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Transposable elements in malaria mosquito genome may offer a tool for control of disease spread

Virginia Tech

(Blacksburg, Va.) -- Malaria, caused by a parasite transmitted by the Anopheles gambiae mosquito, kills more than a million people every year and sickens millions more. The insect is becoming increasingly pesticide resistant. But prevention of the disease through genetic control of the mosquito has become more possible with the completion of the first draft of the genome sequence of A. gambiae by scientists led by Robert Holt of Celera Genomics. The genome is the complete set of genetic material including genes and other segments of DNA in an organism.

More than a hundred researchers in more than a dozen labs contributed to this effort. The sequence was posted in March and a subsequent article in Science analyzes the information and reports important findings ("The Genome Sequence of the Malaria Mosquito Anopheles gambiae," Oct. 4, 2002. Holt and Frank Collins of the University of Notre Dame, corresponding authors,).

Among the co-authors are Virginia Tech researchers Zhijian (Jake) Tu, assistant professor of biochemistry, graduate student Jim Biedler, and postdoctoral associate Hongguang Shao, whose focus is the mobile genetic elements, or transposable elements, which make up more than 16 percent of the genome.

Tu's group is one of several labs involved in characterizing transposable elements (TEs) -- segments of nucleic acids, or genetic material, that move around the genome and have a significant impact on its structure and size. Other labs working on TEs in the malaria mosquito include the groups of Peter Atkinson at the University of California at Riverside, Collins, Christos Louis at IMBB-FORTH, Crete, and David O'Brochta at the University of Maryland. Collins coordinated the efforts on TE analysis.

"If you look at the genome as an ecological system, TEs are different lineages that co-evolve with the rest of the genome" says Tu. "They evolve different relationships with the genome. Some are genetic parasites; they appear to do nothing except replicate within the genome. Others are used by the host -- the individual organism's genetic machinery --to perform biological functions."

Transposable elements were first noticed by Nobel scientist Barbara McClintock in the 1940s, when she observed that sometimes, when wildtype corn mutated, the mutated stock would later appear to revert at high frequency. "She had discovered that the mutation and reversion was caused by segments of the DNA moving in and out of a genetic locus in the genome," says Tu. "Until then, we thought of the genome as static."

Now researchers know that portions of DNA can produce the enzyme to cut itself out of the genome, then paste itself in elsewhere. In addition to this DNA-mediated TE, there is RNA-mediated TE. The RNA-mediated TE makes many RNA counterparts of itself in a process called transcription. The RNA molecules are copied into DNA (reverse transcription), and then integrated back into the genome.

Tu and colleagues expect that TEs may be used to introduce new genes into the mosquito genome -- gene vectors within disease vectors, such as a gene to block transmission of disease into the mosquito, halting the malaria parasites' cycle.

Another use for TEs is as markers, says Tu. "Because they are scattered throughout the genome, they can be used to distinguish between populations of mosquitoes of the same species."

This is important in the current research, using the newly sequenced A. gambiae genome. Within the same species of malaria mosquito, some populations are better carriers of disease and some are more resistant to pesticides. "There is a genetic basis for these differences and these markers can help us determine these differences," says Tu.

Tu's group is working on three types of TEs: non-long terminal repeats (non-LTR), short interspersed repetitive elements (SINEs), and miniature inverted repeat transposable elements (MITEs) within A. gambiae. The non-LTR and SINEs are RNA-TEs. MITEs are DNA-TEs. Using computer programs developed at Virginia Tech and freeware from NCBI, they have discovered new families and characterized them. "We are trying to look at the whole genome and to see how many SINEs, non-LTRs, and MITEs there are, how they are distributed, and how we can use them as genetic tools," says Tu.

Tu's lab is also working on mosquitoes that carry Dengue Fever and Yellow Fever and is starting work on species that carry West Nile virus.

Tu's work on characterization and organization of transposable elements in mosquito genomes has been funded by the National Institutes of Health since his arrival at Virginia Tech in 1999.

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Visit Dr. Tu's lab at: www.biochem.vt.edu/faculty/tu.htm

An article by Tu in the Feb. 13, 2001 Proceedings of the National Academy of Sciences reports the work by Tu's lab on MITEs and the new computer program used to discover diverse families. (www.pnas.org/cgi/doi/10.1073/pnas.041593198)

An article in the November 2001 journal, Genetics (159:1104-1115), by Hongguang Shao and Tu reports on the characterization of a super family DNA TEs in the mosquitoes that carry Dengue Fever and Yellow Fever, and their potential for the genetic manipulation of mosquitoes. (www.genetics.org/cgi/content/full/159/3/1103)

Learn about Barbara McClintock and her research at www.nobel.se/medicine/laureates/1983/

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