Department of Ecology and Evolutionary Biology and Museum of Zoology, University of Michigan, Ann Arbor
Correspondence: E-mail: mindell{at}umich.edu.
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Abstract |
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Key Words: retron Archaea group II intron Methanosarcina origin of introns retroelement
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Introduction |
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Retroids have not previously been identified in Archaea. Three groups of retroids are found in Bacteria and organelles: retrointrons, retrons, and retroplasmids. Retrointrons are self-splicing RNAs that can act as retroelements when they encode an RT open reading frame (ORF). The majority of retrointrons identified are group II introns; a twintron is a group II intron with another inserted into it, and group III introns are abbreviated versions of group II introns. Group II introns are found in the mitochondria of plants and Fungi and the chloroplasts of euglenoids and algae, as well as in Bacteria such as Cyanobacteria and -Proteobacteria (reviewed in Zimmerly, Hausner, and Wu 2001). Retrointrons have six conserved RNA secondary structure domains, and the RT ORF, when present, is located in domain 4.
Another group of retroids, called retrons, are found in some Bacteria and encode DNA and RNA complexes, referred to as "multicopy single-stranded DNA," or msDNAs, which are synthesized by RT (reviewed in Lampson, Inouye, and Inouye 2001). The function of msDNA remains unknown. In addition to the RT ORF, retrons consist of two loci that are situated in opposite directions: msd encodes the DNA strand of the msDNA, and msr encodes the RNA strand of msDNA. Two sets of inverted repeats direct the proper folding of the RNA to allow it to serve as a primer and template for cDNA synthesis.
A third group of retroids, called retroplasmids, are found in the mitochondria of Fungi and are linear (Walther and Kennell 1999) or circular (e.g., Natvig, May, and Taylor 1984; Pande, Lemire, and Nargang 1989) plasmids that contain and are replicated by RT.
Retroids in Archaea and the Origin of Introns
Assessing the presence of retroids in Archaea, particularly retrointrons, is relevant to several questions concerning early evolution, and one such question is the origin of the spliceosome and its associated introns in eukaryotes. Although it has been proposed that spliceosomal introns were part of the prototypical gene and that introns were "early" (e.g., Gilbert, Marchionni, and McKnight 1986), much recent evidence supports the later advent of spliceosomal introns in eukaryotes (e.g., Logsdon 1998). Similarly, because retrointrons are present in many extant Bacteria, mitochondria, and chloroplasts but not present in Archaea or in the nuclear genome of eukaryotes, it is thought that they originated not in the progenote, but later in Bacteria. Similarities in structure and function suggest that these retrointrons may be related to the spliceosome. According to the "mitochondrial seed" hypothesis, retrointrons, which originated in Bacteria, were introduced via the mitochondrial endosymbiont into the eukaryotic nuclear genome, where the five domains of the retrointron catalytic core structure split into pieces and evolved into the five small nuclear RNAs (snRNAs) that form the spliceosome (Michel and Lang 1985; Sharp 1985; Roger and Doolittle 1993; Sontheimer and Steitz 1993; Eickbush 1999; Simpson, MacQuarrie, and Roger 2002). If retrointrons found in Archaea are sister to retrointrons in Bacteria, this would be consistent with the "introns early" hypothesis, which suggests that introns were present in the progenote, their common ancestor. However, if retrointrons were transferred more recently to Archaea and are paraphyletic in analyses with bacterial retrointrons, this would be consistent with the hypothesized late advent of introns in Bacteria and subsequent transfer via the mitochondrial endosymbiont (seed) to eukaryotes.
Like the snRNAs of the spliceosome, the self-splicing RNAs of retrointrons display many of the properties of hypothesized catalytic RNAs in the RNA world (Madhani and Guthrie 1994; Jeffares, Poole, and Penny 1998). A homologous relationship has been proposed between these extant RNAs and catalytic RNAs from the RNA world. Support for such homology is contingent upon the hypothesized ancestral form of retrointrons. Retrointrons have been observed in two forms: as RNA catalytic domains only and as RNA catalytic domains along with an RT ORF (Zimmerly et al. 1995). If the similarities between the hypothetical ribozymes of the RNA world and the catalytic RNAs of retrointrons are homologous rather than convergent, then retrointrons without RT should be older than retrointrons with RT (Lambowitz and Belfort 1993; Wank et al. 1999). Alternatively, if retrointrons with RT are older, it would suggest that a retroelement independently gained catalytic RNA activity (Curcio and Belfort 1996; Zimmerly, Hausner, and Wu 2001). It seems only reasonable to ask, therefore, if there are retrointrons in Archaea and if they have RT ORFs or not.
