Discovering new hormones, receptors, and signaling mediators in the genomic era.

The human genome has 3 billion base pairs with 3–5% as coding exons that account for about 100,000– 140,000 genes. The Human Genome Project is scheduled to complete the sequencing of the entire genome in the next few years. At the present time, the Expressed Sequence Tags (ESTs) in the GenBank represent .60% of the human genes. Mammalian genes exist in families as reflected by the presence of multiple paralogs. With recent advances in bioinformatic tools, the massive resources in the GenBank are easily accessible to investigators through the Internet and allow opportunities for discoveries that could impact all fields of biomedicine. Using Internet-based tools to search the massive genome databases, it is possible to identify new endocrine genes based on evolutionary conservation, domain homology, and tissue expression patterns. Examples for the discovery of paralogous genes include: LGRs (leucine-rich repeat containing, G protein-coupled receptors) that are evolutionarily conserved as compared with gonadotropin and TSH receptors, and RIFs (relaxin-insulin-like factors) that show domain conservation with known growth factors. Using the GenBank searches, polymorphism of previously characterized genes can also be identified. The rapid pace of genomic revolution allows the discovery of new genes in the endocrine systems, identification of new drug targets, analysis of genetic susceptibility of individuals to endocrine diseases, and customized drug therapy based on gene polymorphism. It is anticipated that the future integration of gene sequence-based approaches with transcript expression profiles and protein functions will lead to a more complete understanding of the circuitry controlling the endocrine pathways. GENOMIC REVOLUTION The recent genomic revolution officially started in 1992 with the launching of the Human Genome Project (1). It is anticipated that, within the next few years, sequencing of the entire 3 billion (3 3 10) base pairs of the human genome will be completed. At the present time, the complete genomic sequences of more than 2 dozen organisms including yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans are already available. This progress has been compared with the completion of the Periodic Table of the Elements at the end of the 19th century (2) and became possible through the largely automated sequencing of libraries of genomic DNA and expressed sequence tags (ESTs) that represent fragments of sequenced cDNAs from diverse tissues. At the beginning of April 2000, the GenBank contained more than 2.4 billion bases of human genome sequences and the complete sequencing of the entire human genome has just been announced (for an update of deposited sequences see http://www.ornl.gov/hgmis/project/ progress.html). In addition to ESTs, these sequences are represented by single-pass genome survey sequences (GSS) encompassing the ends of large genomic fragments, unfinished and unordered highthroughput genomic sequences (HTGS), and finished nonredundant (NR) sequences. Among the various GenBank sequences, the EST database is particularly useful for identifying novel genes (3, 4). These short sequences represent transcribed genes and contain continuous protein coding regions. The 1.8 million human ESTs presently in the GenBank have been clustered into approximately 92,224 unique transcripts (Unigene Build 107, Jan. 27, 2000) based on their overlapping sequences, therefore accounting for more than 60% of human genes (http://www.ncbi.nlm.nih. gov/UniGene/Hs.stats.shtml). It is clear that the EST sampling approach has identified a majority of transcripts encoded by our genome. Indeed, more than 90% of known or nonredundant genes of human or 0888-8809/00/$3.00/0 Molecular Endocrinology 14(5): 594–604 Copyright © 2000 by The Endocrine Society Printed in U.S.A.