Results affect malaria research
Andrew Thagard
News Writer
A sequence of 260 million letters, consisting of only A, T, C and G specifically arranged that's what Notre Dame's Center for Tropical Disease Research and Training Director Frank Collins and his fellow researchers have to show for over two years of work.
This sequence, however, isn't a random assortment of letters. It represents the genome of Anopheles gambiae, the primary mosquito species responsible for transmitting the malaria parasite to humans. It is the second insect genome to be sequenced ever.
Collins and a team of researchers, including scientists at Celera Genomics presented their findings earlier this week at a Washington D.C. press conference sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the organization that provided the bulk of the funding for this endeavor, and in a series of articles featured in the journal "Science."
Getting started
Sequencing the mosquito genome involved a combination of preliminary research, laboratory work, computerized sequencing machines and gene placement.
According to Collins, researchers raised a laboratory population of genetically similar insects, ground them up, extracted and amplified the DNA and used machines housed in Celera to do the actual sequencing using human derived algorithms.
"I would say it [the sequencing process] is really tedious," said Nora Besansky, Associate Professor of Biology and fellow researcher at the Center. "It's what you do with it [the genome] afterward that's fascinating. Just determining the order of four nucleotides isn't very interesting; in fact it's mind-bogglingly boring. It's deciphering the code and figuring out what it means that's going to be interesting and that's going to take years."
The machines, however, do "shotgun" sequencing, printing out sequences of DNA segments in the order that they're processed. It was up to researchers like Maureen Hillenmeyer, a 2002 Notre Dame graduate and assistant to Collins at the Center, to put the sequences together using bioinformatics, a computational technique.
"Our lab was involved in assembling 50 to 100 scaffolds in the right order," she said.
In fact, the results presented by Collins and other researchers are just a rough draft of the mosquito's genome. Scientists have to analyze and present the information in a computerized database complete with interpretative information before it can be truly used by the scientific community.
"[The genome] has got gaps and interpretations of what are supposed to be genes based on software, not on biological experimentation," Collins said. "There's going to be a continuing effort
of `finishing' and some additional experiments to validate the data."
From the start, the project has been a massive collaborative effort between scientists and laboratories around the world and when the genome is presented in database format it will be available to anyone interested in doing additional research.
Assessing the implications
The mapping of the mosquito's genome, according to Besansky, completes the genome sequencing of organisms involved in the malaria cycle. The disease, prominent in sub-Saharan Africa, is caused by the parasite Plasmodium falciparum which first resides in mosquito and then human hosts.
Scientists recently sequenced the human genome and researchers presented the 23 million base pair sequence of the malaria parasite at a press conference this week.
"This is a big milestone," Besansky said. "We've sequenced the genome. All of these bits of data were integrated to give a product that is biologically real. It will enable us to locate genes of interest that affect specific biological phenomena."
"Now everyone interested in working on this mosquito is bumped so far ahead of where they were," Collins added. "It's going to speed up research."
Knowing the genomes of the parasite and two hosts involved in the spread of malaria allows scientists to better understand the disease and pursue more specific preventative and treatment techniques.
Researchers, for example, can use the parasite genome to assess vaccines and drugs used to combat malaria, and knowledge of the mosquito genome will aid in the development of better insecticides and possibly the creation and release of competing mosquitoes that are genetically engineered not to carry the disease-spreading parasite.
Work at Notre Dame
Already, researchers at Notre Dame's Center have studied proteins found on the mosquito and compared the gambiae to that of another malaria-transmitting mosquito, Anopheles funestus.
Notre Dame Biology major Andrew Serazin and Besansky have published an article in "Science" to supplement Collins' article that compares the two mosquitoes' genetic information. The article concludes that although the insects are only separated by five million years a relatively short time in evolutionary history there are significant differences in their genomes, suggesting that different methods need to be used to combat the spread of malaria from these two vectors.
"The hope was that the map for gambiae would also work for funestus," Besansky said. "It doesn't. The order of genes between the mosquitoes has been so scrambled [over evolutionary history] that you cannot predict the locations of sequences on one using the other with any degree of accuracy."
Cate Hill, another undergraduate involved with the Center, contributed to a study of transmembrane proteins that may serve as possible targets for new insecticides.
Besansky, however, warned that seeing today's research applied directly in nature will not occur overnight.
"From the point of view of technology, there's already something out there that works pretty well in the lab," she said. "Maybe 10 years from now we might be prepared to do some release."
Down the road
Helping to sequence the gambiae genome is just one of many research projects currently taking place at the Center, a facility that the Notre Dame community is largely unaware of.
"It's pretty cool," Serazin said. "We do have a renowned center for vector biology. It [the results] can definitely transfer into some public health measures. It's an outgrowth of Notre Dame's social justice mission and disease research is definitely involved in that."
David Severson, a professor of biological sciences and a colleague of Collins and Besansky, has just received a grant to map the genome of Aedes aegypti, a mosquito that transmits yellow fever.
"I think it points out that there will be a lot of noteworthy information coming out of this center in the near future," Besansky said.
All News Stories for Friday, October 4, 2002
