Drosophila Genetic Reference Panel bridges genotype-phenotype gap
How long does it take a fruit fly to emerge from a cold-induced coma? How resistant is a fruit fly to starvation? How quickly can a fruit fly settle down after it is startled?
The answer to these complex traits rests with genes, many of them that interact in complicated ways to produce an end result that is a phenotype or outward sign, said an international group of scientists, led by those from North Carolina State University, the Baylor College of Medicine Human Genome Sequencing Center and Campus Universitat Autònoma de Barcelona.
To answer questions about the flies and point the way toward fine-tuning similar human studies, the scientists developed the Drosophila melanogaster Genetic Reference Panel. A report on their work appears in the current issue of the journal Nature.
Quantitative genetic traits
Genome-wide association studies of the three traits – cold tolerance, starvation resistance and startle response – "reveal hundreds of novel candidate genes, highlighting our ignorance of the genetic basis of complex traits," the researchers said in their report.
These "quantitative" genetic traits reflect the contribution of many genes to a different phenotype or outward appearance or behavior. Studies with fruit flies may give clues about how such research should be conducted to researchers who use human genome-wide association studies to look for causes of complicated chronic diseases such as heart problems or cancer.
"Current sequencing capabilities made it possible for us to achieve this tool," said Dr. Stephen Richards, assistant professor in the BCM Human Genome Sequencing Center and an author of the report. The Baylor center did much of the genome sequencing, but the story really started with Dr. Trudy Mackay, professor of genetics at North Carolina State and one of the report's major authors. She began the process by collecting fruit flies from a farmer's market in her home state and from them bred several hundred different kinds (lines) of fruit flies who vary by quantitative phenotypes, both physical and behavioral.
"The big problem is that in many aspects of biology today, from humans to breeding agriculturally important plants and animals to understanding evolution, we need to understand how to predict phenotype (appearance, behavior or other outward characteristic) when we have information on an organism's genotype," said Mackay. "In the world of human genetics, millions of dollars have been spent on genome-wide association studies where we had individuals affected or not with a common disease and 500,000 SNPs (single nucleotide polymorphisms or single letter differences in the genetic code). The community was positive that we would see great fruits from that effort. It was a little surprising to find that we weren't accounting for much variation at all."
That sparked the idea that more information on genetics would be helpful. To start, scientists looked to the classic model organisms – the fruit fly or Drosophila melanogaster.
"Each of our lines of fruit flies is genetically different, but within each line, all the flies are the same. Using them, researchers around the world can look at a favorite complex trait and know they are looking at the same flies. It is a living library of genetic variation in the world's premier model organism," she said.
The report describes results from the development of 168 lines of fruit flies and the measurements related to the three survival-related traits. The amount of data was tremendous, even though the genome of the fruit fly is only one-tenth that of a human.
Some of the findings may lead to new understanding, said Richards.
"The SNPs we found in startle-resistance genes were in genes known to affect glial development in the brain," said Richards. "You can imagine a story where brains differ among fruit flies and some are more reactive than others. We had similar levels of success for starvation resistance and cold tolerance."
Researchers making use of the new tool can get the flies from the stock center and the genome sequences from BCM, he said.
Dr. Antonio Barbadilla, another of the paper's authors and associate professor of genetics and microbiology at the University Autònoma of Barcelona, said, "The most unexpected and significant result if the apparent existence of a threshold for recombination above which the correlation between nucleotide polymorphism and recombination vanishes, indicating the recombination plays a fundamental role in the adaptability of a genomic region."
The fourth major author of this paper is Dr. Eric A Stone, also of North Carolina State. Other BCM authors include Dianhui Zhu, Yi Han, Crystal Bess, Kerstin Petra Blankenburg, Lesley Chaboub, Mehwish Javaid, Joy Christina Jayaseelan, Shalini N. Jhangiani, Fremiet Lara, Sandra L. Lee, Mala Munidasa, Donna Marie Muzny, Lynne Nazareth, Irene Newsham, Lora Perales, Ling-Ling Pu, Carson Qu, Jeffrey G. Reid, Kim C. Worley, Yuan-Qing Wu, Yiming Zhu and Richard A. Gibbs.
Funding for this work came from the National Institutes of Health, the National Human Genome Research Institute, the NVIDIA Foundation and El Ministerio de Ciencia e Innovacion in Spain.