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Title: Early Diversification of the Tumor Necrosis Superfamily in Teleosts: Genomic Characterization and Expression Analysis

item Wiens, Gregory - Greg

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/16/2007
Publication Date: 6/15/2007
Citation: Glenney, G.W., Wiens, G.D. 2007. Early Diversification of the Tumor Necrosis Superfamily in Teleosts: Genomic Characterization and Expression Analysis. Journal of Immunology, 178:7955-7973.

Interpretive Summary: Infectious disease is a significant factor hindering rainbow trout (Onchorynchus mykiss) aquaculture in the US. In 2004, 29.2 million rainbow trout were lost on fish farms and infectious disease accounted for 81.7 percent of this loss. A better understanding of the fish immune system is required to improve health and disease resistance. A first step toward this goal is the identification and characterization of genes that regulate the immune response to pathogens. In mice and humans, tumor necrosis factor and related proteins play important roles in controlling inflammation, activation, and development of the immune system. In this study, we identified forty-four new gene sequences that were either from rainbow trout, Atlantic salmon, zebrafish, pufferfish, or stickleback fishes. Comparison of the protein sequences and the gene locations allowed us to identify whether these newly-identified genes were related to those in mammals or whether they were unique to fish. Several were unique to fish including: BALM, TNF-New, and four TRAIL-like variants. We identified, for the first time in any fish species, the counterparts of human genes CD40L, TWEAK, APRIL, BAFF, LIGHT, FasL and RANKL. We failed to identify counterparts of OX40L, CD27L, CD30L, and GITRL that are important for T cell activation and immune function. The expression of seven genes were measured in rainbow trout immune and non-immune tissues. The presence of some TNF family genes, and the absence of others, will lead to a better understanding of how the fish immune system functions and how it may differ from mammals.

Technical Abstract: The tumor necrosis factor superfamily (TNFSF) of proteins are cytokines involved in diverse immunological and developmental pathways. Little is known about their evolution or expression in lower vertebrate species. Bioinformatic searches of Zebrafish, Tetraodon, and Fugu genome and other teleost EST databases identified forty-four novel gene sequences containing a TNF homology domain. This work reveals: 1) teleosts possess orthologues of BAFF, APRIL, EDA, TWEAK, 4-1BBL, FasL, LIGHT, CD40-L, RANKL, and possibly TL1A; 2) the BAFF-APRIL subfamily is enriched by a third member, BALM, unique to fish; 3) orthologues of lymphotoxin alpha and beta were not clearly identified in teleosts, and are substituted by a related ligand, TNF-New; 4) as many as four TRAIL-like genes are present in teleosts, as compared to only one in mammals, and 5) T cell activation ligands OX40L, CD27L, CD30L, and GITRL were not identified in any fish species. Finally, we characterize mRNA expression of TNFSF members CD40L, LIGHT, BALM, APRIL, FasL, RANKL, TRAIL-like, and TNF-New, in rainbow trout, Oncorhynchus mykiss, immune and non-immune tissues. In conclusion, we identified a total of fourteen distinct TNFSF members in fishes, indicating expansion of this superfamily prior to the divergence of bony fish and tetrapods, approximately 360-450 million years ago. Based on these findings, we extend a model of TNFSF evolution and the co-emergence of the vertebrate adaptive immune system.