Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
Correspondence: E-mail: silvoc{at}mrc-lmb.cam.ac.uk.
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Abstract |
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Key Words: AID APOBEC antibody gene diversification hypermutation RNA editing DNA deamination immunity
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Introduction |
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APOBEC1 was the first member of the family to be discovered (Teng, Burant, and Davidson 1993) and has been used as a paradigm for subsequent investigations. However, here we use phylogenetic sequence analysis to gain insight into the likely ancestral function of the AID/APOBEC family and conclude that APOBEC1 is a recent evolutionary arrival and that AID and APOBEC2 are the ancestral family members. It is possible, therefore, that RNA editing is a recently acquired activity for an AID/APOBEC family member and may not have provided the major driving selective force for the evolution of the family.
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Materials and Methods |
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To minimize the risk that relevant, available genes had been omitted from the pool, Blast searches were performed using human AID/APOBEC sequences as queries on specific EST (frog, chicken, horse, cow, and pig) and genome databases (H. sapiens, M. musculus, R. norvegicus, T. rubripes, D. rerio, C. elegans, D. melanogaster, D. discoideum, S. cerevisiae, S. purpuratus, and C. intestinalis). The final data set consisted of 160 protein sequences belonging to characterized or putative deaminases.
Owing to the divergence in the primary sequences among the various groups of deaminases, we restricted our phylogenetic analysis to the region containing the zinc-coordinating motif. Most vertebrate deaminases (dCMP, Cytosine, and AID/APOBEC) encode the [HC]XE-PCXXC signature of the zinc-coordination motif on a single 150-nt to 300-nt exon: for these deaminases, the analyses were performed using the sequence of this exon. In the case of cytidine deaminases and ADAR/ADATIs, where the zinc-coordinating motif is encoded on more than one exon, we used a 150amino acid sequence corresponding to the exon boundaries of the zinc domain of the (dCMP, Cytosine, and AID/APOBEC) deaminases. Regarding the double-domained APOBEC3s, we divided the molecules according to the domain boundaries and considered each of them individually. DNA sequences from the exon encoding for the zinc-coordinating domain were used to generate the tree shown in figure 2. Sequences were aligned with ClustalX (Thompson et al. 1997) using the [HC]XE and PCXXC motifs as guides: the resulting alignment was used to generate a phylogenetic tree (the alignments are available as Supplementary Material online).
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Logo alignments (Schneider and Stephens 1990), for consistency given the restricted distribution of AID/APOBEC genes, were generated using only animal sequences.
Analysis of Synteny
Maps were derived using the assemblies from human (release 34), murine (release 32), chimpanzee (release 22.1.1), rat (release 22.3b.1), chicken (release 22.1.1), pufferfish (release 22.2c.1) and zebrafish (release 22.3b.1) genomes. Where adequate annotation was not available (in particular for the chicken and the pufferfish genomes), the genes flanking the AID/APOBEC1, APOBEC2, and APOBEC3 loci in human and mouse were Blasted against the relevant genomes and, from the results, the genomic contigs then compared with the human/rodent loci.
Assaying Mutator Activity
The pufferfish AID cDNA was assembled by joining PCR-derived exons from a genomic DNA library (details of the primers used are in table 1 of Supplementary Material online). The prokaryotic expression plasmid was generated by cloning the assembled cDNA as an NcoI/BamHI fragment into pTrc99A (Petersen-Mahrt, Harris, and Neuberger 2002). Mutation analyses were performed as described in Petersen-Mahrt, Harris, and Neuberger (2002) using E. coli strains KL16 (Hfr (PO-45) relA1 spoT1 thi-1) and its ung-1 derivative (BW310). Bacterial cultures were grown at either18°C for 32 h or 37°C for 14 h.
Serine Codon Preference in Fish IgV Genes
The sequences of pufferfish and zebrafish genomic immunoglobulin V genes were retrieved from the Ensembl database and checked for presence of the heptamer/nonamer rearrangement signal sequences at their 3' ends. The V gene sequences were then aligned with ClustalX and the resulting alignment used to generate a tree and assign individual V gene sequences to the different locus and family groups. CDRs were identified by similarity to those in published fish V gene sequences (Widholm et al. 1999; Danilova et al. 2000).
Cloning of Dogfish AID
Degenerate primers (see table 1 in Supplementary Material online) were used for RT-PCR amplification of AID cDNA from stimulated spleen cells of spotted dogfish (Scyliorhinus caniculus).
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Results and Discussion |
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The tree (fig. 1A) reveals the segregation of the different deaminase genes into four major clusters. One comprises the cytidine deaminases (CDAs) and another the AID/APOBEC homologs. A third comprises a family of putative RNA-binding proteins and many of the adenosine deaminases that work on RNA (ADAR1, 2, and 3) as well as ADAT1 (which is a tRNA modifying adenosine deaminase). The fourth is a functionally heterogeneous grouping in which the known dCMP deaminases, ADAT2s and ADAT3s form distinct clusters. The other members of the group include cytosine deaminase (an activity that has been identified in fungi but not described in metazoa) as well as a variety of sequences encoding genes of unknown function.
