Genetics, Systems Biology
University of California, Los Angeles
Dr. Kruglyak is also a professor in the Department of Human Genetics and the Department of Biological Chemistry at the David Geffen School of Medicine at the University of California, Los Angeles. He is also a founding member of the Computational Biosciences Institute.
Genetic Basis of Individual Variation
Some people find one thing they do well and stick with it. But that's not Leonid Kruglyak's style.
Over the past decade, he has moved nimbly between computational and experimental approaches to genetics, learning new skills and developing new techniques when they become necessary to home in on what he considers the most important questions. As a result, he has infused the field of genetics with new and innovative ideas time and time again.
Kruglyak was trained in theoretical physics as an undergraduate at Princeton University and in graduate school at the University of California, Berkeley. So when he decided to become a geneticist in 1993 and joined Eric Lander's laboratory at the Whitehead Institute for Biomedical Research as a postdoctoral fellow, he brought a strong background in quantitative analysis.
Lander, who had earlier made a similar switch from mathematics to genetics, was at that time one of the leaders of the Human Genome Project. Together, he and Kruglyak published a groundbreaking series of papers on how to use DNA data to search for genes involved in disease. These papers still guide how scientists think about complex genetic traits in human populations.
While the importance of these findings rippled through the genetics community, Kruglyak got restless. Even as he continued to publish widely noticed papers—now from his own lab at the Fred Hutchinson Cancer Research Center—he was yearning to expand his research program beyond computational biology. There were so many confounding factors complicating the analyses of human genetics, and Kruglyak suspected that a simpler system would help reveal some of the guiding principles that were at work.
His appointment as an HHMI investigator in 2000 gave him the chance. "I asked HHMI if I could use some of their money to set up a wet lab to study yeast genetics. They said, 'We take the idea of funding people and not projects seriously, so sure, go ahead.'"
Kruglyak had never before worked in a wet laboratory. But within a year, his research program was generating important results. For example, he and his colleagues showed that differences in the activity of any given gene in yeast are controlled by a complex array of proteins and DNA sequences that are both close to the gene and far away. "At that time we didn't really understand genetic complexity in any organism," he says. "It was easier to explore in a model system like yeast."
Kruglyak also embarked upon his most widely known project while he was in Seattle, in collaboration with Elaine Ostrander, an expert on dog genetics who worked down the hall from him. The two sometimes mulled over projects they could do together, and the result was a 2004 paper that traced the evolution of 85 dog breeds, showing that several of them have ancient origins but most have more modern European roots. Their conclusions sparked some controversy among dog breeders, but later research supported and extended their findings.
The next year Kruglyak accepted an offer to join the faculty at his alma mater. It meant giving up his HHMI position, but Princeton's interdisciplinary Lewis-Sigler Institute for Integrative Genomics—which houses biologists, physicists, computer scientists, and chemists under one roof—seemed the ideal environment for the kind of science at which Kruglyak excels. Also, he says, 'there was special appeal in returning to my alma mater and working with Princeton's talented undergraduates and graduate students.'
When he arrived at Princeton, Kruglyak knew he wanted to continue his studies of yeast genetics. But he thought it was time to take on studies that could offer a new level of information as well. So he added the wormCaenorhabditis elegans to the model organisms studied in his lab. "It was a natural extension of what we had been doing," he says. "C. elegans has sophisticated behaviors that are implemented by a nervous system. It has development and physiology that can only be found in multicellular organisms. Working with it has been a lot of fun."
Using two common strains of C. elegans, Kruglyak and his colleagues have created more than 200 inbred crosses, each with a different combination of the parental genomes. With these crosses, they are mapping the genetic origins of traits that differ between the two strains, such as their tendency to avoid certain odors. They also found a previously unnoticed genetic incompatibility between natural strains of C. elegans that divides the species into two classes. When a nematode from one class mates with one from the other, the resulting offspring produce many dead embryos. The two incompatible classes appear to be maintained by unknown selective forces that balance the classes. Kruglyak's lab is investigating how this unusual incompatibility results in embryonic death.
As he maneuvers between research models, Kruglyak maintains that understanding how genes shape traits in the organisms he studies will help guide future studies of medical and agricultural importance, in his own lab and in others. And he is always thinking about what to do next. "What's exciting is how quickly the field is changing. Things that were dismissed as science fiction five years ago are now being done. It's a field where you have to peer into the future and see what you're going to be able to do, and then figure out how you can put yourself in a position to do that."