Structural and functional genomics and evolutionary relationships in the cluster of genes encoding murine 2',5'-oligoadenylate synthetases Tomoji Mashimo, a Philippe Glaser, b Marianne Lucas, c Dominique Simon-Chazottes, a Pierre Emmanuel Ceccaldi, d Xavier Montagutelli, a Philippe Despre `s, c and Jean-Louis Gue ´net a, * a Unite ´ de Ge ´ne ´tique des Mammife `res, Institut Pasteur, 75724 Paris Cedex 15, France, b Laboratoire de Ge ´nomique des Microorganismes Pathoge `nes, Institut Pasteur, 75724 Paris Cedex 15, France, c Unite ´ des Interactions Mole ´culaires Flavivirus-Ho ˆtes, Institut Pasteur, 75724 Paris Cedex 15, France, d De ´partement de Virologie, Institut Pasteur, 75724 Paris Cedex 15, France Received 3 January 2003; accepted 30 May 2003 Abstract 2',5'-Oligoadenylate synthetases (2',5'-OASs) are interferon-inducible enzymes. Some of these proteins play an important role in cellular physiology, in particular, in the innate defense mechanisms against RNA virus infections. In the present publication we report the complete genomic structure of the cluster of genes encoding mouse 2',5'-OAS, with all its transcription units, their predicted functions, and their evolutionary relationships. We found that mouse Oas2/Oas3 genes have a genomic structure similar to that of human OAS2/OAS3, while the mouse equivalent of human OAS1 is composed of eight (Oas1a to Oas1h) tandemly arranged transcription units. For all these eight genes a specific inducible promoter controls transcription. The possible functions of this family of proteins are discussed. © 2003 Elsevier Inc. All rights reserved. Keywords: 2',5'-Oligoadenylate synthetases; Evolution; Functional genomics; mouse In mammals, 2',5'-oligoadenylate synthetases (2',5'- OASs) represent a relatively homogeneous family of enzy- matic proteins with a remote evolutionary origin, since molecules with a similar structure have been identified in a wide range of species including birds [1], reptiles [2], and even the marine sponge Geodia cydonium [3]. At least some of these proteins are interferon-inducible enzymes and play an important role in the host’s innate defense mechanisms against viral infections, in particular where positive- stranded RNA viruses are concerned [4 – 8]. Recently, we and others reported that a nonsense mutation in the gene encoding the Oas1/L1 isoform of the mouse is constantly associated with, and presumably responsible for, the sus- ceptibility of several inbred strains to experimental infec- tions with flaviviruses [9,10]. This antiviral activity of 2',5'- OASs might also be direct and interferon-independent, since plants transgenic for genes of this family and for the gene encoding RNase L were found to be resistant to ex- perimental infections with a number of viruses such as tobacco mosaic virus, cucumber mosaic virus, and potato virus Y [11,12]. Finally, in addition to the role they play in the host’s defense mechanisms, proteins of this family have been demonstrated to play a role in some other important cellular processes such as growth control, differentiation, and apoptosis [13–17]. Considering the multiplicity of the OAS-encoding genes [4 – 8], their evolutionary conservation, and the fundamental functions they appear to be involved in, it is reasonable to assume that this family of genes is important for the main- tenance of homeostasis at the cellular level and, accord- ingly, it would be interesting to investigate in detail the regulation and function(s) of each of its individual mem- bers, using some of the modern strategies of genetic engi- neering, both in vitro and in vivo, in the laboratory mouse. * Corresponding author. Fax: +33-1-45-68-86-34. E-mail address: guenet@pasteur.fr (J.-L. Gue ´net). R Available online at www.sciencedirect.com Genomics 82 (2003) 537–552 www.elsevier.com/locate/ygeno 0888-7543/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0888-7543(03)00176-9