10:41am Thursday 24 August 2017

Digging deep into the malaria mosquito genome

* Anopheles gambiae mosquito after a bloodmeal.

Image courtesy of Muhammed Mahdi Karim, Dar es Salaam, Tanzania

And the major perpetrator is the Anopheles gambiae mosquito, which transmits the malaria-causing Plasmodium parasite to its victims when it takes bloodmeals. But not all A. gambiae mosquitoes do so with equal success or even under the same conditions. This is because this mosquito species is branching out genetically, or speciating, creating new populations with very different characteristics.

To the eye, all A. gambiae mosquitoes look the same. But the details within their genomes – their genetic makeup – tell stories of increasing diversity that scientists want to read, in the attempt to understand why different groups of A. gambiae mosquitoes thrive in different environments. To hone in on these differences, researchers at the Broad Institute of MIT and Harvard in collaboration with Imperial College, London have created a new genomic tool to identify the precise genetic differences between groups of A. gambiae mosquitoes. This tool maps single nucleotide polymorphisms (SNPs) – single letter differences in the mosquito’s genome. The researchers have found that by using these so-called SNP arrays they can precisely identify the genomic differences between various groups of A. gambiae mosquitoes. Their work is published in the October 21 online version of Science.

“This is the first high-throughput genotyping tool to study the enormously variable A. gambiae mosquito,” explains co-lead author Daniel Neafsey, a computational biologist in the Broad’s Microbial Genome Analysis and Annotation group who co-developed the technique. By linking particular genetic variations with particular mosquito populations, researchers and public health officials hope to determine exactly what types of mosquitoes they are dealing with in particular geographic areas and ecological settings.

Because of their genetic variability, A. gambiae mosquitoes can transmit the malaria parasite in multiple environments. Researchers and public health officials have found that A. gambiae has diverged into multiple populations that thrive during the rainy season or during the drier season that follows. This adaptation of mosquitoes to varying seasonal conditions has led to longer periods of malaria transmission in some parts of Africa. In some locales, resistance to insecticides has arisen and spread within mosquito populations, frustrating control of malaria vector mosquitoes with insecticides. In other places, Anopheles mosquitoes are splitting into new populations that bite during the daytime, when it is harder to protect people from mosquitoes, compared to traditional populations that bite at night and can be stopped by sleeping under insecticide-treated bednets.

“All of this diversity and more requires more than a generic eradication or vector control plan,” says Neafsey. “You have to know what bug you are dealing with to more effectively combat such an efficient disease carrier.” Neafsey has made his career at the Broad centered on the understanding the transmission of malaria to humans.

Along with co-first author Mara Lawniczak of Imperial College London, Neafsey identified the SNPs using sequences from multiple A. gambiae strains. They placed the SNPs on an array creating a high-throughput genotyping tool. Says Neafsey, “We are catching speciation right in the process and we are seeing effectively a chimeric structure in the genome where some parts are totally isolated and some parts are not.” This explains why some genes are prevented from flowing freely between groups of mosquitoes, in the process diversifying the A. gambiae species.

The SNP array used for the analysis included 400,000 SNPs found in two predominant species of A. gambiae mosquitoes. “Prior to this, the most widely used tool we had for finding genetic differences between populations included only about 40 potential markers,” says co-author Marc Muskavitch, an associate researcher at the Broad Institute, DeLuca Professor of Biology at Boston College, and Adjunct Professor of Immunology and Infectious Diseases at the Harvard School of Public Health. “With this new tool, we have expanded the assayable marker set 10,000-fold, meaning we now have a much greater power to distinguish population and genetic structure within this mosquito.”

Muskavitch and colleagues reported the first genome assembly for another disease-transmitting mosquito, Culex quinquefasciatus, in an earlier Science paper published on October 1. In a companion paper in the same issue, these researchers described the responses of Culex, Anopheles, and Aedes mosquitoes—the three types of mosquitoes that transmit human illnesses like West Nile Virus, malaria, and Dengue Fever—to disease-causing pathogens like the Plasmodium parasite, viruses and filarial worms, and to bacteria. (Read more about the implications of this work at the BroadMinded blog.)

Going forward, the team hopes this tool will be useful for discovering genes that are critical to preventing the Plasmodium parasite from infecting the mosquito hosts and transmitting disease. Organizations like the Gates Foundation and the Swiss-based Medicines for Malaria Venture are heavily funding new strategies to stop malaria transmission. “But if there are invisible barriers to gene flow in certain places you are not aware of, finding ways to influence disease transmission could be compromised,” says Neafsey. So there is a basic requirement for strategies like this SNP array to understand the barriers and canals through which genes flow within and between different populations.

“This tool may also be useful for discovery of genes that confer insecticide resistance to mosquitoes,” adds Muskavitch. A growing body of evidence suggests resistance may be due to multiple genes of partial effect, rather than single genes with major consequences. The use of this SNP array will provide opportunities to identify critical genetic variation between mosquito populations resistant or sensitive to different insecticides. Armed with this information, researchers hope to better understand how mosquitoes resist insecticides, and generate tools to monitor insecticide resistance in malaria mosquito populations.

Paper(s) cited: 
Neafsey, DE, et al. SNP Genotyping Defines Complex Gene-Flow Boundaries Among African Malaria Vector Mosquitoes. 22 October 2010. Science 33:6003, 514 – 517 DOI: 10.1126/science.1193036.

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