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Virus Genes 16:1, 13±21, 1998
                                                         # 1998 Kluwer Academic Publishers, Boston. Manufactured in The Netherlands.




                                          Origin and Evolution of Viruses

                                        JOHN HOLLAND1* & ESTEBAN DOMINGO2
     1
         Department of Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093±0116 USA
                                                       E-Mail: jholland@ucsd.edu.
             2
               Centro de Biologia Molecular Severo Ochoa Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
                                                   E-Mail: edomingo@mvax.cbm.uam.es.




Virus Origins                                                           in the cases of bacteriophage Mu (which is both a
                                                                        virus and a transposon) and retroviruses (which are
The origin(s) of viruses can not be known with                          retrotransposons containing a functional envelope
certainty. PCR and other sensitive molecular techni-                    gene). As Temin pointed out (10), non-viral retroid
ques will reveal some viral genome sequences from                       elements can become retroviruses only when such
the relatively recent past, but very ancient viral                      retrotransposing protoviruses acquire envelope genes
genomes will remain a matter for speculation.                           from another viral or cellular source by recombina-
Numerous theories have been advanced regarding                          tion. DNA viruses and (non-retrovirus) RNA
virus origins (reviewed in 1) and all necessarily                       riboviruses may also arise by recombinational (or
involve speculation. However, comparative sequence                      reassortment) reshuf¯ing of cellular and viral or
analysis strongly suggests that both RNA (2) and                        plasmid/episome/transposon mobile element genes.
DNA (3) viruses have deep, archaic evolutionary                         Botstein (11) theory of modular evolution of DNA
roots both for genome structural organization and as                    viruses is quite plausible. It envisions virus evolution
regards certain genomic and protein domains. It is                      by recombinational arrangement of interchangeable
also clear that both DNA and RNAviruses can emerge                      genetic elements or modules. The advantage of such
and evolve by a variety of mechanisms including                         modular evolution is obvious. It allows virus genes,
mutation, recombination and reassortment. This can                      protein domains, regulatory systems, etc. to evolve
involve point mutation, insertions and deletions,                       independently under a wide variety of selective
acquisition or loss of genes (and gene domains, or                      conditions. Thus, one module might have undergone
sets of genes), rearrangement of genomes and                            its most recent evolution as part of an integrated
utilization of alternate reading frames or inverted                     episome, another as part of a transposon, a third as a
reading frames (1±6).                                                   plasmid element, yet another as part of a cellular gene
   Recombination can create new viruses by cap-                         or an integrated defective virus, etc. Such modular
turing genes or gene segments or sets of genes either                   mobility obviously can relax evolutionary constraints
from cellular nucleic acids or from other viruses. The                  which would prevail if all were required to co-evolve
presence of cellular genes within virus genomes has                     within a single genomic unit. Of course, it will be an
long been recognized (5). Likewise, the resemblance                     extremely rare event which could bring about a
of viruses to plasmids, episomes and other mobile                       fortuitous compatible recombination of indepen-
DNA or RNA replicons such as transposons or                             dently-evolving modules to create a new virus
retrotransposons is obvious (1,7±9). The only clear                     having good biological adaptive capacity. But
distinction between many such mobile elements and                       signi®cant virus emergences are likewise extremely
viruses is the maturation of the latter within capsids                  rare occurrences and the probabilities for emergence
(and envelopes) to affect ef®cient transmission and                     of a drastically different virus solely by mutational
target cell receptor speci®city. This is well-illustrated               changes within a single genome are generally orders
14      Holland and Domingo

