Variation in Antiviral 2′,5′-Oligoadenylate Synthetase (2′5′AS) Enzyme Activity Is Controlled by a Single-Nucleotide Polymorphism at a Splice-Acceptor Site in the OAS1 Gene

Abstract

It is likely that human genetic differences mediate susceptibility to viral infection and virus-triggered disorders. OAS genes encoding the antiviral enzyme 2',5'-oligoadenylate synthetase (2'5'AS) are critical components of the innate immune response to viruses. This enzyme uses adenosine triphosphate in 2'-specific nucleotidyl transfer reactions to synthesize 2',5'-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. We showed elsewhere that constitutive (basal) activity of 2'5'AS is correlated with virus-stimulated activity. In the present study, we asked whether constitutive activity is genetically determined and, if so, by which variants. Analysis of 83 families containing two parents and two children demonstrated significant correlations between basal activity in parent-child pairs (P<.0001) and sibling pairs (P=.0044), but not spousal pairs, suggesting strong genetic control of basal activity. We next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism at the exon 7 splice-acceptor site (AG or AA) of the OAS1 gene. At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity (0.44 vs. 0.20; P=3 x 10(-11)). Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes (tested by analysis of variance; P=1 x 10(-14)). Allele G generates the previously described p46 enzyme isoform, whereas allele A ablates the splice site and generates a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.

Common polymorphic transcript variation in human disease

“…The most significant probe set can hybridize only to the extended transcript variant and can thus differentiate between them; as shown in Figure 2A, not a single CEPH individual overlaps in expression level of this probe set between genotypes (P < 10 À89 ). OAS1 is an enzyme involved in innate antiviral response with splice variants that are known to affect susceptibility to viral infection (Bonnevie-Nielsen et al 2005) and multiple sclerosis (Fedetz et al 2006). The same splice site SNP known to associate with disease susceptibility was recently shown also to associate with splicing of OAS1 in CEPH cell lines (Kwan et al 2007), a finding that is confirmed by our analysis (Supplemental Fig.…”

“…(Graham et al 2007;Kozyrev et al 2007). b OAS1 splice variants have also been associated with multiple sclerosis (Fedetz et al 2006) and viral infectivity (Bonnevie-Nielsen et al 2005).…”

“…1B), suggesting that variation near the 39-ends of transcripts (including alternative 39-UTRs and alternative polyadenylation sites) tends to show the strongest genetic determination. The top two genes (IRF5 and OAS1) (Fig 2A,B; Table 1) have both previously been shown to exhibit genetically controlled PTV in these cell lines (Bonnevie-Nielsen et al 2005;Graham et al 2007;Kwan et al 2007). IRF5 is a transcription factor that acts downstream from Toll-like receptors and has been implicated as The distribution of heritabilities (h 2 ) for the normalized expression of 170,956 probe sets.…”

Molecular Genetic Analysis of the Idd4 Locus Implicates the IFN Response in Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice

“…The gene encoding 2Ј-5Ј-oligoadenylate synthetase-like protein 2 (Oasl2) warrants special attention. Oasl2 belongs to the IFN-induced OAS family of genes, with critical functions in innate immune responses to viruses (54,55). OAS proteins produce 2Ј-5Ј-oligoadenylates, required to activate latent ribonucleases, leading to viral RNA degradation and inhibition of viral replication.…”

Distinct Antiviral Roles for Human 2′,5′-Oligoadenylate Synthetase Family Members against Dengue Virus Infection

“…By alternative splicing, these genes encode 10 different isoforms, including five OAS1 isoforms (p42, p44, p46, p48, and p52), two OAS2 isoforms (p69 and p71), a single OAS3 (p100), and two OASL isoforms (p30 and p59) (13)(14)(15)(16)(17). Human OAS1, OAS2, and OAS3 are composed of one, two, and three OAS domains and form a tetramer, a dimer, and a monomer, respectively (18), whereas human OASL lacks OAS activity (15,16,19).…”