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The zinc coordination motif of the AID/APOBEC family conforms to the HAE consensus common to the other deaminases (except for cytidine deaminases, which display CAE) (fig. 1B). The alignments also highlight distinctive features of the AID/APOBEC family. Thus, several individual amino acids are conserved downstream of the PCXXC motif (e.g., several leucines, an arginine, and a glycine) and a conserved phenylalanine is found two positions downstream of the HAE motif, which has been shown to be important in RNA binding by APOBEC1 (Navaratnam et al. 1995). In addition, we identify a CYX[VI]TW[YF]XS[WS]S consensus that is located on the amino-terminal flank of the PCXXC motif and which is not found in the non-AID/APOBEC pyrimidine deaminases.
APOBEC2 and AID Homologs Trace Back to Bony Fish
Members of the AID/APOBEC gene family can be separated into AID, APOBEC1, APOBEC2, and APOBEC3 clusters based on the sequences surrounding the putative zinc coordination motif (fig. 2). Database screening reveals homologs of mammalian AID and APOBEC2 in chicken, frog, and bony fish. Indeed, whereas the genome sequences of pufferfish and zebrafish reveal the presence of a single AID ortholog (Zhao et al. 2004; Saunders and Magor 2004), both species of bony fish harbor two distinct APOBEC2 paralogs (fig. 2). The existence of duplicate APOBEC2s likely reflects the genome duplication that appears to have occurred at the origin of the ray-finned fishes (Taylor et al. 2003; Christoffels et al. 2004).
Regarding chromosomal location, both the AID and APOBEC2 loci are located in a syntenic region in human, mouse, and chicken. Microsynteny for the AID locus is also maintained in pufferfish (fig. 3A), but the incompleteness of its genome sequence precludes determination of whether microsynteny is also conserved with APOBEC2.
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To ascertain whether the gene identifiable in bony fish as the sequence homolog of mammalian AID does indeed exhibit a similar DNA deaminating activity, we exploited a bacterial genetic assay for mutator activity. A pufferfish AID cDNA was expressed in E. coli, but initial experiments monitoring the frequency of rifampicin resistant mutants after growth at 37°C failed to reveal any mutator activity. However, bearing in mind that fish are cold-blooded, we repeated the assay, but this time allowing the bacteria to grow at 18°C (as opposed to 37°C). A clearly enhanced mutation frequency caused by pufferfish AID was now detected (fig. 4A). As expected for mutation through cytosine deamination, this stimulation of mutation was augmented in a background deficient in uracil-DNA glycosylase. As judged by analysis of the distribution of mutations conferring resistance to rifampicin, the fine target specificity of pufferfish AID is broadly similar to that of human AID (fig. 4B).
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The phylogenetic relationships of the sequences (fig. 1A and 2) suggest that APOBEC1 (and APOBEC3 [see below]) are most likely to have arisen by duplication of the AID (as opposed to the APOBEC2) locus. The similar location of the intron/exon boundaries in AID, APOBEC3, and APOBEC1 as compared with those in APOBEC2 (fig. 7A) is consistent with this suggestion. The presumed duplication of AID that gave rise to APOBEC1 resulted in the two genes being closely related on the chromosome. There is, however, a striking contrast between the AID/APOBEC1 loci in primates and rodents. Whereas in human and chimpanzee, AID and APOBEC1 are separated by approximately 1 Mb and are in the same transcriptional orientation, in rodents they are located within approximately 30 kb and are oppositely oriented (fig. 3A). The fact that the chicken genomic region surrounding AID resembles the rodent genomic region suggests that the difference between human and rodent loci originated in a 1 Mb inversion containing the APOBEC1 locus that took place after the rodent/primate divergence.
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Evolution of the APOBEC3 Family
As with APOBEC1, orthologs of APOBEC3 are also restricted to mammals. However, whereas there is a single APOBEC3 gene in mouse and rat as judged from genomic databases (as well as by Southern blot analysis [data not shown]), there are eight APOBEC3 genes in the human. Six of these genes, designated APOBEC3A to APOBEC3G, form a 130-kb cluster on chromosome 22 (Jarmuz et al. 2002). (The sequence originally designated APOBEC3E appears likely in the light of EST evidence to encode the second domain of the APOBEC3D [see also Wedekind et al. {2003}]). Inspection of databases also reveals two additional APOBEC3 genes. One, which we designate APOBEC3H (equivalent to ARP10 [Wedekind et al. 2003]) is expressed at least in lymphoid tissue and placenta, as judged from EST databases and is located 14 kb downstream of the APOBEC3G locus. The other (NCBI LOC196469) is on human chromosome 12q24.11 and is likely a pseudogene originated from a very recent duplication of the APOBEC3G gene. It has two partial putative zinc domains, lacks introns (figure 1 in Supplementary Material online), and has no ESTs unequivocally ascribable to it.
