Department of Biology and Molecular and Cellular Biology Program, Arizona State University
Abstract
The mammalian 2'5' oligoadenylate synthetases (2'5'OASs) are enzymes that are crucial in the interferon-induced antiviral response. They catalyze the polymerization of ATP into 2'5'-linked oligoadenylates which activate a constitutively expressed latent endonuclease, RNaseL, to block viral replication at the level of mRNA degradation. A molecular evolutionary analysis of available OAS sequences suggests that the vertebrate genes are members of a multigene family with its roots in the early history of tetrapods. The modern mammalian 2'5'OAS genes underwent successive gene duplication events resulting in three size classes of enzymes, containing one, two, or three homologous domains. Expansion of the OAS gene family occurred by whole-gene duplications to increase gene content and by domain couplings to produce the multidomain genes. Evolutionary analyses show that the 2'5'OAS genes in rodents underwent gene duplications as recently as 11 MYA and predict the existence of additional undiscovered OAS genes in mammals.
Introduction
Interferons (IFNs) function as antiviral cytokines in both mammals and birds. They interfere with viral replication by inducing several effector proteins, including those that block viral protein synthesis. The 2'5' oligoadenylate synthetases (2'5'OASs) form one such set of enzymes (reviewed in Lengyel 1982
; Sen and Lengyel 1992
; Rebouillat et al. 1999
). When activated by double-stranded RNA, 2'5'OAS catalyzes the polymerization of ATP into 2'5'-linked oligoadenylates, pppA(2'p5'A)n (1
n
30), which bind to and activate a latent endonuclease, RNaseL (Kerr and Brown 1978
; Floyd-Smith, Slattery, and Lengyel 1981
; Zhou, Hassel, and Silverman 1993
). RNaseL activation is short-lived because pppA(2'p5'A)n is rapidly degraded by cellular phosphodiesterases and 2'5' exoribonucleases (Schmidt et al. 1979
; Schröder et al. 1980
). Because double-stranded RNA is frequently produced during viral infections, activation of 2'5'OAS prevents viral replication by degrading mRNA (Rice et al. 1985
; Chebath et al. 1987
; Kumar et al. 1988
). Although 2'5'OAS activity is highest in virus-infected cells, these enzymes may also function to regulate the stability of RNAs that control normal cellular processes such as cell division, differentiation, and apoptosis (Kumar et al. 1994
; Diaz-Guerra, Rivas, and Esteban 1997
; Salzberg et al. 1997
; Yu and Floyd-Smith 1997
).
The 2'5'OASRNaseL system has been most extensively characterized for primates (human) and rodents (mouse and rat). There are three 2'5'OAS genes in humans, encoding small (p40/p46), medium (p69/71), and large (p100) isoforms which are found on human chromosomal segment 12q24.1 (Hovnanian et al. 1998
). Alternative splicing of transcripts from individual genes generate the p40 and p46 isoforms, as well as the p69 and p71 isoforms (Benech et al. 1985
; Marié and Hovanessian 1992
). Alignment of the putative translation products has identified a homologous sequence of about 350 amino acid residues that is present as a single domain in p40, two domains in p69, and three domains in p100 (Benech et al. 1985
; Marié and Hovanessian 1992
; Rebouillat et al. 1999
). Functional interaction between domains is likely, since the p40 isoform is only active as a tetramer and the p69 isoform functions as a dimer (Ghosh et al. 1997
; Sarkar et al. 1999a
). Another gene (OASL) encoding a protein with significant sequence similarity to the three 2'5'OAS genes (p40, p69, and p100), but lacking 2'5'OAS activity, has been mapped to human chromosome segment 12q24.2 (Hartmann et al. 1998
; Rebouillat, Marie, and Hovanessian 1998
; Hovnanian et al. 1999
).
In mice, several isoforms of 2'5'OAS have been identified which correspond to the small, medium, and large size classes of the human enzymes (Hovanessian 1991
; Rebouillat et al. 1999
). A related sequence p54OASL has also been identified in mice. 2'5'OAS activity has been detected in rats, pigs, marmots, and rabbits (Hartmann et al. 1998
), among other mammals.