The apparent lack of retroids in Archaea, given the abundance and variety of forms of retroids in Bacteria and organelles, has been an enigma. However, in the recently published genomes of the acetate-utilizing archaeal methanogens Methanosarcina acetivorans (Galagan et al. 2002) and M. mazei (Deppenmeier et al. 2002), several ORFs are annotated as RT. These annotations led us to the characterization of 18 retroids clustered at seven loci of the M. acetivorans genome and four retroids at two loci of the M. mazei genome, almost all of which are retrointrons. These first retroids to be identified and examined in Archaea indicate an intriguing record of duplication and horizontal transmission.
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Materials and Methods |
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To estimate phylogeny, we used a Bayesian inference (BI) approach (Yang and Rannala 1997; Mau, Newton, and Larget 1999) with Metropolis-coupled Markov chain Monte Carlo, or (MC)3, to approximate the posterior probabilities (PP) of the trees in MrBayes 3.0alpha (Huelsenbeck and Ronquist 2001). Bayesian inference has advantages over other methods of phylogenetic inference in interpretation of results, consistency (Wilcox et al. 2002) and computational speed (Larget and Simon 1999). Although some simulations have demonstrated artifactually high PP support values, they also indicate that the reliability of the results depends on appropriateness of the model (e.g., Suzuki, Glazko, and Nei 2002). To address this, we used a substitution model known to outperform other models on RT amino acid sequences, rtREV (Dimmic et al. 2002), and estimated the parameter for the
distribution of rates. The search was run twice, starting from random trees with four simultaneous Markov chains and sampling every 100 generations. The proportion of searches in which any given node (set of relationships) is found during the chain is an approximation of its posterior probability and provides an indication of support for that node based on the data set. For comparison to BI, we also used maximum-parsimony (MP) and neighbor-joining (NJ) distance in PAUP* (Swofford 2002) with 1,000 bootstrapped data sets, and summarized as a 50% majority-rule tree.
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Results |
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The 21 RT ORFs identified in M. acetivorans and M. mazei all significantly fit the RVT HMM, and we used RVT to align them. From the resulting alignment, it was apparent that at three loci in M. acetivorans (3, 4, and 5) an RT ORF had been split in two by the addition of another RT ORF. This is similar to the arrangement of chloroplast "twintrons," which are retrointrons within retrointrons (Copertino and Hallick 1991). For further comparative analysis, the split ORFs of the external introns were concatenated: MA4627 and MA4625 at locus 3, MA2799B and MA2796 at locus 4, and MA4184 and MA4182 at locus 5 (fig. 1). The RT subdomains of MA4183 and MA2797 are identical, so only a single sequence was used to represent them. Additionally, the HMM identified an RT ORF in M. acetivorans, MA2102 at locus 7, with similarity to retrons. When the resulting 17 RT ORFs (16 retrointrons + 1 retron) are aligned with RVT, the alignment contains 239 out of 260 amino acids in the RVT HMM.
According to the HMM alignment, the retron RT and seven of the 16 retrointron ORFs have all seven subdomains (tables 1 and 2). Nine RTs contain two to four subdomains, and one RT, MA2799, has only a single subdomain. The ORF of retrointrons also contains domains 0, X, and Zn, the presence of which is variable in the ORFs discussed here (Dai and Zimmerly 2003).
Loci 1, 2, and 6 in M. acetivorans each contain a single retrointron, as identified by the presence of an RT ORF, flanked by a transposase domain. Loci 3, 4, and 5 each contain a twintron and an additional retrointron downstream, with respect to the direction of replication, and locus 5 has an additional downstream retrointron. The retron at locus 7 is flanked upstream by a hypothetical protein and downstream by a type I site-specific deoxyribonuclease. In M. mazei, locus 8 contains three retrointrons separated by transposase domains in various orientations, and locus 9 contains a single retrointron. Arrows at the end of each locus in figure 1 indicate the replication direction. The retrointrons at four of the six loci of M. acetivorans and one of two loci of M. mazei are oriented opposite the direction of replication. The retron at locus 7 (MA2102) of M. acetivorans is also oriented opposite the direction of replication.
