 10.1126/ science.1138595) FURTHER READING Sinkins, S. P. & Gould, F. Gene drive systems for insect disease vectors. Nature Rev. Genet. 7, 427–435 (2006) WEB SITE Bruce Hay’s laboratory: http://www.its.caltech.edu/~haylab RESEARCH HIGHLIGHTS NATURE REVIEWS | GENETICS VOLUME 8 | MAY 2007

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© 2007 Nature Publishing Group

DOI:10.1038/nrg2112

URLsEntrezMyd88http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=35956

Bruce Hay’s laboratory: http://www.its.caltech.edu/~haylab

T E C H N O LO GY

Driving out insect-borne pathogensA potential way to tackle pathogens such as malaria and dengue is to use transgenic insect vectors that are refractory to parasite transmission. However, there is a question mark over whether these modified vectors could successfully infiltrate the wild population. Using the fruitfly as a model, a recent study shows how this could be achieved: the authors have created a transgene that drives its own spread throughout an insect population.

To have a chance of taking over a population, transgenic vectors must have a fitness advantage over unmodified insects. Chen and colleagues showed how such an advantage can be generated in a Drosophila melanogaster population. They made a transgene carrying a ‘toxin’ that is expressed specifically in the female germ line, consisting of two microRNAs (miRNAs) that silence Myd88, a gene that is essential for embryonic development. The transgene also includes an ‘antidote’

— a version of Myd88 that is expressed in embryos and is immune to the effects of the miRNAs. The authors confirmed that when a trans-genic female lays eggs, offspring that lack the transgene die as embryos — owing to a lack of Myd88 expression — whereas transgenic offspring survive.

The authors generated fly popula-tions that contained the transgene at a 25% allele frequency to test whether it could drive itself throughout the insect population. Flies that lacked the transgene consistently disappeared after 10–12 generations, demonstrat-ing successful population replacement.

For a transgenic vector to reduce disease, the gene that encodes the effector function — the means of making the insect refractory to pathogen transmission — would need to be tightly linked to the genes that mediate drive. This would be essential to prevent them from being separated by chromosomal rear-rangements, which would ultimately

lead to the loss of the effector gene from the population.

The transgene that was used in this study lacks an effector, so the authors instead looked at whether separation of the toxin and antidote could be prevented. This could indeed be achieved, by placing the toxin within an intron of the antidote, in the opposite orientation. When females that were homozygous for this transgene were crossed with males that lacked the transgene, embryonic survival was reduced to about 20% (as compared with the expected 100% survival), perhaps owing to inef-ficient antidote splicing. However, population replacement would still be expected to occur with this transgene, although at a slower rate.

There is some way to go before this strategy could be put to use; for example, suitable maternal- and zygote-specific genes and promoters must be identified in mosquitoes to engineer the driver functions. However, this study provides a proof-of-principle that one potentially serious obstacle to such an approach can be overcome.

Louisa Flintoft

ORIGINAL RESEARCH PAPER Chen, C.-H. et al. A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 29 March 2007 (doi: 10.1126/science.1138595) FURTHER READING Sinkins, S. P. & Gould, F. Gene drive systems for insect disease vectors. Nature Rev. Genet. 7, 427–435 (2006)WEB SITE Bruce Hay’s laboratory: http://www.its.caltech.edu/~haylab

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | GENETICS VOLUME 8 | MAY 2007