Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK1
Author for correspondence: Michael Worobey.Fax +44 1865 310447. e-mail michael.worobey{at}zoo.ox.ac.uk
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Introduction |
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Two distinct but not mutually exclusive types of genetic exchange operate in RNA viruses. The first, reassortment, occurs only in multipartite viruses and involves swapping one or more of the discrete RNA molecules that make up the segmented viral genome. Antigenic shift in influenza A virus is an example of this sort of genetic exchange and serves as a good illustration of the potential evolutionary significance of such events. A second process, recombination, can occur in either segmented or unsegmented viruses when `donor' nucleotide sequence is introduced into a single, contiguous `acceptor' RNA molecule to produce a new RNA containing genetic information from more than one source. In this paper we focus on this type of genetic exchange. First, we briefly review current knowledge of RNA virus recombination and describe new methods for detecting its occurrence using gene sequence data. We then discuss some of the evolutionary implications of virus recombination and some of the constraints that may shape the variety of RNA virus recombination.
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Recombination in RNA viruses |
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Despite producing distinct kinds of hybrid RNAs, as well as defective interfering (DI) RNAs (Lazzarini et al., 1981 ), the different types of recombination appear to be variations on a common theme. To date, almost all studies on the mechanisms of recombination in RNA viruses have supported a copychoice model, originally proposed in the case of poliovirus (Cooper et al., 1974
) and now well studied in a number of experimental systems (Duggal et al., 1997
; Jarvis & Kirkegaard, 1992
; Kirkegaard & Baltimore, 1986
; Nagy & Bujarski, 1995
, 1998
; Nagy et al., 1998
; Simon & Nagy, 1996
; for a recent review see Nagy & Simon, 1997
). Under this model, hybrid RNAs are formed when the viral RNA-dependent RNA polymerase complex switches, mid-replication, from one RNA molecule to another. This results in homologous recombination if the replicase continues to copy the new strand precisely where it left the old one, and aberrant or nonhomologous recombination if it does not. This template-switching mechanism is fundamentally different from the enzyme-driven breakagerejoining mechanism of homologous recombination in DNA, not least because it invokes replication as a necessary component of the process. Finally, Chetverin et al. (1997)
presented evidence for a splicing-like, transesterification mechanism to explain the in vitro generation of recombinants between RNAs associated with Qß bacteriophage a possible exception to the copychoice model of recombination in RNA viruses. Whether such a mechanism operates in vivo remains to be seen; however, end-to-end joining is not regarded as a likely mechanism for homologous recombination.
There is now a fairly rich literature documenting recombination in RNA viruses. Many excellent recent reviews have dealt comprehensively with aspects of recombination in experimental and natural settings with respect to animal viruses (Lai, 1992 , 1996
; Ball, 1997
; Strauss & Strauss, 1997
), plant viruses (Lai, 1992
; Simon & Bujarski, 1994
; Roossinck, 1997
; Aaziz & Tepfer, 1999
) and bacteriophages (Mindich, 1996
; Chetverin, 1997
). Recently, reports describing homologous recombination in rotaviruses (Suzuki et al., 1998
) and in hantaviruses (Sibold et al. , 1999
) have added double-stranded and negative-sense RNA viruses, respectively, to the long list of RNA viruses in which homologous recombination has been detected. The emerging significance of RNA virus recombination is all the more fascinating given the fact that until the comparatively recent publication by Cooper et al. (1974)
which showed that mutants of poliovirus could be mapped by recombination analysis recombination was not thought to be a property of RNA genomes.