Birds, like mammals, have an interferon-inducible antiviral system, which includes a 2'5'OAS-RNaseL system. A single chicken 2'5'OAS gene has been identified which shows sequence similarity with mammalian 2'5'OAS genes (Hartmann et al. 1998
; Yamamoto et al. 1998
). Components of the 2'5'OAS system have also been detected in reptiles and amphibians (Cayley et al. 1982
). The 2'5'OAS-RNaseL system has not been extensively characterized for nonvertebrates. However, high levels of 2'5'OAS activity have been reported for a marine sponge (Geodia cydonium) (Kuusksalu et al. 1995, 1998
). Protein binding to the effector oligonucleotide, as well as its function in the antiviral host defense system, has not been established for nonvertebrates.
The recent accumulation of 2'5'OAS sequences from mammals and birds provides us with an opportunity to understand the evolution and diversification of 2'5'OAS genes. Furthermore, a partial sequence of human chromosomal fragment 12q24.1 (PAC RPCI1-71H24) containing known human OAS genes is now available; hence, the genomic structure and phylogenetic history of the human 2'5'OAS locus can now be determined. In this paper, we employed a molecular evolutionary approach for this purpose.
Materials and Methods
A 162,346-bp human genomic PAC clone (PAC RPCI1-71H24) was scanned for putative open reading frames (ORFs) using the ORF-Finder software (T. Tatusov and R. Tatusov, NCBI). ORFs were tested for significant sequence similarity to all nonredundant GenBank CDS translations + PDB + SwissProt + PIR + PRF using BLASTP (Altschul et al. 1990
). Nucleotide sequences of all ORFs showing significant sequence similarity to the known 2'5'OAS cDNA sequences were then aligned using CLUSTAL W (Higgins, Thompson, and Gibson 1996
).
All published 2'5'OAS polypeptide sequences were retrieved from GenBank, and all very short and redundant sequences were removed from further analysis. Two cDNA sequences (accession numbers M63849 and M63850) were 99% identical to human 2'5'OAS sequences and were excluded from further analysis because their origins were not known with certainty (Rebouillat et al. 1999
). A list of GenBank/EMBL accession numbers and references are given in table 1
. A protein sequence alignment was constructed for these sequences using CLUSTAL W, and the alignments were manually corrected. We used the slow-and-accurate alignment option in CLUSTAL W, along with a BLOSUM30 amino acid substitution matrix. Penalties for alignment gap creation and gap extension were set at 10 and 0, respectively. The former is recommended by default in CLUSTAL W, and the latter was chosen because higher gap extension penalties produced poor alignments due to the presence of multiple evolutionarily related domains within genes. Final evolutionary analyses were conducted on an alignment consisting of protein sequence of all homologous OAS domains (fig. 4
). This alignment was constructed using the default options in CLUSTAL W.
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To place a temporal perspective on the evolution and diversification of the OAS gene family, we estimated the divergence time for different branching points in the inferred phylogeny using the molecular clock concept (Zuckerkandl 1987
). A Poisson model of amino acid substitution was used to correct for multiple substitutions, and the equalities of evolutionary rates in sister lineages were tested using the two-cluster relative-rate tests (Takezaki, Rzhetsky, and Nei 1995
), as implemented in the PHYLTEST program (Kumar 1995
).
Results
Genomic Structure of the Human OAS Locus
The ORF-Finder predicted 936 potential ORFs in the human PAC clone RPCI1-71H24. BLASTP analysis of these ORFs and the exploration of the related literature yielded 33 exons matching the known OAS sequences (fig. 1A
). The most distal region containing six exons matching p40 (Benech et al. 1985
) is 13-kb long. This segment is within 19 kb of a 37-kb region containing 15 novel exons that can be aligned to form three domains (N, amino; M, middle; C, carboxyl) for the p100 OAS cDNA (see Rebouillat et al. 1999
). The intron separating domains N and M and that separating M and C are 0.8 kb each. The proximal region contains 11 exons spanning 32 kb that match two domains (N and C) of the cDNA sequence for p69. A 4.5-kb intron is found between these two domains. The p100 and p69 genes are separated by a 4-kb intergenic region. Therefore, the three OAS genes occupy 103 kb of the 163-kb genomic fragment. Table 2
shows exon and intron lengths of human p40, p100, and p69 genes. In total, the OAS protein-coding sequences account for a small fraction of the genomic fragment occupied by this gene cluster. Since no other putative genes were found within the chromosomal region containing p40, p100, and p69 genes, these genes appear to form an uninterrupted cluster on human chromosome 12 (fig. 1A
).
