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Harmit Malik explores the genetic "arms races" that drive evolution

Harmit Malik explores the genetic "arms races" that drive evolution

From Dr. Harmit Malik's point of view, evolution is sometimes like a long-lived dispute between neighbors. Neighbor A plows his sunny backyard into a vegetable patch. Neighbor B, who longs for a shade garden, plants a tree that grows so tall that it casts darkness over his land and the sun-loving tomatoes next door. Neighbor A cuts down the tree.

Each individual's pursuit of his selfish interests spurs the other to respond in kind, which keeps the landscape in an endless state of redesign. If neither one moves or changes tastes, they will be resigned to a future of turmoil driven by their competing desires.

Analogous conflicts in nature drive evolutionary change when two competing biological interests come head to head. Predators and prey often influence the evolution of one another, and the same can happen among genes in the same cell that produce proteins of opposing function.

Malik, who joined the Basic Sciences Division last fall, believes that the human body is full of examples of conflict-driven changes that shape our own evolution. Although hidden from plain sight, about 10 percent of an organism's genes-the DNA blueprints for proteins-may be engaged in battle. His research seeks to find proteins that appear to be evolving rapidly, a clue that they are engaged in one of these genetic arms races. In most cases, the source of the conflict has yet to be discovered, but once identified could reveal previously unknown examples of adaptation in response to potential sources of infection or even deadly diseases like cancer.

Although evolution is a subject that preoccupies numerous scientists, Malik's deep knowledge of multiple fields of biology puts him in a unique position of strength to answer many important questions, said Dr. Mark Groudine, director of the Basic Sciences Division.

"Harmit is an extraordinary intellectual with broad interests and deep knowledge in many fields, and he has a uniquely creative and fearless approach to his research," he said. "This has enabled him to make unexpected discoveries, such as finding an example of rapid evolution in a protein involved in chromosome partitioning during cell division, a process that we would expect to be have evolved to a stable, optimum state. His ideas are having an enormous impact on the field," he said.

The aspects of evolution that interest Malik are different from changes driven by massive external pressures like climate. In those cases, optimal traits tend to become fixed in a population.

"Evolution loves to optimize," he said. "Once an optimal state is reached, there is little tendency to tinker with it. But the arms races we are finding suggest that there are ongoing competing interests that are driving change. Some call this coevolution, but it is really a constant state of conflict."

Conflicts such as those that result from incompatible survival strategies of a virus and the host it infects may sometimes leave one party with a less-than-optimal solution. Viruses often co-opt a protein on the surface of a cell to serve as a portal for entry. The viral coat will evolve to stick effectively to the cell-surface protein, which normally performs some useful function for the cell. In response, the protein might evolve to be a less-effective receptor for the virus. Yet if the protein is vital to the survival of the cell, its range of possible changes might be too limited to deter the virus in any significant way. The cell might have to compromise with a less-functional protein to deter infection, or to take its chances on infection to retain a protein that does its job properly.

Malik points to cancer as an extreme example of the negative consequences that could result from conflict that is driven by selfish survival interests.

"Humans are multicellular organisms in which the growth of cells must be precisely controlled," he said. "Tumors are a clutch of cells that ignore these controls. From an evolutionary perspective, it is an advantage for the cancer cells to grow at the expense of their healthy neighbors-but it's a short-lived benefit because evolutionary success depends on the whole organism."

Disease-host interactions are among the most predictable examples of biological arms races. Malik's lab has also discovered evolutionary struggles in unexpected places.

"Some of the examples of rapid evolution we have discovered are taking place in proteins required for cell survival that have been well studied but were not thought to be evolving," he said. "Because they perform critical functions and have counterparts in most organisms, we say they are highly conserved. They would not be expected to undergo any adaptive change."

As a postdoctoral fellow in Dr. Steven Henikoff's lab at the center, Malik made the surprising discovery of rapid evolution occurring in a fruit-fly protein called Cid. The protein is critical for the equivalent partitioning of chromosomes during cell division. Cid binds to parts of the chromosome called centromeres, which serve as attachment sites for the fibers that pull newly duplicated chromosomes apart.

"Nothing could be more important than centromeres," Malik said. "Yet they evolve quite rapidly."

More recently, Malik's lab has found that a protein responsible for duplicating chromosomes-one of life's most essential functions-may also be rapidly evolving.

"This is very mysterious," he said. "Proteins that are involved in DNA replication are among the most conserved proteins that we can imagine. It will be very interesting to find out what type of conflict is causing this adaptive evolution."

To hunt for rapidly evolving genes, Malik examines closely related species to identify equivalent genes from each organism. He looks for those whose DNA sequences differ in significant ways among species. Some DNA sequence differences result in changes to their respective proteins that noticeably affect protein function. This suggests that an arms race might be taking place because nature has not settled on an optimal form. Once candidates are identified, the researchers must hunt for the opponent or opponents in the conflict in order to develop hypotheses to explain why the adaptive evolution is taking place.

Most of his laboratory's work is carried out with fruit flies, which serve as a useful model system for understanding related phenomena in many other organisms. To identify human genes undergoing rapid evolution, he compares the human genome to that of its closest relative, the chimp.

Arms races examined

Several arms races are under investigation in Malik's lab. Dr. Danielle Vermaak, a research associate, studies a fruit fly protein important for organizing heterochromatin, parts of the genome that contain few genes that are often kept silent. The protein is undergoing adaptive evolution for reasons that are currently under investigation.

Dr. Sara Sawyer, a postdoctoral fellow, is investigating a host-virus interaction in animals where a particularly inventive defense strategy employed by host genomes is being counteracted by viruses like HIV-1 that destroy the host-encoded poison.

Research technician Monica Rodriguez is testing a hypothesis to explain why the Cid protein is undergoing rapid evolution. They speculate that the driving force is a competition between the chromosomes of an egg-producing cell, which will be partitioned into four cells, only one of which can survive to become the egg.

Malik's research interests evolved from diverse educational experiences. Born and raised in India, he earned an undergraduate degree in chemical engineering from the prestigious Indian Institute of Technology in Mumbai. As a graduate student at the University of Rochester, he began his studies of molecular evolution in the lab of Dr. Tom Eickbush. He joined Henikoff's Basic Sciences lab in 1999, where his exceptional research earned him a job offer from the division, which Groudine said has rarely hired from within.

Despite competing offers from universities that have top-ranked departments of zoology and evolution, Malik chose to study among faculty best known for their strengths in molecular and cell biology. He described the collegial atmosphere and the overall research excellence of Fred Hutchinson as the major draws, as well as the proximity to a strong zoology department at the University of Washington.

He doesn't have any worries that the differing interests of his laboratory neighbors will result in perpetual conflict. Rather, he expects the blending of research viewpoints will result in the productive evolution of his own career.

"Evolutionary biologists have made enormous insights into why genes and genomes have evolved the way they have." he said. "On the other hand, molecular biologists have been able to provide exquisite detail into how proteins function. My research hopes to draw from both disciplines, to simultaneously explain both the "why" and the "how" of the mystery of rapidly evolving genes."

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