Hutch News

A stickler for genetic detail

April 3, 2003
Dr. Katie Peichel setting pinfish trap

On the shore of Lake Washington near Magnuson Park, Dr. Katie Peichel anchors a nylon rope attached to pinfish trap designed to catch small fish such as sticklebacks, the tiny research subjects that may hold genetic clues to human characteristics.

Photo by Todd McNaught

To the casual observer, the silver fish with red bellies and blue eyes that make their home in Dr. Katie Peichel's laboratory are simply a bright spot amid the usual Petri plates and test tubes.

Yet when Peichel discusses the merits of her collection of three-spine sticklebacks, it's clear that the tiny tank dwellers are no mere house pets. In her view, they are precious research subjects that hold clues to cancer, the evolution of humans and maybe even the psychology behind a flirtatious encounter at a sports bar.

A geneticist by training, Peichel makes a convincing case that the stickleback - best known as a study subject of ecologists - is an untapped mine of insight into how groups of genes collaborate to dictate such biological mysteries as disease susceptibility, mate selection and the origin of new species.

"In humans, many important characteristics are what we call complex traits," said Peichel, who joined the Human Biology Division in January.

"That means they aren't controlled by single genes. It's been very difficult to identify all the genes that contribute to a complex human trait like susceptibility to cancer or diabetes or how an individual responds to a particular drug."

That's where the stickleback may swim to the rescue.

"Many of the traits we're studying in the stickleback are also likely to be due to multiple interacting genes," she said. "And while there are many similarities between the genomes of humans and sticklebacks, the smaller size and the ability to manipulate the stickleback genome makes it much more amenable to genetic analysis."

Genetic blueprint

Before joining the center, Peichel created a valuable tool for her studies that also will prove useful for researchers around the world: the first detailed map of the stickleback's genetic blueprint. The work was published in 2001 in Nature.

Peichel's insightful approach to developing a model system for human genetic analysis is exactly why Human Biology recruited Peichel from Stanford University to join its diverse group of human-disease gene hunters, said Dr. Barbara Trask, division director.

"Katie's work addresses one of the greatest challenges for human biology and disease research: how to sift through all the ways that the DNA of different people can vary to identify the set or sets of differences that define a particular trait, such as an individual's risk of developing cancer, mental illness or other disease," she said.

"Such traits are not caused by a mutation in a single gene, but rather are the collective effect of subtle differences in many genes and their interaction with environmental factors.

"Katie's choice to use the stickleback fish to address these complex problems is a brilliant one, as it promises to bridge the intellectual gap between genetic analyses of humans and inbred model organisms, such as the laboratory mouse."

As a graduate student at Princeton University, where she studied genes that control skeletal development in mice, Peichel hardly had heard of sticklebacks, much less ever considered the fish a subject worthy of a geneticist's attention. But when she began postdoctoral research in the Stanford lab of Dr. David Kingsley, also a specialist in how the mouse skeleton forms, the stickleback caught her eye as an ideal model system to study evolution.

"There is incredible diversity among skeletons of different animals," she said. "In many cases, the same basic pattern is there, but parts have become specialized for the organism. For example, a bat can fly because it has very long fingers to support the wings."

Skeletal diversity

Peichel and Kingsley reasoned that to identify the genes that control development of specialized structures like wings or fins, they would need to identify an organism that exhibited skeletal diversity within its own population. At the same time, individuals within this diverse population had to be similar enough to mate with one another, at least in the laboratory, so that the inheritance of their bodily structures could be analyzed in subsequent generations.

After a summer-long search, Peichel settled on the stickleback as the perfect model. The three-inch fish inhabit freshwater habitats of coastal regions throughout the northern latitudes, including the Pacific Northwest.

"Sticklebacks have tons of diversity," she said. "Ten thousand years ago, sticklebacks were marine fish. When the glaciers melted, they invaded new freshwater lakes and streams with many different ecological conditions. The fish in these lakes and streams can look incredibly different from one another."

Among the features that differ for fish of different habitats are the size of their trio of spines, the number and size of bony plates on the animals' sides and the length of their snouts and jaws.

Even within a single lake, two distinct forms of sticklebacks can evolve, depending on whether the fish live close to shore or in open water. By mating fish from two such habitats and analyzing their offspring, Peichel hoped to answer one of evolution's biggest puzzles: How many genetic changes must there be for a new trait to evolve, and which of the new traits are important to create new species?

Biologists typically classify species as distinct when two populations are said to be reproductively isolated, meaning that they no longer mate with one another. In studying two forms of sticklebacks in British Columbia's Priest Lake, researchers have found that while the two forms don't normally interbreed, they mate in the laboratory to produce viable offspring.

Because they have evolved from one another so recently, their differences are not great enough to preclude mating, even though the two populations would not normally do so in their natural environment.

Using a genetic map she created, Peichel correlated inheritance patterns of the spine and plate characteristics unique to each type with the parts of the stickleback genome that control the traits. She and her colleagues found that different genes affect these different skeletal structures, an asset that presumably allows the fish to evolve forms that are specialized for their habitat. For example, fish living in open water might need longer spines to fend off bird predators and longer snouts to feed more easily on plankton.

Mate selection

While she continues to have an interest in skeletal evolution, Peichel expects that her genetic map also will help scientists probe the genetic basis of one of the most intriguing outcomes of species evolution: the behavior of mate selection.

Three-spine sticklebacks go through an elaborate seasonal courtship ritual in which males become brightly colored, attract the eye of an available female and "dance" in a zigzag pattern to attract a female to visit his nest.

"When you think of it, it's not all that different from the stereotype of a pick-up scene in a bar," Peichel laughed. "It's almost scary to think about how much behavior might be under genetic control."

Although human behavior may not have evolved to be as predictable as that of a tiny fish, the stickleback may end up teaching researchers much about the emergence of the human species.

"Humans evolved in roughly the same amount of time - about 10,000 years - as the sticklebacks we're studying," she said. "The level of polymorphism, or the amount of variability of genes among individuals, is about the same in both."

A closer inspection of the range of such variability will be essential to understanding why some individuals are more likely to develop diseases like cancer and why not all people respond to treatments in the same way. While the stickleback may never develop diabetes or breast cancer, it's likely that the variability in its own genes will provide crucial clues to the understanding of human genetic variation.

That, Peichel said, "is why a cancer center is a great place for me to be."

 


Peichel seeks biologists to teach at Katmandu medical school

In addition to her fascination with stickleback-fish biology, Dr. Katie Peichel's other career passion is teaching.

After completing postdoctoral studies at Stanford University, Peichel spent six months teaching basic science and biochemistry at a new medical school in Nepal.

A Nepalese doctor trained in the United States established Katmandu University Medical School in 2001. The school, which has an English language-based curriculum modeled after that of Harvard Medical School, seeks American scientists to teach courses to medical students.

Graduate students, postdoctoral fellows and faculty interested in learning more about teaching in Nepal can contact Peichel for information at cpeichel@fhcrc.org.

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