The human 2',5'-oligoadenylate synthetase locus is composed of three distinct genes clustered on chromosome 12q24.2 encoding the 100-, 69-, and 40-kDa forms.

The 2',5'-oligoadenylate synthetases (OAS) represent a family of interferon-induced proteins implicated in the mechanism of the antiviral action of interferon. When activated by double-stranded RNA, these proteins polymerize ATP into 2'-5'-linked oligomers with the general formula pppA(2'p5'A)n, n >/= 1. Three forms of human OAS corresponding to proteins of 40/46, 69/71, and 100 kDa have been described. Based on the deduced amino acid sequences of the corresponding cDNAs, these OAS share a homologous region of about 350 amino acid residues that could represent the functional domain of OAS; the 40/46 proteins contain one single domain, whereas the 69/71- and the 100-kDa proteins contain two and three adjacent domains, respectively. Here we show that the cDNAs for OAS-40/46, OAS-69/71, and OAS-100 hybridize to distinct interferon-induced mRNAs of 2 kb; 2.8, 3.3, 3.9, and 4.5 kb; and 7 kb, respectively. By in situ hybridization, we assign the human OAS-40/46, OAS-69/71, and OAS-100 genes (referred to as OAS1, OAS2, and OAS3, respectively) to a unique cytogenetic location on chromosomal region 12q24.2. We constructed a YAC, PAC, and cosmid contig carrying the three OAS genes and provide evidence that the three genes are clustered within a single PAC clone of 130 kb. The three OAS genes are flanked by markers WI-10614 (cen) and D12S2293 (tel) and are contained within three sets of overlapping cosmid clones. They share the same orientation of transcription and are arranged in the order cen- 5'-OAS1-OAS3-OAS2-3'-tel. We suggest that clustering of these genes reflects their evolutionary relationship possibly through the duplication of the conserved functional domain. This ready-to-sequence PAC and cosmid contig provides a valuable tool for identifying regulatory elements involved in the transcription of the OAS genes when induced by interferon and for elucidating the exon-intron organization of these genes. Copyright 1998 Academic Press.