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New tools for detecting recombination in viruses |
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Several methods for detecting recombination events and locating breakpoints are graphical in nature, exploiting the fact that many recombinant sequences are mosaics comprising regions with quite different phylogenetic histories. One of these, Split Decomposition analysis (Bandelt & Dress, 1992 ; Huson, 1998
), presents conflicting phylogenetic signal in a single diagram. If no recombination has occurred in the sequences tested, the splits-graph tends to resemble a dichotomously branching phylogenetic tree, because this adequately describes sequence relationships. However, in datasets containing conflicting signal due to the presence of recombinant and hence `mosaic' sequences, the tree-like pattern is often replaced by a more complicated `network' that indicates a history of genetic exchange. It is worth noting that conventional phylogenetics programs are constrained to produce simple branching trees and can lead to serious misinterpretation if sequence alignments are not carefully examined for evidence of recombination prior to tree reconstruction.
Several other graphical applications, including `bootscanning' (Salminen et al., 1995 ), `PhylPro' (Weiller, 1998
), `TOPAL' (McGuire & Wright, 1998
) and `DIVERT' (Gao et al., 1998
), use `sliding windows' to detect discordant sequence relationships suggestive of recombination. Bootscanning is an aptly named phylogenetic approach that initially produces a tree from a small window at one end of a sequence alignment and assesses its robustness using bootstrapping. The window is then incrementally shifted along the alignment and a new bootstrap tree is produced for each resulting subset of the alignment. Significant topological changes in the position of a sequence in different windows indicate possible recombination. PhylPro and TOPAL both slide a pair of adjacent windows along the sequence alignment. Each of these methods employs a different measure of phylogenetic signal, but in both the phylogenetic information contained in one window is compared to that in the neighbouring window. In the absence of recombination all windows are expected to show similar patterns. On the other hand, if recombination has occurred, some adjacent windows are expected to contain conflicting signal and the difference between them should be greatest when they straddle a recombination breakpoint. DIVERT, the simplest of the sliding window graphical methods (and often the most effective), outputs a graph of genetic distance comparisons between a chosen sequence and comparison sequences, which can show runs of sequence similarity and dissimilarity suggestive of recombination. Diversity plots have been used to great effect in the search for recombinant human immunodeficiency virus and simian immunodeficiency virus strains (Gao et al., 1998
, 1999
) and are ideally suited for detection of RNA virus homologous recombination (Worobey et al., 1999
).
Many of these programs permit a simple qualitative assessment of possible recombination breakpoints based on the visual analysis of their output. However, for cases where putative recombinants and reasonably close relatives of their acceptor and donor sequences are available, more sophisticated procedures exist for locating crossover points. Informative Sites Analysis (Robertson et al., 1995 ), a parsimony-based adaptation of the maximum
2 test (Maynard Smith, 1992
), uses the distribution of polymorphic sites between a probable recombinant and its putative `parents' to estimate recombination junctions. The results can then be compared to randomized distributions of polymorphic sites to assess their significance. A similar method, LARD (Holmes et al. , 1999
), uses a maximum likelihood method to infer the optimal breakpoints for a possible recombinant, then uses simulated sequences to test the statistical significance of the results.
Some other methods attempt to quantify the amount of recombination between a set of sequences, rather than document specific recombination events, often using the degree of linkage equilibrium. One way this can be done is with the Index of Association. Using this statistical test, which was designed to detect associations between alleles at different loci, it is possible to measure the extent of linkage equilibrium within populations (Maynard Smith et al., 1993 ). Another, based on a direct phylogenetic analysis, is the Homoplasy Test (Maynard Smith & Smith, 1998
). Here, the number of homoplasic (i.e. convergent and parallel) base changes in data observed after construction of a maximum parsimony tree is compared to that number expected by chance. Excessive homoplasies are the fingerprint of recombination. (WWW links to the Homoplasy Test package and to TOPAL, PhylPro, bootscanning and the maximum
2 method can be found at http: // igs-server.cnrs-mrs.fr / anrs / phylogenetics / RAP_links.html.)