For each of the nine loci that contain RT ORFs in the two genomes, Blast searches were used to characterize intergenic regions. Short stretches (50 to100 bp) of unique nucleotide sequences that are repeated three to 29 times elsewhere in the genome were identified (fig. 1). We also used a Blast search to identify putative retrointron RNA domains on each side of the retrointron ORFs. Although we identify many of the group II RNA domains using this method, Dai and Zimmerly (2003) provide a more detailed analysis of these domains, and we have annotated figure 1 accordingly.
Phylogenetic Analysis
We used the 239 amino acid alignment (based on RVT, described above) of the 16 retrointron and one retron RT ORFs to build an archaeal-specific HMM, called ARCH-RVT. ARCH-RVT was used to search all nonredundant GenBank CDS translations+PDB+SwissProt+PIR (November 1, 2002) and returned a set of 335 ORFs (excluding ORFs from M. acetivorans and M. mazei) with bit scores of 17 or greater, suggesting that they are members of the same family as the archaeal RTs, and with an E value (expectation value) of 0.05 or less, which indicates that the bit score is better than expected from random sequence. We aligned the resulting sequences with RVT, clustered them into 70% identity groups using BlastCLUST, retained only a single representative from each group, and added in the 17 archaeal sequences (16 retrointrons and one retron), resulting in a final alignment 260 amino acids long with 177 unique RT sequences.
BI analyses for this alignment resulted in the topology shown in figure 2. A burn-in period of 1.2 x 106 generations was necessary for the chains to reach stationarity, and the chains were run for an additional 1 x 106 generations to sample the posterior probability landscape. The phylogeny identifies the major monophyletic lineages of RT related to retrons and retrointrons, including 64 non-LTR retrotransposons (retroposons), three retroplasmids, 22 retrons, and 88 retrointrons. Retroposons provide an appropriate outgroup to retroplasmids, retrons and retrointrons for phylogenetic analysis and were used to root the tree in figure 2 (Nakamura et al. 1997). In the overall phylogeny the major clades of retroids (retroplasmids, retrons, retroposons, and retrointrons) are each monophyletic. Retrointrons and retrons are sister clades and retroplasmids are sister to them.
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A second group of 13 retrointrons arises in the crown of the algal chloroplastlike group. It consists of two clades, which we named archaeal groups and ß. Archaeal group
consists of retrointrons from both M. mazei and M. acetivorans. In this clade, the external ORFs of the twintrons (loci 3, 4, and 5 in M. acetivorans) are basal to the two retrointrons found directly downstream of the twintrons (loci 4 and 5 in M. acetivorans) or alone (locus 6) and basal to three retrointrons from M. mazei (locus 8). The archaeal
/ß clade is sister to two bacterial full-length retrointrons, one from E. coli plasmid p0157 (ORF L0272) and another from P. putida (ORF494), which is at the locus of a transposon (Dai and Zimmerly 2002).
A third archaeal retrointron, MM3360, located alone at locus 9 of M. mazei, is in a group sister to the algal chloroplastlike group. MM3360 is sister to a retrointron fragment M.t.F1 from the bacterium Mycobacterium tuberculosis (Dai and Zimmerly 2002). M.t.F1 contains RT subdomains 1 to 3, whereas MM3360 contains subdomains 6 to 7. Interestingly, directly upstream of the M.t.F1 fragment is a microsatellite repeat. However, no such repeat is detectable surrounding MM3360.
The monophyly of retrointrons is supported by 84% PP, and the bacterial group C is supported as the basal retrointron group with 77% PP. Other major groups of retrointrons represented in figure 2 include bacterial group B, the fungal mitochondrial group, and potentially bacterial group A, represented by a single E. coli ORF (2443214). The basal position of the bacterial groups B and C is in agreement with previous analyses (Zimmerly, Hausner, and Wu 2001). No retrointrons from liverworts or plants in the mitochondrial group or euglenoids in the algal chloroplastlike group are present in the phylogeny.
The clade comprising the 22 retrons is shown in figure 3. This is a larger sample of retrons than has been previously examined (Lampson, Inouye, and Inouye 2001). The phylogeny identifies several new putative retrons and significantly extends the taxonomic distribution of retrons in Bacteria. Previously, retrons have only been identified in the -Proteobacteria and
-Proteobacteria. This analysis reveals retrons present in Cyanobacteria, Fusobacteria, Firmicutes, and ß-Proteobacteria, as well as in Archaea. The archaeal retron, MA2102, is sister to the Firmicutes retron, Staphylococcus aureus Sav2209.