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The exon-intron boundaries for the -I, ß-II,
-III,
-IV, and
-V junctions are in intron phases 0, 1, 0, 2, and 0, respectively (table 2
). If an intron interrupts the coding sequence between first and second codon positions, then the intron is said to be in phase 1. Phase 2 introns interrupt the codon between the second and third positions, and phase 0 introns are found between codons. Identity of intron phases among different domains indicates that the genomic structures of human 2'5'OAS genes have remained unchanged since their origin, with the exception of the splice site mutation in p100M. Conservation of the genomic sequence around the exon-intron boundaries is further reflected in the preservation of nucleotide sequences around the homologous exon-intron and intron-exon boundaries (fig. 3
), as inferred using the Schneider and Stephens (1990)
and Gorodkin et al. (1997)
methods.
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Five rodent sequences comprise subgroup C-II, which shares a most recent common ancestor with subgroup C-I (BCL = 100%). These five rodent sequences are further subdivided into groups C-IIa (Rno-oas2, Mmu-L1) and C-IIb (Rno-oas, Mmu-L2, Mmu-L). Groups C-I and C-II diverged before the primate-rodent split; this divergence was followed by the emergence of subgroups C-IIa and C-IIb in the common ancestor of murid rodents (mouse and rat). Within Mus, the presence of two distinct p40-like genes (Mmu-L2 and Mmu-L) shows recent evolution of additional genes. Rutherford (1991)
noted that Mmu-L1 and Mmu-L2 are linked. In light of the close relationship of the Mmu-L1, Mmu-L2, and Mmu-L sequences (fig. 5
), it is likely that all three genes form a linked unit. Therefore, p40 genes compose a multigene family within rodents.
The mammalian p40 genes are closely related to the p100C and p69C domains (BCL = 91%). Together, they compose the supergroup C. Human and mouse OASL proteins, lacking 2'5'OAS activity, show a statistically supported cluster (BCL = 98%) and group with the known bird OAS (Gga-oas) sequence (BCL = 67%; group D). In an attempt to determine the root of this tree to identify the most ancient group(s), we used the marine sponge sequence (Gcy) in phylogenetic analysis. However, the root could not be placed reliably in that phylogenetic analysis, because sequence similarity between Gcy and all other sequences is less than 20% (table 3 ). Therefore, the status of the marine sponge sequence as a member of the OAS gene family is uncertain at this time, and thus it is not included in figure 5 .
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The human genome contains 15 times as many genes as yeast (Goffeau et al. 1996
) and 5 times as many genes as Caenorhaditis elegans (The C. elegans Sequencing Consortium 1998
). Much of this increase in gene content is due to gene duplications through a variety of mechanisms, including chromosome, genome, and individual gene duplications, and the recruitment of preexisting modules to form new composite genes (Ohno 1970
; Nei 1987
; Li 1997
). The gene family containing the vertebrate OAS genes is one gene family which has expanded by gene duplications, domain coupling to form multidomain genes, block duplications to produce copies of multiple genes at the same time, and domain duplications within genes, as discussed below.
Evolution by Gene Duplication
We begin with the evolution-by-gene-duplication scenario for p40, p100C, and p69C, which show the highest sequence similarity and form a statistically supported group to the exclusion of all other domains (fig. 5
). Because p40, p69C, and p100C do not occupy adjacent positions in the human genome (fig. 1A
), an explanation of their origins by recent tandem duplications would require multiple gains and losses of domains. Instead, they appear to have shared a common ancestor in the earliest stages of the OAS gene family expansion. This is illustrated in a parsimonious gene duplication scenario given in figure 6 , which is based on the phylogeny in figure 5
and the relative positions of OAS genes on the human genome.
