STATE-OF-THE-ART LECTURE I
Monday, July 29, 2002, 10:00 AM-10:45 AM
Grand Ballroom V & VI
Chair: Menon, Jairam1, 1
Speaker: Hsueh, Aaron1, 1
(SA1) IMPACT OF THE GENOMIC REVOLUTION ON REPRODUCTIVE SCIENCES.
Hsueh, Aaron1, Hsu, Sheau Yu1, Nakabayashi, Koji1, Vitt, Ursula1, Ben-Shlomo, Izhar1, Leo, Chandra1, 1 Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA
ABSTRACT- Recent publication of entire genomic sequences for human and multiple model organisms allows an unprecedented opportunity to elucidate the evolutionary origin of all human genes. A "molecular clock" paradigm using DNA as a timepiece can be implemented to sort out the origin of complex gene networks and pathways in the human body. For reproductive biologists, this breakthrough facilitates the analysis of reproductive genes by tracing their phylogenetic roots based on the comparison of homologs from human and lower species. The present talk will focus on two areas. 1. DISCOVERY OF NEW LIGANDS AND RECEPTORS: Using GenBank searches, we identified new hormones and receptors based on the evolutionary tracing approach. Because of the co-evolution of ligands and their cogent receptors, analysis of human genomic sequences allows one to predict the pairing of these elements. We have identified novel human paralogs for glycoprotein hormone subunits (alpha 2 and beta 5), relaxin/insulin-like factors, and CRH-related polypeptides. In addition, we isolated a group of five orphan LGRs (leucine-rich repeat-containing, G protein-coupled receptors) homologous to LH, FSH and TSH receptors. The matching of polypeptide hormones and receptors led to the finding of a new heterodimeric glycoprotein hormone thyrostimulin (alpha 2/beta 5) as an agonistic ligand for the TSH receptor and two selective ligands for the type 2 CRH receptor (stresscopin and stresscopin-related peptide; Nature Med, 7:605 2000). In addition, the elusive receptors for the classic hormone relaxin were identified as LGR7 and LGR8 (Science, 295: 671 2002). 2. STUDIES BASED ON AN ORGAN-SPECIFIC DATABASE: In the postgenomic era, one can obtain a global perspective on the function of all human genes to provide an integrated view of physiology and pathophysiology. An organ-based approach has been used to set up a database integrating existing text-based literature on individual ovarian genes and their sequence-based data in the GenBank. The Ovarian Kaleidoscope database (OKdb; http//ovary.stanford.edu) has accumulated nearly one thousand individual gene pages that are searchable based on gene function, cellular localization, chromosomal position, ovarian cell type, ovarian function, mutant phenotypes, and other criteria. Using this organ-based database, it is possible to set up gene pathway maps for DNA array analysis, identify key gene networks essential for infertility phenotypes, compare chromosomal synteny regions for finding candidate fertility genes, categorize cell-specific and hormonally co-regulated genes for promoter analysis, and document potential ligands and receptors in the paracrine regulation of follicular development (Endocrinology June, 2002). Global analysis of gene function and relationships in an organ-specific manner provides a functional genomic paradigm for the future understanding of the physiology and pathophysiology of diverse reproductive organs and other tissues.
KEY WORDS: Genomics, Hormones, Receptors, Ovary