Despite the broad notoriety of sharks, snakes, scorpions and other formidable creatures, mosquitoes remain the deadliest animal on the planet… by far. Mosquito-transmitted malaria remains the number one worldwide killer among vector-borne diseases, claiming more than 400,000 human lives in 2019.
In order to engineer advanced forms of defense against malaria transmission, including targeted CRISPR and gene drive-based strategies, scientists require intricate knowledge of the genomes of vector mosquitoes.
Mahul Chakraborty—a project scientist at the University of California, Irvine, working with colleagues at the Tata Institute for Genetics and Society (TIGS) at UC San Diego and India, and the Institute of Bioinformatics and Applied Biotechnology in Bangalore, India—has produced a groundbreaking new reference genome for the Asian malaria vector mosquito Anopheles stephensi. Full details of the genome, which the scientists say is now on par with the best animal genomes available to science (humans and fruit flies), are published in the journal BMC Biology.
“Anopheles stephensi is a major malaria vector mosquito in urban areas of South Asia and has recently invaded the horn of Africa. It is predicted to become a major urban malaria vector in Africa, putting 126 million urban Africans at risk,” said paper coauthor Ethan Bier, a UC San Diego distinguished professor of cell and developmental biology and science director for TIGS-UC San Diego. “The new genome assembly is a comprehensive and accurate map of genomic functional elements and will serve as a foundation for the new age of active genetics in An. stephensi. This smoothly knit collaborative effort highlights the benefits and value of multi-UC initiatives.”
With the newly upgraded Anopheles stephensi genome, Chakraborty and colleagues unearthed more than 3,000 genes that previously evaded scrutiny. The newly revealed genes, which offer fresh gene-drive targets, play key roles in blood feeding and the metabolism of ingested blood meal, reproduction and immunity against microbial parasites.
The discoveries include 29 formerly undetected genes that play crucial roles in resistance to chemical insecticides, a development that lends itself to the urgency of addressing growing Asian and African An. stephensi populations with insecticide-resistant mutations. The findings also offer clues suggesting that the molecular basis of insecticide resistance may differ between sexes.
“This work will aid in basic studies of genome evolution and inform strategies aimed at eliminating one of the world’s long-time disease scourges,” said paper coauthor J.J. Emerson, an associate professor of ecology & evolutionary biology at UCI. “Collectively, these results and resources underscore the significance of previously hidden genomic elements in the biology of malaria mosquitoes and will accelerate development of genetic control strategies of malaria transmission.”
The researchers also reconstructed—much more so than in the past—the complex, previously-recalcitrant DNA sequences of the Y sex chromosome, revealing genes involved in male development and active selfish genetic elements that parasitize the genome only in males. The authors show that previously invisible mobile genetic elements act as an important source of genetic novelty in this species, serving as substrates to create structural variants and providing raw materials for adaptation to chemical insecticides.
“This reference genome and its excellent quality should help malaria biologists in India and the rest of the world, particularly in view of the national goal of malaria elimination in India by 2030,” said TIGS Global Director Suresh Subramani, a distinguished professor in the Division of Biological Sciences at UC San Diego.
The report’s full author list includes: Mahul Chakraborty, Arunachalam Ramaiah, Adriana Adolfi, Paige Halas, Bhagyashree Kaduskar, Luna Thanh Ngo, Suvratha Jayaprasad, Kiran Paul, Saurabh Whadgar, Subhashini Srinivasan, Suresh Subramani, Ethan Bier, Anthony James and J.J. Emerson.
Funding for the research was provided by National Institutes of Health (grants K99GM129411, R01GM123303-1 and R01 GM117321), a Paul G. Allen Frontiers Group Distinguished Investigators Award, TIGS-UC San Diego and TIGS-India.
Note: Bier has equity interest in two companies he co-founded: Synbal Inc. and Agragene, Inc., which may potentially benefit from the research results. He also serves on the Synbal Inc.’s board of directors and scientific advisory board, and on Agragene Inc.’s scientific advisory board.