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The next event in the history of OAS gene family evolution was a chromosomal segment duplication. Two of these genes were the ancestors of the modern human p59 and p40 genes, and the other pair underwent domain coupling to form a two-domain gene (p69). The two-domain gene, reported only in mammals, duplicated again to give rise to a total of three genes (p40, p69, and p100). Subsequently, an internal domain duplication converted the two-domain p100 gene into a three-domain gene. Due to extensive heterogeneity of evolutionary rates among lineages in this gene, the timing of this duplication event cannot be established unless homologous sequences are known from other mammals. However, this internal domain duplication appears to have occurred much later than the initial origin of the p100 gene, as indicated by the length of the ancestral branch for p100M and p100N. In this regard, it is interesting to note that the 6465-cM segment of mouse chromosome 5 shares an ordered two-gene conserved synteny with human chromosomal segment 12q24.112q24.3 (Mouse Genome Database 1999
). In this case, two loci, Tbx5 and Tcf1, in mouse chromosome 5, are also found in human chromosome 12 at positions 12q24.1 and 12q24.3, respectively. Therefore, the human OASL, p40, p100, and p69 2'5'OAS genes are flanked by the two loci in an apparent conserved synteny. This suggests that the current genomic structure of the human OAS genes was established in the earliest known history of placental mammals.
In rodents, there are multiple p40-like genes (groups C-IIa and C-IIb) with high sequence similarity to the human and other rodent p40 genes (group C-I). The first gene duplication that led to the emergence of the ancestor of group C-II genes occurred in the common ancestor of primates and rodents. This was followed by a gene duplication in the ancestor of murid rodents (rats and mice). Because groups C-I and C-IIb show similar rates of evolution, we estimated the divergence time for the split of C-IIa and C-IIb in a lineage-specific manner by using only the C-IIb lineage length to date the divergence of C-IIa and C-IIb. In this case, the length of the C-IIb lineage from the common ancestor of C-I and C-IIb is 0.2132, and that from the common ancestor of C-IIa and C-IIb is 0.0866. Assuming a divergence time of 110 MYA for humans and mice (Kumar and Hedges 1998
), the rate of evolution is computed to be 1.9 x 10-3 substitutions/Myr. This suggests the presence of one gene duplication ~65 ± 11 MYA to produce subgroups IIa and IIb, followed by a gene duplication within subgroup C-IIb in mice 11 ± 4 MYA. Therefore, the 2'5'OAS gene family in rodent genomes has expanded recently to include multiple small 2'5'OAS isoforms.
The Hsa-OASL and Mmu-OASL genes form a sister group to the bird Gga-oas sequence. Based on the evolutionary relationships, we would expect Hsa-OASL and Mmu-OASL to be orthologous. However, the evolutionary distance observed between these two sequences is much larger than that expected for two orthologous sequences between these mammals if Gga-oas is an outgroup. In fact, if we conservatively assume that the branch connection between the two OASL genes with the bird sequence is the oldest splitting point, then the assumption of a molecular clock indicates a minimum divergence time of 276 MYA for Hsa-OASL and Mmu-OASL, which predates their species divergence by 160 Myp. This suggests either that the mammalian OASL genes have been evolving two times as fast as bird sequences or that the OASL genes are paralogous.
Gene Content in Vertebrate Genomes
Based on the evolution by gene duplication scenario in figure 6 , a number of predictions can be made about the gene contents in genomes of different vertebrates (table 4
). Within vertebrates, the OAS gene activity is induced by IFN in all mammals tested, and chicken IFN strongly induces 2'5'OAS in cultured cells. RNaseL activity is also detected in chicken cells, in which it appears to be involved in mediation of an antiviral response (West and Ball 1982
; Sokawa and Sokawa 1986
; Hartmann et al. 1998
; Yamamoto et al. 1998
). 2'5'OAS and pppA(2'p5'A)n-binding activities have also been detected in three reptilian species, Agama caudospinosa, Gekko gekko, and Mabuya brevicollis, suggesting that they may also have this inducible antiviral system (Cayley et al. 1982
). Therefore, the most recent common ancestor of birds and mammals may have already contained an OAS gene with 2'5'OAS and pppA(2'p5'A)n-binding activities. While the amphibians contain low levels of pppA(2'p5'A)n-binding activity, the 2'5'OAS activity has not been detected (Cayley et al. 1982
) to date. Neither 2'5'OAS nor pppA(2'p5'A)n-binding activity has been detected in fish (Salmo trutta). Therefore, the evolution of the 2'5'OAS host-defense activity appears to be specific to tetrapods, and the earliest gene duplication events do not seem to have occurred prior to the amphibian and amniote divergence 350 MYA (Benton 1993
; Kumar and Hedges 1998
).
