May 14, 2004
Researchers Snare New Cilia Genes
Howard Hughes Medical Institute researchers have used a combination
of brainpower and computer power to identify a multitude of new genes
that control the formation of tiny, hair-like cilia that stipple the
surfaces of many organs in a wide variety of creatures.
The genes are considered important because of the ubiquity of cilia,
which are critical for transport and sensory structures located
throughout the human body — including the brain, nose, ears, eyes,
lung, kidneys and sperm.
“We used two months of computer analysis to discover genes that would have taken seven or eight years of genetic screening to isolate.”
Charles S. Zuker
Led by Howard Hughes Medical Institute investigator Charles S.
Zuker, the researchers reported their findings in the May 14, 2004,
issue of the journal Cell. Zuker and his colleagues at the
University of California, San Diego, collaborated on the studies with a
co-author from the Max Planck Institute of Biochemistry in Germany.
According to Zuker, the cilia genes they identified may prove
important in understanding the causes of genetic diseases involving
cilia. “There have been a number of genetic disorders that
produce very complex syndromes, affecting tissues that appear to be
completely unrelated to each other,” said Zuker. “For
example, there are disorders that affect a person's retinas, kidneys
and lungs. Clinicians have begun to realize that what's common among
these organs is that they all have ciliated cells.
“Now that we have massively expanded the number of candidate
genes that can be examined for mutations in these disorders, it is far
more likely that the culprit gene defects will be identified,” he
said.
The scientists' broad genomic comparison of species was sparked by a
discovery by the paper's first author, Tomer Avidor-Reiss, said Zuker.
“He found that genes he had laboriously isolated in fruit flies
that were responsible for cilia needed for the senses of hearing and
balance were highly conserved in nearly all of the ciliated organisms
for which genomes had been sequenced. But they were absent in every one
that had no cilia. It was a stroke of genius on Tomer's part to propose
that we could perform large-scale comparisons of entire genomes of such
organisms to quickly identify new genes involved in cilia
formation.”
Seeing an opportunity, the researchers chose to compare the genomes
of eight organisms, including those that had retained cilia in their
anatomy and those that had lost the structures during evolution. The
ciliated organisms included human, fruit fly, roundworm, an algae and
the organisms that cause malaria and sleeping sickness. The
non-ciliated organisms were the mustard plant, yeast and an amoeba.
“It was a process that could be called `in silico
subtraction,'” said Zuker of the computer analysis they
performed. “In essence, we screened the genomes in such a way
that those of the non-ciliated organisms could be subtracted from those
of the ciliated ones.” The result, said Zuker, was an array of
genes that included the genes associated with cilia formation.
Using various forms of their computational genomic subtraction
strategy, the researchers identified genes common to all ciliated
organisms, as well as those that are restricted to particular subtypes
of cilia. These subtypes include those that are motile — such as those
found in sperm and lungs — and those of a type called
“compartmentalized” that are key structures in sensory
organs- including the senses of vision, hearing and olfaction. In all,
the researchers identified 187 cilia-related conserved genes from the
over 150,000 genes analyzed.
To confirm that the genes their studies revealed were, indeed,
important to cilia formation, they screened the collection for the
presence of known cilia formation genes. They found that the vast
majority of known genes were contained in those uncovered in their
study.
To demonstrate that new genes discovered by their computational
method actually functioned biologically to construct cilia, the
researchers then concentrated on a set of six compartmentalized genes
known as “outer segment genes,” or OSEGs. Specifically,
they did experiments to prove that these genes were expressed in
sensory neurons in the fruit fly, and that they were necessary for
normal cilia formation in those cells. Zuker and his colleagues also
showed that the proteins produced by the genes function as critical
“cargo carriers” that transport molecules necessary for
cilia formation and function.
Zuker noted that this comparative genomic strategy could
significantly speed gene discovery. “We believe that this
analysis saved us several years of work,” he said. “We used
two months of computer analysis to discover genes that would have taken
seven or eight years of genetic screening to isolate.
“The technique is also quite generalizable,” said
Avidor-Reiss. “All you need is a biological process that is
conserved in the genomes of enough species to be compared, and
selectively lost in others.”
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