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Discussion |
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The retroids in seven of the nine loci from M. acetivorans and M. mazei described here are oriented opposite the direction of replication in their respective genomes. Typically, the majority of genes in Archaea are transcribed in the same direction as DNA replication; however, in several archaeal genomes, including Pyrococcus horikoshii, P. abyssi, and P. furisus, around half of the genes are transcribed in the opposite direction of replication (Zivanovic et al. 2002). Although colinearity of transcription and replication might not be under heavy constraint in M. mazei and M. acetivorans as it is in other prokaryotes such as E. coli and Bacillus subtilis, selection generally appears to favor colinearity for highly expressed genes in Archaea as in Bacteria.
The phylogeny diagnoses the relationship between major groups of retroids: retrointrons, retrons, retroplasmids, and retroposons (fig. 2). Here, retrointrons and retrons are sister groups, whereas Nakamura et al. (1997), using a smaller data set and Neighbor-Joining, found retroplasmids and retrons as sister groups.
The phylogeny indicates common ancestry of the archaeal retroids with retroids from Bacteria, and four lateral transfers from Bacteria to Archaea (figs. 2 and 3). In light of the fundamentally similar genome organization of Bacteria and Archaea (Baumann, Qureshi, and Jackson 1995), we are not surprised retroids found in Archaea are related to those of Bacteria and organelles rather than eukaryotes. The difference in GC content between the retron MA2102 and the genome of M. mazei is consistent with LGT, and the presence of retrointrons at several different loci in M. acetivorans and two different loci in M. mazei, rather than at a single locus (Deppenmeier et al. 2002), suggest multiple LGTs and/or mobility of the retrointrons within Archaea. Zimmerly, Hausner, and Wu (2001) inferred horizontal transfer of retrointrons within and between bacterial genomes and the organellar genomes of Fungi and algae. A large amount of LGT was generally observed from Bacteria in the M. acetivorans and M. mazei genomes (Deppenmeier et al. 2002; Galagan et al. 2002). For example, in M. mazei, 30% of ORFs have their most significant Blast match in Bacteria, with about 16% having significant matches only in Bacteria, including 56 of the 102 transposases (Deppenmeier et al. 2002). Rates of apparent LGT from Bacteria to M. acetivorans are similarly high (Galagan et al. 2002) and have been observed elsewhere in Archaea (Nesbo et al. 2001). LGT can be attributed to proximity of local populations of Archaea and Bacteria (Deppenmeier et al. 2002).
The presence of a retron (MA2102) in M. acetivorans, as well as first observation of retrons in the bacterial groups Firmicutes, Fusobacteria, Cyanobacteria, and ß-Proteobacteria (fig. 3) adds to the mystery concerning the function of msDNAs. Retrons encode DNA and RNA complexes, referred to as "multicopy single-stranded DNA," or msDNAs, found in some Bacteria and synthesized by RT (reviewed in Lampson, Inouye, and Inouye 2001). However, the function of msDNA is unknown.
Origins of Retrointrons in Methanosarcina acetivorans
Of particular interest are the 13 retrointrons, including several twintrons, in the archaeal /ß clade. As in all other known twintrons, the internal intron of the M. acetivorans twintrons disrupts the functional domain of the external intron. The excision of all the internal introns, prior to that of the external, is essential for complete twintron excision (Copertino and Hallick 1991). The insertion of a mobile intron into another already fixed intron is the most likely method of twintron formation.
We propose that the phylogeny (fig. 2) and relative chromosomal location (fig. 1) suggest three major events that led to the current diversity and distribution of this clade in Archaea:
(1) Group diverged from group ß upon transfer into M. acetivorans from Bacteria. (2) Transfer of group
from Bacteria to M. acetivorans, followed by the insertion of a group
retrointron into the ancestral
(perhaps at locus 4), formed a twintron. Subsequently, this twintron retrotransposed, or was otherwise duplicated, to loci 3 and 5. It is also possible that the insertion of
into
occurred three times (at loci 3, 4, and 5) or that LGT of the twintron from Bacteria to M. acetivorans occurred three times, although we consider these possibilities to be unlikely. Two single
element and two ß elements are found downstream of the twintrons, and while the origin and timing of these insertions is not clear, it is possible that they are the result of cis retrotransposition of the twintron after excision of the internal intron. (3) The crown position of the M. mazei
retrointrons with respect to the M. acetivorans retrointrons suggests possible LGT from M. acetivorans to M. mazei.