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How clonal are viruses? |
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Whatever the circumstances of the survival and subsequent diversification of particular recombinants, it is now evident that many pass through the narrow gates of natural selection and contribute to the diversity seen in RNA viruses. The production of new strains having genomes comprising regions with different histories has important implications for the way we think about virus evolution. For one, it means that there is no single phylogenetic tree that can describe the evolutionary relationships between viruses; the recombinative nature of viruses simply precludes the possibility of a `true' phylogenetic taxonomy. Far from being an incidental process best ignored when considering virus relationships and history, recombination may have played a crucial role in generating many of the taxonomic groups we recognize (Koonin & Dolja, 1993 ) today's hopeful monster giving rise to tomorrow's genus or family of viruses. Some studies of recombination have even led to recommendations that higher-than-family taxonomic units should be avoided altogether (Goldbach, 1992
).
The inappropriateness of tree-like representations of evolutionary relatedness may also apply within some virus species. In principle, the possibility of homologous recombination between similar strains means that the population structure in viruses could range from completely clonal, if no recombination has taken place, to panmictic, if recombination has been common enough to effectively randomize loci. Although significant progress has been made studying population structure in other organisms (Maynard Smith et al., 1993 ), similar work remains to be done for RNA viruses.
Many taxonomic groupings of viruses for example both the Togaviridae and the Coronaviridae include members that, while clearly sharing homologous genes, differ in the order in which these genes are organized along the genome, another indication that recombination has been important in their evolutionary history. Other cases exemplified by the haemagglutinin-esterase gene known to be present in at least three virus genera (Snijder et al. , 1991 ) show recombination as the engine driving modular evolution, whereby functional modules from different sources are brought together to create new viruses. The discovery of recombination in an increasing number of viruses, in addition to presenting phylogenetic and taxonomic difficulties, challenges the desirability of using short sequence regions as markers for entire virus genomes (for instance in molecular epidemiology studies) since they may not accurately reflect true genetic or antigenic characteristics.
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Evolutionary advantages of recombination |
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Although such direct experimental evidence has yet to demonstrate a similar advantage for recombination, in principle it too could serve to efficiently remove disadvantageous alleles from a population by combining mutation-free parts of different genomes. Indeed, suggestions have been made that reassortment in segmented RNA viruses and recombination in monopartite RNA viruses represent alternative evolutionary strategies for genetic exchange in this group (Chao et al., 1992 ). While this idea is fascinating, it is interesting to note that reassortment and recombination are not mutually exclusive and that several segmented viruses also experience recombination, sometimes frequently. These include the bacteriophage
6 (Mindich et al., 1992
), rotaviruses (Suzuki et al., 1998
), influenza A virus (Khatchikian et al., 1989
), hantaviruses (Sibold et al., 1999
), flock house virus (Li & Ball, 1993
) and many plant viruses (Bujarski & Kaesberg, 1986
; Greene & Allison, 1994
; Robinson, 1994
; Rott et al., 1991
). As if to prove this point, Masuta et al. (1998)
recently reported an interspecific hybrid of two cucomoviruses that arose by both reassortment and recombination.
Nonetheless, a great deal of evidence indicates that some RNA viruses do benefit from the genome-purging effects of recombination. A multitude of experimental studies have shown that weak or even non- replicative mutant strains can recombine to form viable, highly fit viruses. Examples include the functional chimeras formed between nonreplicating RNAs and DI RNAs of tombusviruses (White & Morris, 1994 ), infectious recombinants produced by different combinations of mutationally altered Sindbis virus RNAs (Raju et al. , 1995
; Weiss & Schlesinger, 1991
) and wild-type revertant recombinants of Qß phage mutants (Palasingam & Shaklee, 1992
) and of bromovirus mutants (Rao & Hall, 1993
).
