Genomic evolution of major malaria-transmitting mosquito species uncovered

New research into the genetics of Anopheles funestus (An. funestus), one of the most neglected but prolific malaria-transmitting mosquitoes in Africa, has revealed how this species is evolving in response to malaria control efforts.

Reported today (18 September) in Science, researchers from the Wellcome Sanger Institute together with leading scientists across Africa sequenced hundreds of An. funestus mosquitoes collected throughout the continent to explore the genetic variation in the species, including changes driving its adaptation to control methods.

The results of the study provide a new understanding of An. funestus that can be used to inform further work towards malaria elimination in sub-Saharan Africa.

The mosquito species An. funestus is one of the most widespread in Africa. Females of the species are highly anthropophilic, meaning they are attracted to humans as a source of blood, which they need to develop their eggs. They also have a significantly longer lifespan than other malaria-transmitting mosquito species. An. funestus is also extraordinarily adaptive. For example, in some areas, it has evolved from biting indoors in the evening to biting outdoors during the day, likely in response to the use of mosquito nets. Together, these characteristics make them formidable malaria transmitters in the part of the world where malaria remains most devastating. In 2023 the World Health Organisation African Region reported 569,000 malaria-related deaths.

Having a comprehensive understanding of the genetics of each major malaria-transmitting mosquito species is essential for implementing effective malaria control and preventing deaths.

To support this, mosquito biologists across Africa together with the team at the Sanger Institute collected and sequenced the whole genomes of 656 modern An. funestus mosquito specimens that were collected from 2014 to 2018. They also sequenced 45 historic specimens from the Natural History Museum in London and the IRD in France that were collected between 1927 and 1967 to understand the evolutionary patterns and changes in the species across 16 African countries and the past century.

The team found high levels of genetic variation in An. funestus across Africa and discovered that samples originating from equatorial countries shared many genetic similarities despite covering a 4,000-kilometre range. This suggests that they likely belong to one large, interconnected population. However, some samples from this region, such as those from North Ghana and South Benin, were isolated and genetically distinct from the interconnected population. This shows some populations mix widely, while others remain separate. Such population structure has important implications for mosquito control.

By looking at the DNA of the historic samples, the team was able to highlight the fast-evolving nature of An. funestus. One key mutation linked to insecticide resistance, which is widespread among the modern populations, was already present in the mosquitoes from the 1960s. However, other mutations that make mosquitoes resistant were absent from the historic mosquitoes, suggesting that these became beneficial for the mosquitoes only later, as different insecticides were used in subsequent decades.

New biological tools are being used to combat malaria, such as the use of gene drive. The team discovered that a key target for gene drive in An. gambiae – another major malaria-transmitting mosquito species – is very similar in An. funestus. This is encouraging as it suggests that the doublesex gene drive system developed for An. gambiae can be adapted to work in An. funestus as well.

This study describes how the genetics of An. funestus should inform future research and surveillance strategies that aim to reduce the spread of malaria. The data from this study has also been incorporated into the MalariaGEN Vector Observatory that hosts DNA data from multiple Anopheles species alongside tools for researchers to use in order to analyse data.

Dr Marilou Boddé, first author and Postdoctoral Fellow formerly at the Wellcome Sanger Institute and now at Institut Pasteur de Madagascar and LIB Bonn, Germany, said: “An. funestus is genetically complex and evolving fast under pressure from insecticide use. This work is progress in generating a foundational genomic understanding of An. funestus. The insights from this study are crucial for designing future tools that need to work across entire continents for the benefit of those living in countries affected by malaria."

Erica McAlister, Senior Curator at the Natural History Museum, said, "The Museum’s collection has been vital for developing methods and providing answers. When asked about why we still develop collections, these sorts of studies remind us that we often just don’t know what we can ask of from our specimens. We need to ensure that the collections are looked after and enhanced ready for whichever high-impact question might come next."

Professor Charles Wondji, from the Liverpool School of Tropical Medicine and based at the Centre for Research in Infectious Diseases in Cameroon, said: “For too long An. funestus has been neglected despite its key role in malaria transmission across Africa. I am thus delighted that this continent-wide whole genome study of the genetic structure of An. funestus is now published. My team is proud to have contributed to this major milestone that will facilitate the implementation of future control interventions against this major vector.”

Dr Mara Lawniczak, senior author and Senior Group Leader at the Wellcome Sanger Institute, said: “We find some populations readily sharing variation across the African continent, while others are close neighbours but genetically distinct. This is a challenge for vector control. Even if the Gambiae Complex disappeared today, malaria would still rage through Africa until An. funestus is also effectively targeted. We hope the greater understanding of the high levels of genetic diversity and the complex population structure we uncover here will underpin smarter surveillance and targeted vector control.”

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