Interestingly, six of the eight loci in M. mazei and M. acetivorans that have retrointrons also contain transposases. It has been suggested that the abundance of bacterial and archaeal transposases in the Methanosarcina genomes are an indication of their extensive utilization of LGT to promote genetic diversity (Deppenmeier et al. 2002).
Potential Impact of Retroids on Archaeal Genomes
The Methanosarcineae are the most metabolically versatile methanogens known, and although vertical evolution and LGT themselves are probably the major driving forces, the presence of retroids in Methanosarcina is also correlated with this metabolic expansion. Retrointrons can act as retroelements, particularly in Bacteria (Dai and Zimmerly 2002), thereby contributing to genome expansion and rearrangement (Sellem, Lecellier, and Belcour 1993). The number and duplicated nature of retrointrons found in M. acetivorans, together with its relatively large genome size, suggests they may have contributed to the "strikingly wide and unanticipated variety of metabolic and cellular capabilities" observed in the M. acetivorans genome (Galagan et al. 2002).
Only two of the 16 (12.5%) completely sequenced archaeal genomes contain retroids, M. mazei (4 RTs, 4 Mb) and M. acetivorans (10 RTs,
6 Mb) (as of November 1, 2002). One previous study (Ben-Mahrez et al. 1991) suggested possible biochemical RT activity in the halophile Halobacterium halobium, however the complete sequencing of the H. halobium genome failed to confirm this. In comparison, 24/85 (28%) of completely sequenced whole-bacterial chromosomes and 23/64 (36%) of completely sequenced unique whole-bacterial genomes contain RT (unpublished data). Some studies have suggested a correlation between retroid abundance and genome expansion (e.g., Elsik and Williams 2000; Shirasu et al. 2000), and it is perhaps no coincidence that M. acetivorans and M. mazei are the only two archaeal genomes sequenced that are greater than 3.5 Mb. Although the evidence is suggestive, there is no clear correlation in Bacteria between RT abundance and genome size (unpublished data).
Implications for Hypotheses of the Origin of Catalytic RNAs and Introns
Whereas some retrointrons in M. acetivorans do not contain RT, many do contain an RT ORF (this study; Dai and Zimmerly 2003). The widespread distribution of retrointrons with RT is consistent with the retroelement ancestor hypothesis, which predicts that retrointrons are ancestors of retroelements that gained RNA catalytic function and supports the idea that the catalytic RNA activity of the spliceosome and retrointrons is independently derived (convergent) rather than homologous with ribozymes from the RNA world (Lambowitz and Belfort 1993; Wank et al. 1999; Toor, Hausner, and Zimmerly 2001).
The retrointrons observed in Archaea, given current sampling and the phylogeny in figure 1, are due to LGT. The sample of Archaea, thus far, is small and sequencing of additional archaeal diversity is necessary. However, origins of archaeal retrointrons linked to LGT suggests that introns were either lost from Archaea at an early point in time or, more likely, that their origin in Bacteria came about after existence of the progenote. This distribution is also consistent with the retroelement ancestor hypothesis, described above. LGT between Bacteria and Archaea is consistent with the substantial horizontal transfer of retrointrons that has been observed within Bacteria (Zimmerly, Hausner, and Wu 2001; Dai and Zimmerly 2002). The three LGTs of retrointrons from Bacteria to Archaea inferred in this study are remarkably parallel to the hypothesized introduction of the spliceosome and its associated introns into eukaryotes by retrointrons, perhaps seeded by the mitochondrial endosymbiont (Michel and Lang 1985; Sharp 1985; Roger and Doolittle 1993; Sontheimer and Steitz 1993; Eickbush 1999; Simpson, MacQuarrie, and Roger 2002). The similarity in structure and function between the five domains of retrointrons and the five snRNAs of the spliceosome led to the suggestion of homology between these two types of introns and the hypothesis of a mitochondrial seed. Although previous studies have inferred LGT of introns among and between bacterial and organellar genomes (e.g., Zimmerly, Hausner, and Wu 2001), we are only aware of one other event of intron LGT that crosses the major divisions of life (under the paradigm that organelles are part of the Bacterial division). Kudla et al. (2002) inferred in the monocot Washingtonia robusta that a retrointron sequence was transferred from the mitochondrial to the nuclear genome and part of the retrointron was used to build a spliceosomal intron in the alcohol dehydrogenase gene. We consider this transfer from the mitochondrial to nuclear genome and the LGT from Bacteria to M. acetivorans and M. mazei as evidence supporting the viability of the mitochondrial seed hypothesis for the origin of the spliceosome.
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Acknowledgements |
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Footnotes |
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