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The OAS genes contain several highly conserved subregions. These include a glycine-rich region, GGS(S/T)(G/A)(K/R)/GT, an adjacent DAD motif, and an FDVLP motif within the ß exons of the small isoforms and the ß exons of the C-terminal domains of p69 and p100 (group C in fig. 5
). The glycine-rich region resembles an ATP/GTP-binding motif (Hartmann et al. 1998
; Rebouillat et al. 1999
). Molecular modeling analysis suggests that these C-terminal domains form a
ßß
ßßß structure corresponding to the three-dimensional crystal structures of several DNA and RNA polymerases (Sarkar et al. 1999b
). In DNA polß, three aspartate residues corresponding to aspartates within the DAD and FDVLP motifs of OAS form the active site of the enzyme. Mutation of any of these aspartates to alanine inactivates OAS, suggesting that they are essential for catalytic activity (Sarkar et al. 1999b
). Similar protein folding of this region to DNA polß suggests that the OAS enzymes may have evolved from an ancestral polymerase.
Interestingly, the DAD motif in group C domains is also found in a distantly related Gga-oas sequence, which also has OAS activity. In contrast, the OASL genes have lost this signature, as have the N and M domains (groups A and B in fig. 5
). Therefore, domains in groups A and B may have lost the catalytic activity after gene/domain duplications. The small isoform (group C), which presumably evolved first, is active only as a tetramer (Ghosh et al. 1997
), where the p69 isoform is a dimer (Marié, Rebouillat, and Hovanessian 1999
; Sarkar et al. 1999b
) and the p100 isoform is active as a monomer (Rebouillat et al. 1999
).
Given that the tetrameric protein needs only one domain to retain catalytic activity, the additional domains did not need to retain the conserved DAD motif (Sarkar et al. 1999b
). This suggests that domain duplication and linking into a single transcription unit might have evolved to increase the efficiency of function enzyme production, rather than substantially altering the gene function by specific mutational changes in the protein sequence. The apparent recent divergence of multiple rodent genes that are not shared among human genes suggests that the evolution of the OAS locus may be an ongoing process in which mammals continue to develop new defensive strategies against viral pathogens.
Expansion of the OAS gene family points to the concurrent evolution of specific and innate immunity in early mammalian history. This component of the antiviral system appears to have evolved only in tetrapods, and, once evolved, it became established in these genomes. The antiviral activity for this system can be demonstrated in many highly divergent organisms. For instance, plants are not known to have a 2'5'OAS-RNaseL system (Cayley et al. 1982
; Mitra et al. 1996
); however, the addition of pppA(2'p5'A)n to tobacco (Nicotiana glutinosa) confers resistance to tobacco mosaic viral infection (Devash et al. 1984
), and the expression of mammalian 2'5'OAS in transgenic potato plants correlates with resistance to potato virus X (Truve et al. 1993
). In this regard, the fact that these genes appear to have undergone gene duplications recently, at least in placentals mammals, may further suggest that stronger antiviral response confers selective advantage.
Thus, the OAS genes involved in the antiviral response originated early in the ancestors of the modern tetrapods and underwent expansion in mammals. This expansion led to the evolution of genes with OAS activity, which is required in the innate immunity response known to exist uniquely in vertebrates. The expansion of the immunoglobulin and the major histocompatibility complex (MHC) genes in response to selective pressures is well known. Proliferation of the OAS gene family for facilitating an antiviral response could have occurred as a mechanism for increasing the overall magnitude of induction in response to interferons or other inducers. Alternatively, the ancestral and the duplicated genes could have evolved and diversified to provide for distinct mechanisms of induction and/or distinct enzymatic properties. In the present case, the adaptive nature of the antiviral host-defense and the existence of the cellular machinery to evolve a new developmental pathway appear to have led to the generation of a dynamic gene family.
Acknowledgements
We thank S. Gadagkar and S. J. Newfeld for helpful comments on an earlier version of this manuscript. This research was supported by an NIH grant to S.K. and a research incentive award to G.F.-S. from Arizona State University.
Footnotes
Shozo Yokoyama, Reviewing Editor
1 Keywords: phylogeny
oligoadenylate synthatase genes
gene duplication
molecular evolution
host defense
2 Address for correspondence and reprints: Sudhir Kumar, Department of Biology, P.O. Box 871501, Arizona State University, Tempe, AZ 85287-1501. E-mail: s.kumar{at}asu.edu
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