Plant viruses have also been observed to repair their genomes by recombining with host transgene transcripts (Borja et al., 1999 ; Gal-On et al., 1998
; Greene & Allison, 1994
; Rubio et al., 1999
). Similarly, in one experiment with a deletion mutant of mouse hepatitis virus (MHV) transfected with a synthetic RNA that contained the deleted region (Koetzner et al., 1992
), and another with an influenza A virus mutant with a damaged neuraminidase gene (Bergmann et al., 1992
), recombination successfully repaired defective genes. Studies of recombination in bacteriophages, too, indicate a repair function for recombination (Mindich et al., 1994
). RNA recombination even appears to provide a telomerase-like function by repairing the 3' ends of satellite RNAs of both turnip crinkle virus (Burgyan & García-Arenal, 1998
) and cucumber mosaic virus (Simon & Nagy, 1996
).
Unintentional `natural experiments' with some viruses point to the same conclusion. The frequent recovery of recombinant isolates of poliovirus (Georgescu et al., 1994 ; Kew & Nottay, 1984
) and infectious bronchitis virus (Jia et al., 1995
; Kusters et al., 1990
; Wang et al., 1994
) that result from recombination involving vaccine strains shows that recombination has the potential to produce `escape mutants' in nature as well as in experiments. Recently, recombination has also been detected in other RNA viruses for which multivalent vaccines are in use or in trials (Holmes et al., 1999
; Suzuki et al., 1998
; Worobey et al., 1999
). We think the potential for recombination to produce new pathogenic hybrid strains, and the possible impact of such escape recombination, needs to be carefully considered whenever multivalent live-attenuated vaccines are used to control RNA viruses. Assumptions that recombination either does not happen or is unimportant in RNA viruses have a history of being proved wrong.
In addition to the evidence favouring a role for genetic exchange in eliminating deleterious alleles, many recombinant RNA virus strains provide ample indication that recombination can generate beneficial new variation. In some viruses this new variation is achieved by borrowing genetic material from their hosts. One intriguing example of this is bovine viral diarrhoea virus (BVDV), a pestivirus that recombines with host cellular protein-coding RNA. As a result of virushost recombinations, cytopathogenic BVDVs can develop from non- cytopathogenic ones and cause a lethal syndrome, mucosal disease, in the hosts (Meyers et al., 1989 ). Influenza A virus has also been observed to recombine with cellular RNA, resulting in increased pathogenicity for the hybrid viruses (Khatchikian et al. , 1989
). Recombination between virus and host genetic material evidently occurs in plant viruses as well, as illustrated by a luteovirus isolate with 5'-terminal sequence derived from a chloroplast exon (Mayo & Jolly, 1991
) and closteroviruses which have acquired host cellular protein-coding genes (Dolja et al., 1994
) which are nonessential for replication and virion production (Peremyslov et al., 1998
).
A link between recombination and increased pathogenicity has also been revealed in cases that do not involve recombination with host genes. Template jumping during replication in viruses infecting cats has produced, on multiple occasions, the pathogenic strains known as feline infectious peritonitis viruses (FIPVs) by altering asymptomatic feline enteric coronaviruses, differing from them only by deletions of around 100 bp in predictable locations (Vennema et al., 1998 ). Another coronavirus, feline coronavirus (FCoV) type II, appears to be a homologous (or aberrant homologous) recombinant of FCoV type I and canine coronavirus (Herrewegh et al., 1995
). Like FIPVs, FCoV type II viruses may have arisen on different occasions from separate recombination events (Motokawa et al., 1996
).
Experimental studies provide further signs of the ability of recombination to generate useful, new variation. In one particularly striking display of this, MS2 phage mutants lacking the sequence for important stem-and-loop secondary structures repeatedly reconstructed them via nonhomologous recombination (Olsthoorn & van Duin, 1996 ).
