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Comparing genomes of different species can tell you when new genes evolved
and what they do for their respective hosts. But pinpointing the ancestry of
any given gene is a complex computational task. Now, powerful new software
makes gene "archeology" considerably easier, reports a team of investigators
at Carnegie Mellon University. The scientists, who are making this software
publicly available for the first time, are presenting their findings May
20005, at the RECOMB meeting in Cambridge, Mass by Lauren Ward.

"Our software considers thousands of evolutionary scenarios to obtain the
best guess about when a given gene arose," said Dannie Durand, associate
professor of biological sciences at the Mellon College of Science (MCS) at
Carnegie Mellon. "This software can help scientists use evolutionary clues
to understand what genes do in modern organisms."

For example, using the program, called Notung, investigators now can
identify genes that arose very recently. New genes can appear when one gene
is duplicated and the second copy evolves to take on a different role inside
the cell. In vertebrates, for instance, extra gene copies led to features
like paired appendages. New genes often arise in response to environmental
stresses, such as pesticides or drugs, and they help the organism to fight
back. Over time, gene copies also can be lost.

"You could use this information to plan additional gene studies or suggest
strategies for circumventing drug and pesticide resistance in parasites,"
Durand said. "Other uses could include identifying potential detoxification
enzymes for bioremediation and designing breeding programs that would
enhance pest resistance in cash crops."

Already, Notung is helping to bridge studies of molecular evolution with
laboratory research, according to Durand. Her team has collaborated with a
number of scientists studying different multi-drug resistance (MDR) and
detoxification genes in several species. One of Notung's strengths is its
ability to use information about gene duplications and losses. Until
recently, most researchers created evolutionary trees of different gene
families by comparing gene sequence data alone. These data reflect
small-scale (microevolutionary) events in the form of gene mutations. But
equally important in governing gene evolution are gene duplications and
losses ? considered large-scale (macroevolutionary) events.

Notung is the first to incorporate both sets of events to build a tree,
using a powerful algorithm that finds all possible trees with the fewest
gene losses and duplications.

"Using our method, we can incorporate a broader collection of evidence in
the reconstruction of a gene family tree," Durand said. Notung's user
graphical interface makes it easy for the user to manipulate and interpret
the output. The user interface also allows scientists to analyze trees that
are too big to deal with manually. Durand has used Notung to study gene
trees from families with as many as 350 member genes.

Through a series of steps, users can rearrange a massive gene tree with
hundreds of branches and no apparent structure so that it becomes a highly
organized tree with a distinct root and a clear, concise history of
duplications. (See illustration.) "These parsimonious trees give us the
simplest possible explanations for how a gene evolved, and simpler is
usually better," Durand said.

Durand is collaborating with a team at the University of Puerto Rico in
searching for MDR genes that confer drug resistance in malarial parasites.
The same genes confer pesticide resistance in plants. Durand's team used
Notung to find separate clusters of very old MDR genes and more recent MDR
genes, suggesting that the latter MDR genes may have arisen in response to
environmental selection.

In another initiative, she is working with investigators at the Pittsburgh
Supercomputing Center in studies of glutathione S transferases. Some members
of this superfamily of detoxification enzymes are thought to protect us from
PCBs and other pollutants. By combining ecological and biochemical data with
these analyses, molecular evolutionists could identify duplicated genes that
are potential sites of rapid change in response to environmental forces. And
identifying these genes would be the first step in developing targeted
therapies designed to thwart pesticide or drug resistance, according to
Durand.

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MCS maintains innovative research and educational programs in biological
sciences, chemistry, physics, mathematics and several interdisciplinary
areas. For more information, visit www.cmu.edu/mcs.

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