Environmental Factor, January 2007, National Institute of Environmental Health Sciences
Distinguished Lecturer Aaron Hsueh
By Eddy Ball
Aaron J. W. Hsueh, Ph.D., presented the most recent talk in the 2006-2007 NIEHS Distinguished Lectures series at 11:00 AM on December 12 in Rodbell Conference Center. Hsueh is a professor and head of the Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University. His topic was "Coevolution and Bioinformatic Discovery of Polypeptide Ligands and Receptors."
Laboratory of Signal Transduction Supervisory Biologist John Cidlowski, Ph.D., was the sponsor of Hsueh's lecture. Cidlowski described the guest lecturer as a leader in a number of fields related to reproductive physiology, with a specific emphasis on the ovary. "His lab was the first to describe the role of apoptosis in the ovary," Cidlowski said. "He is simply a world authority in ovarian function... and continues to lead the way in understanding ovarian function."
Hsueh's lecture focused on his recent work using a bioinformatics approach to discover a new family of G-protein coupled receptors and new polypeptide ligands. Although many in the field had thought that all of the receptors and ligands had already been discovered, Hsueh took an evolutionary genomic analysis approach to match ligands and receptors based on the co-evolution of genes.
The lecture began with a discussion of integrating Darwin's theory of evolution from a common ancestor with data from the Human Genome Project. This orientation led Hsueh and his colleagues to look at all of the genomes and take a comparative genome approach to hormone analysis. They used genomic sequences for human and multiple model organisms to elucidate the evolutionary origins of human genes.
Working with the hypothesis that the basic signaling pathways were probably already fixed in lower life forms, the researchers analyzed gene sequences to see how they changed from lower to higher forms, a process Hsueh compared to reading through the Library of Life. Tracing the evolution of the genes, Hsueh's lab examined orthologs, which are highly conserved in function and sequence through evolution, and paralogs, which show evolutionary adaptation through species.
"Based on the lower species' receptors," Hseuh explained, "we searched the human genome." The researchers found orthologs in life forms as ancient as the sea anemone. "Then we went the other way," Hseuh continued, identifying fixed sequence elements in novel paralogs and discovering new ligands that had not been described before. Because the human genome is completely sequenced, Hseuh was also able to determine whether known paralogs were also playing some roles that were not completely understood.
"I hope this concept is not just for the receptor, but for any of the genes you are dealing with," Hseuh told his audience. His lab's work focused on hormones because that was its primary research interest. Theory of evolution-driven genome searches, he concluded, should be applicable to any physiological process being studied. "I hope this concept will help in other fields also, in terms of what is going on."