New Screening Technique May Speed Hunt For Genes
GAINESVILLE, Fla. — The hunt to find a gene that causes a disease typically costs hundreds of thousands of dollars and requires years of research – and it still may fail to turn up the sought-after culprit, driving the research back to square one.
The result is that while the genes involved in a few inherited diseases such as cystic fibrosis have been identified, many have not. Now, two scientists say they may have found a way to make the search more economical and speed it up.
In an article to appear online in the Proceedings of the National Academy of Sciences next week, scientists from the University of Florida and Purdue University report merging two established genetic-screening techniques to create one that’s better. The new technique narrows the pool of “candidate” genes in a study from thousands of possibilities to fewer than 100 – perhaps as few as 20. Although it remains to be tested, the result should help scientists zero in on target genes in animals such as mice and flies often studied as models for people because of their similar genetic makeup.
“What this does is eliminate a huge number of candidate genes to leave just a handful that we can follow up on,” said Marta Wayne, an evolutionary geneticist and assistant professor of zoology at UF who is one of the two authors of the journal article.
The Human Genome Project and similar efforts have resulted in the identification of many of the genes in people and many animals, such as fruit flies. But scientists still don’t know the function of most of these genes.
The numbers are daunting. Fruit flies have around 14,000 identified genes, while people are estimated to have at least 30,000 genes. So, when hunting the genes responsible for inherited traits, say Alzheimer’s disease or alcoholism, scientists use screening techniques to narrow the field of possibilities. The problem is, current methods reduce the number to about 1,000 genes, forcing scientists to rely on their intuition and experience in order to pick one of them for further study.
“This approach adds an additional quantitative step, giving the scientists options instead of having to rely on subjective information,” said Lauren McIntyre, an assistant professor of agronomy and member of the Computational Genomics Group at Purdue.
Wayne’s research centers on perhaps genetic science’s most classic organism: the fruit fly, Drosophila melanogaster.Female flies of this species have varying numbers of ovarioles — chambers in their ovaries through which eggs pass — based on where their ancestors are from: flies from populations near the equator have fewer ovarioles than flies elsewhere. Wayne wanted to find the genes responsible for this variation, which is significant to her research on fruit flies’ evolution because it relates to the numbers of eggs the flies lay and how quickly they reproduce.
Wayne used a popular screening method, called quantitative trait locus mapping, or QTL, to identify the regions in the fruit fly genome that might contain the genes responsible for the number of ovarioles. QTL, which screens genes for differences in their DNA, reduced the number of candidate genes from the total of 14,000 to around 5,000. The scientists then used a newer method called microarray mapping, which screens genes based on their RNA amounts, to comb this smaller pool of genes for the same types of ovariole-related characteristics that the QTL method identified. RNA, or Ribonucleic acid, is a chemical that plays an important role in cell activities. The result diminished the pool from 5,000 possibilities to between 20 and 50.
“We hypothesize that a gene showing evidence for differences at both the DNA and the RNA level is a reasonable choice for a candidate gene,” McIntyre said.
Sergey Nuzhdin, an associate professor of evolution and ecology at the University of California-Davis, said other scientists saw the need to combine QTL and microarray mapping, but that Wayne and McIntyre were the first to pull it off. “They were able to merge these two emerging disciplines to be able to derive nontrivial conclusions,” he said.
The research required Wayne and the technicians in her laboratory to spend hundreds of hours dissecting thousands of flies. Each dissection involved picking apart a 3-millimeter fly under a microscope using two needles attached to toothpicks. The fly’s ovary is an artichoke-like structure occupying most of itsabdomen. The goal was to count each of the ovary’s average of 15 ovarioles so the researchers could localize where the genes were in the genome.
The next step in the research is to show that the gene or genes among the small pool identified by the merged technique is, in fact, responsible for the number of ovarioles. They are confident the method will work. Assuming they’re correct, it could have wide implications for genetic screening of other so-called model systems, or animal systems, used to identify genes in people.
People and animals share a single common ancestor, Wayne said. As a result, many of their genes are identical, including those genes that cause disease. For example, at least 60 percent of the genes known to causes disease in people – including many types of cancer, Alzheimer’s and Huntington’s disease – are found in flies. This makes flies and other animal systems extremely useful for studying people. By speeding the identification of genes in animals, the Wayne-McIntyre screening method could aid the search in people. Modifications of the screening method also could be used directly in humans. “The important thing is that this method has a real potential to decrease the time and effort required for gene discovery,” Wayne said.