Dr. Robert Anholt,
Dr. Trudy Mackay,
News Services, 919/515-3470
State Geneticists Show Ripple Effects of Gene Mutations
a plane arrives late to an airport, it affects more
than just the frustrated passengers on the tardy plane
– the ripple effects could throw the entire day’s
timetable off schedule.
Similarly, in a new study, North Carolina State University
geneticists have found that changes to genes regulating
olfactory behavior in the fruit fly Drosophila melanogaster,
a popular insect model for genetics, have far greater
implications than previously appreciated.
The study is presented in a paper published in the Sept.
7 online edition of Nature Genetics.
Dr. Robert Anholt, professor of zoology
director of NC State’s Keck Center for Behavioral
Biology and the paper’s lead author, said that
in the study of how genes affect behavior, the days
of thinking about genes in a linear fashion are over.
the past, scientists would make a mutation – or
a change in the genetic information – in a gene,
observe the effect on behavior and say that the particular
gene is essential for a particular behavior,”
he said. “But when you perturb a gene, you do
not just perturb a gene. You create, instead, an effect
like the ripples produced when you throw a pebble into
a pond. We need to think in terms of networks that generate
The study breaks new ground because it enabled the scientists
to quantify the extent of the ripples in the genome
that affect behavior, Anholt said.
In previous studies, the scientists introduced little
pieces of DNA, or transposons, randomly into the genome.
“If the transposons insert in a regulatory region
of a gene, or inside a gene, they disrupt the function
of the gene,” Anholt said.
lab studied olfactory behavior because it can be readily
measured and is essential for survival. The investigators
isolated a series of smell-impaired flies that were
genetically identical but with one particular disrupted
gene, and showed enhanced effects when these genes interacted.
were able to place them into a network of genetic interactions
which provided us with a little view of how genes might
work together to determine behavior. Imagine that you
are putting together pieces of a puzzle and there comes
a moment when you get an inkling of what the final picture
might look like,” Anholt said.
In the study published in Nature Genetics,
the scientists took five genes involved in olfactory
behavior in Drosophila melanogaster, extracted
the RNA from these five lines and compared their transcriptomes,
or all the RNA, of males and females separately. It
was important for this study to use a model organism
that can be highly inbred so that all individuals are
genetically identical. Equally important was the use
of sophisticated statistical analyses applied by study
co-author Dr. Trudy Mackay, William Neal Reynolds professor
of genetics at NC State.
we make a perturbation in one gene by introducing a
transposon, what happens to the rest of the transcriptome?
That’s the question we asked,” Anholt said.
“It turns out that the genomic perturbations arising
from a single insertion are substantial. With this experiment,
we could see how many genes were perturbed when we mutated
one gene, but we could also look at the overlap of the
addition, the researchers were able to identify the
numbers of male- or female-specific genes that were
in what Anholt called the “tour de force”
of the study, the researchers attempted to find whether
genes in the ripples actually affect olfactory behavior.
address the issue, the researchers went to the Drosophila
stock center and its collection of mutants and used
a genetic method, pioneered by Mackay, called quantitative
of the genes within ripples resulting from the smell-impaired
mutations themselves affected olfactory behavior. This
means that the interactions that we see in the transcriptome
mirror the genetic interactions that we see at the behavioral
level. It also shows that this approach is a very good
strategy for large-scale gene discovery for behavior.”
says this approach can be applied to any complex trait
in any animal with a controlled genetic background.
the end, we’re trying to find how subtle variations
in genes affect behavior, and how genetic networks change
in response to the environment and during development
and evolution,” he said.
study was done in collaboration with Syngenta’s
Torrey Mesa Research Institute, and the W.M. Keck Foundation
and the National Institutes of Health supported the
Note to editors: An abstract
of the paper follows.
Genetic Architecture of Odor-Guided Behavior in Drosophila:
Epistasis and the Transcriptome
Authors: Robert R.H. Anholt, Trudy F.C. Mackay,
Christy Dilda, Nalini Kulkarni, Indrani Ganguly, Stephanie
Rollmann, North Carolina State University; Sherman Chang,
Kim Kamdar, Torrey Mesa Research Institute; Juan-Jose
Fanara, University of Buenos Aires
Published: Sept. 7, 2003, in the online version
of Nature Genetics
We combined transcriptional profiling and quantitative
genetic analysis to elucidate the genetic architecture
of olfactory behavior in Drosophila melanogaster.
We applied whole-genome expression analysis to five
coisogenic smell-impaired (smi) mutant lines
and their control. We used analysis of variance to partition
variation in transcript abundance between males and
females and between smi genotypes and to determine
the genotype-by-sex interaction. A total of 666 genes
showed sexual dimorphism in transcript abundance, and
530 genes were coregulated in response to one or more
smi mutations, showing considerable epistasis
at the level of the transcriptome in response to single
mutations. Quantitative complementation tests of mutations
at these coregulated genes with the smi mutations
showed that in most cases (67%) epistatic interactions
for olfactory behavior mirrored epistasis at the level
of transcription, thus identifying new candidate genes
regulating olfactory behavior.