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Dannie Durand is an archaeologist, only she does her digging with a computer
rather than a spade, and she excavates genes instead of ancient artifacts,
July 2005 by Jennifer Bails.

Like species, genes evolve over time. Some chunks of DNA get copied, while
others get trimmed away. Individual molecules within a gene's code are
altered.

By analyzing those changes, scientists can trace back a gene's chronology
and map it on the twigs and branches of an evolutionary tree.

Thousands of possible scenarios must be considered to pinpoint the ancestry
of a single gene. Durand, a biology and computer science professor at
Carnegie Mellon University since 2000, has designed a new software tool
called "Notung" to make it faster and easier to dig through the molecular
ruins -- a nascent field known as genetic archaeology.

Last week at the Intelligent Systems for Molecular Biology conference in
Detroit, she demonstrated how her computer program could help researchers
use evolutionary clues to understand what genes do in modern-day organisms.

"Notung is a general tool relevant to a broad range of questions about
evolution, questions about where new genes come from and how they make us
what we are," Durand said. "There is endless amazement in that."

Durand is collaborating with a team of researchers at the University of
Puerto Rico to use Notung to track the history of genes that cause malarial
parasites to become drug-resistant. Finding the genes that appeared most
recently in response to overuse of anti-malarial drugs could help scientists
develop medications to circumvent that resistance.

Similarly, Notung could be used to figure out how weeds evolve to withstand
pesticides or how to enhance pest resistance in cash crops genetically,
Durand said.

Durand is a computer scientist by training who became interested in biology
about a decade ago while attending workshops about evolution and genetics at
Rutgers University in New Jersey.

"I became hooked," said Durand, who now considers herself a computational
molecular biologist, a blend of both fields.

She began working on the Notung program about five years ago, and it became
publicly available on the Internet for the first time this spring.

Notung, a German word meaning "needful," is the name of the magical sword
pulled from an ash tree in the opera "Die Walkure," part of Richard Wagner's
"Ring" cycle. Two members of Durand's research group were opera buffs.

Indeed, the user-friendly software can seem magical at times. Durand can
sift through volumes of complicated DNA sequence information to come up with
a best "guesstimate" of how genes might have evolved over time.

New genes can appear through a process called gene duplication, much like
making a photocopy. The second copy then mutates to take on new roles inside
a cell. In vertebrates, for example, extra gene copies led to features like
paired limbs and larger brains.

Over time, copies also can be lost.

Notung uses information about gene duplications and disappearances to
reconstruct the history of genes. It is the first program to take into
account the large-scale changes along with smaller-scale mutations in the
chemical sequence of a DNA molecule.

The "family" trees generated by Notung provide the simplest explanation for
how a gene developed, based on the scientific principle that less
complicated solutions are more likely to be right. But if the tree generated
by the software doesn't match what scientists already know about the
evolution of a particular gene, they can move branches around to jibe with
reality.

Hugh Nicholas Jr., a senior scientific specialist at the Pittsburgh
Supercomputing Center, said he is using Durand's program to trace the
genetic history of a family of enzymes that help rid the body of toxins --
including some drugs and chemotherapy agents.

Drug companies would like to find ways to turn off some of those enzymes so
they could enhance the body's response to medication. To do so, they have to
understand their genetic evolution, and that's where Notung comes in to
play.

"For this family of proteins, the evolutionary tree is very noisy," Nicholas
said. "(Durand's) software lets you explore alternatives in the parts of the
tree that have the most noise and are therefore the most unreliable. Notung
is the only program available that largely automates this process for you."

[pittsburghlive.com]

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