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Constraints on recombination |
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Having successfully coinfected a single host, divergent viruses must next coinfect a single cell if recombination is to proceed. This step could be blocked by host factors, either by an immune response that keeps virus numbers low enough to prevent multiple infection of any individual cell, or by host cell genetic factors that block entry of more than one virus particle into a cell (Danis et al., 1993 ). Viral factors, interestingly, might also enforce significant constraints at this stage of the model. Recent evidence demonstrates that intracellular competition can be costly to viruses that infect the same host cell (Turner & Chao, 1998
). Those that can selfishly keep cells to themselves by limiting or preventing coinfection should be selectively favoured, and many have evolved mechanisms to do just this (Simon et al., 1990
; Singh et al., 1997
; Turner et al. , 1999
). One of these, vesicular stomatitis virus (VSV), is an RNA virus in which recombination between different strains has not been detected. Might superinfection exclusion be a constraint on recombination in VSV? Another, the segmented bacteriophage
6, seems to limit excessive superinfection but not to the extreme of one- virus-per-cell that would preclude genetic exchange. Instead, it appears to have evolved an optimal coinfection limit of two to three viruses per cell, presumably to balance the costs of intracellular competition with the benefits of reassortment (Turner et al., 1999
). Since the advantage (and cost) of recombination in any particular virus will be mediated by such factors as the selective pressure for novel variation, the importance of interactions between different parts of the genome, as well as the virus mutation rate and population size, we should expect different optima (and therefore different degrees of constraint) in different cases.
If divergent viruses manage to infect the same cell, the next step is simply for one of them to replicate in the presence of the RNA of the other. This is not necessarily inevitable even in coinfected cells. The replication of the 6 RNAs, for example, takes place within a procapsid and it is thought that the entry of two different RNA molecules of the same genomic segment into this sequestered environment is impossible or at least very rare (Mindich et al., 1992
). This could explain the lack of homologous recombination in this phage. Thus the vagaries of RNA replication in certain viruses could impose physical constraints on the production of hybrids.
Template switching by the viral replicase, the mechanism whereby recombinant RNA molecules are actually created, may also be limited by physical constraints. The negative-strand RNA viruses, for example, whose genomes are packaged into filamentous ribonucleoprotein structures by association with N protein, may be less permissive than other RNA viruses to copychoice recombination. And perhaps the most important physical constraint on template switching particularly with respect to homologous recombination is simply the extent of sequence dissimilarity between potentially recombining genomes. Finally, genetic variation in the susceptibility of the viral replicase to jumping (Bujarski & Nagy, 1996 ) no doubt plays a central role in determining how often and by what mechanism particular viruses recombine.
Recombination occurs when these first four steps are fulfilled. Whether incipient recombinants persist, however, depends on the fifth and final step, the selective separation of the wheat from the chaff among hybrids. Although there is strong evidence that genetic exchange can offer advantages in some circumstances, random recombination no doubt destroys more good alleles than it creates. PCR studies which have made possible the characterization of the initial products of recombination those present prior to removal by selection (Banner & Lai, 1991 ; Desport et al., 1998
; Jarvis & Kirkegaard, 1992
) have produced important insights. Banner and Lai's study of coronaviruses (1991), for example, showed that the initial recombination events in their MHV system were almost entirely randomly distributed along the sequence investigated. It was only after passage through cell culture, with the opportunity for selection to remove less fit variants, that crossover sites became `localized' to just a small area of the region examined. With enough passages, the recombinants disappeared altogether. These results indicated that `recombination hotspots' can actually be the result of natural selection on a pool of random recombination crossover junctions, as opposed to elevated recombination rates in particular regions. Crucially, they also suggested that recombination may be more common than often assumed, but may go undetected because of the action of strong purifying selection which will remove new, deleterious combinations of mutations. In light of these studies it is clear that what is meant by `recombination frequency' a term usually used without specified units depends critically on whether we are assessing recombination events before or after selection has acted. A virus which often produces hybrid RNAs under laboratory conditions may very rarely or even never be found to recombine in nature. This difference is analogous to the important distinction between the rate of mutation and the rate of substitution.
Negative selection against non-functional hybrids or those with decreased fitness may impose the strongest constraints of all on the appearance of recombinants. In viruses for which the evolutionary costs of recombination outweigh the benefits, though they may be mechanistically capable of genetic exchange, strong selection will guarantee the elimination of hybrid genomes.
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Conclusion |
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