The region of human chromosome 22 containing the APOBEC3 cluster is syntenic to a segment of murine chromosome 15, the only major difference being the APOBEC3 expansion in human. Interestingly, although APOBEC3 genes are restricted to mammals with homologs absent from the bony fish and chicken genome sequences, synteny between the human, chicken, and pufferfish genomes is evident in the region flanking the APOBEC3 locus. Thus, the genes flanking the human APOBEC3 cluster are conserved in chicken and pufferfish but with the APOBEC3 genes themselves missing, supporting the later origin of the APOBEC3 locus (fig. 3B).
The draft genome of the chimpanzee reveals that orthologs of all the human APOBEC3 genes are present (but with some uncertainty regarding APOBEC3A), including the pseudogene on the chromosome 12, placing the expansion of this locus at the beginning of the primate evolution.
How might the APOBEC3 locus have evolved, given that primates have multiple genes (containing either one or two putative zinc-cordination domains [fig. 7B]), whereas rodents have a sole double-domained APOBEC3? It is not merely a simple case of gene amplification. From the phylogenetic tree shown in figure 2, it appears that the zinc-coordination domains of the APOBEC3s can be grouped into two major clades, labeled Z1 and Z2, with the Z1 group being further divisible into Z1a and Z1b. Thus, for example, whereas the Z1 domains retain the SWS motif upstream of the PC-C, which is common to other AID/APOBEC family members, a threonine residue is found in place of the first serine in Z2 domains.
The double-domained rodent APOBEC3 is a Z1-Z2 composite, whereas all human APOBEC3s have either a Z1 (single-domained) or Z1-Z1 (double-domained) structure, except for human APOBEC3H, which consists of a single Z2 domain. The likely evolution, therefore, is from a common ancestor that harbored both Z1 and Z2 domains in the form of either single- or double-domained APOBEC3 proteins (fig. 7A). Consistent with this proposal, analysis of EST sequence databases from cow and pig (that have diverged before the separation of the rodent/primate lineage [Madsen et al. 2001; Murphy et al. 2001]) reveals that Z1 and Z2 domains are both present in arctyodactyls and contribute to both single-domained and double-domained APOBEC3 proteins (fig. 2).
It is notable that although all the domains of the human APOBEC3 genes, except APOBEC3H, are of the Z1 type, the division of Z1 domains into Z1a and Z1b subgroups reveals a complex set of similarities between the individual Z1 domains of the different APOBEC3 genes (fig. 2 and 6B). In some cases, the C-terminal domain is of Z1a type and sometimes of Z1b type. These sequence relationships suggest that there has been substantial shuffling of sequence information between the domains during evolution. Such amplification and reassortment in the primate APOBEC3 locus is likely to have occurred through unequal crossover/recombination. It is possible that retroviral elements might have facilitated this process, in view of the fact that their relicts sum up to the 19% of the entire human APOBEC3 locus, with repetitive elements (mainly LTRs from ERV class I) heavily represented in the regions flanking APOBEC3G and APOBEC3H (fig. 7C). This hypothesis is supported by the fact that the APOBEC3 pseudogene on chromosome 12 has originated from a retrotranscriptional event. Recently, it has been suggested that evolution of APOBEC3G itself in primates has been driven by positive selection (Sawyer, Emerman, and Malik 2004; Zhang and Webb 2004). Given the demonstrated role of some APOBEC3 members in viral restriction, it may well be that issues pertaining to host/virus interaction have provided the driving force for the rapid expansion of the entire APOBEC3 locus in primates.
Dynastic Relationships of AID/APOBEC Family Members
The results presented here support a scenario in which AID and APOBEC2 are the ancestral members of the AID/APOBEC family with APOBEC1 and APOBEC3 being later arrivals, derived from AID, and restricted to mammals. We cannot formally exclude the possibility that APOBEC1 and/or APOBEC3 arose early but were then lost in fish and chickens. However, because bony-fish diverged from the tetrapod lineage around 450 MYA and birds diverged around 310 MYA (Benton 1990; Kumar and Hedges 1998), this hypothesis would seem unlikely, because it implies that APOBEC1 and APOBEC3 were independently lost in distant lineages.
Although AID homologs can be traced back to cartilaginous fish, and APOBEC2 homologs are at least found in bony fish, homologs are not identifiable for either protein among nonchordates, nor are they present in the genome of Ciona intestinalis, an invertebrate chordate (Dehal et al. 2002; Azumi et al. 2003; the present work). Thus, the phylogenetic sequence analysis provides no indication as to whether AID evolved from APOBEC2 or vice-versa. It will certainly be interesting in the future to gain insight into the physiological function of APOBEC2.
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Supplementary Material |
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Acknowledgements |
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Footnotes |
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2 Present address: Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire, UK.
Claudia Schimdt-Dannert, Associate Editor
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