of magnitude less probable. Sequence space as                date from great antiquity and continue to the present.
elaborated by Eigen and colleagues (12) has incom-           Presently, of course, nearly all new viruses emerge via
prehensibly vast dimensions, and distant, previously         evolution of old viruses. This is compatible with the
unexplored regions of sequence space can best be             deep evolutionary trees deduced for both DNA and
reached (and mutationally explored) by the evolu-            RNA viruses (4) and with the long-recognized
tionary leaps which recombination or reassortment            capacity of viruses to acquire genetic elements from
afford. See Kauffman (13) for detailed discussion of         host cell nucleic acids and form other mobile
this point. Finally, it should be emphasized that            replicons (1).
ordinary RNA viruses (riboviruses), in additional to
DNA viruses and retroviruses, can undergo such
modular evolution via RNA recombination (and                 Virus Evolution
reassortment). The essence of all viruses is obligate
intracellular parasitism coupled with the capacity for       The evolution of existing viruses, as for all living
intimate genetic interactions with the DNA and RNA           things, proceeds via a variety of mechanisms
of their hosts and of cohabiting mobile elements.            including mutation, recombination, reassortment and
   The nature of the earliest viruses can never be           environmental selection. Space limitations prevent
determined, but it is likely that they arose very early      extensive discussion of virus evolution in this short
during the evolution of life on earth. It seems              review, so only major points will be discussed here.
extremely likely that elemental life forms involved          For an excellent recent overview of the molecular
RNA replicons (14) and these might have borne                basis of virus evolution, see (4). More concise
resemblance to present-day RNA replicons such as             coverage is provided in review articles (1,18±22).
viroids, virusoids or viruses. In fact, Robertson (15)
has suggested that very early, primitive autono-
mously-replicating, self-cleaving RNA replicons              RNA Virus Mutation Rates are Very High
akin to present-day viroids might have acquired
additional genes to form conjoined replicons which           It is now clear that all or nearly all RNA viruses have
later evolved into mosaic DNA-based entities.                extremely high mutation rates (18±23). Mutation rates
Hepatitis D virus was suggested as a present day             at individual base sites may vary considerably, but
example of such a conjoined viroid-like RNA                  average nucleotide base misincorporation rates are of
replicon. It contains an open reading frame encoding         the order of 10 À 4 to 10 À 5 (reviewed in 21±23). This
the delta antigen protein joined to the viroid-like          results in the generation of quasispecies mutant
domain. Recently (16), it was shown that liver cells         swarms even when the virus population has just
express a cellular homolog of the delta antigen,             arisen from a clone (21,22,24). A clonal quasispecies
suggesting that hepatitis D virus may have arisen by         virus population is a diverse mixture of virus mutants
the capture of a cellular RNA transcript by a viroid-        differing from each other at one or several genomic
like RNA. A copy choice template transfer                    sites, and can be envisioned as a cloud in sequence
mechanism was proposed for the recombinational               space. A consensus sequence will represent the
capture event. Robertson (15) suggested that such            average sequence at each genome site and the
events occurring early in the primitive RNA world            master sequence(s) represent the most ®t member(s)
could later have given rise to mosaic DNA modules,           of the swarm in any particular de®ned selective
and might even be responsible for the present                environment. When the selective environment
widespread prevalence of split genes and introns and         changes the master sequence(s) and the overall
RNA-catalyzed cleavage and ligation splicing sys-            composition of the quasispecies swarm will also
tems (17). In general, it is quite plausible that not only   change.
viroid-like, but plasmid-like transposon-like, retro-            Obviously, the generation of quasispecies mutant
transposon-like and virus-like autonomously-                 swarms can provide RNA viruses with great adapt-
replicating RNA and DNA elements (replicons)                 ability under conditions in which there is
have been intimately involved in nearly all evolution        environmental change, and in complex mammalian
of life on earthÐboth in precellular and cellular eras.      hosts, viruses always encounter changing conditions
Therefore, it is probable that the origins of viruses        (e.g., different cell types, in¯ammatory responses,
Origin and Evolution of Viruses       15

immune responses, fever temperatures, interferons,           ef®ciently in two very disparate hosts; vertebrates
etc.). It should be emphasized that, whereas the most-       and invertebrate insects (31). Despite this relatively
adapted master sequence(s) and closely-related var-          slow rate of evolution, alphaviruses such as eastern
iants will be the most abundant and most important           equine encephalitis virus (and other arboviruses)
variants under rather constant environmental condi-          undergo signi®cant evolutionary change over the
tions, the opposite will be true under rapidly changing      centuries. For example, it was estimated that the
conditions (e.g., adaptation to a new mammalian host         North and South American antigenic varieties of
or a new arthropod vector). Variants at the periphery        eastern equine encephalitis virus diverged about 1000
of the quasispecies mutant distribution (i.e., those         years ago and the two South American groups
most distantly-related to the previous master                diverged about 450 years ago (30). Venezuelan and
sequence) will usually offer the best opportunity for        eastern equine encephalitis alphavirus complexes
rapid adaptation to the new conditions. Selected             diverged about 1400 years ago (30) while the Old
peripheral variants from the previous mutant distribu-       and New World alphavirus groups diverged roughly
tion will frequently also be peripheral variants in the      2000 to 3000 years ago (32). Even today, new
new distribution as the quasispecies moves through           epidemic/epizootic strains of Venezuelan encephalitis
sequence space to optimize adaptability in the new           emerge from enzootic strains in South America by
environment and generate new master sequences. The           rather minor mutational change (33). Finally, the
very essence of the quasispecies theory of Eigen,            western equine encephalitis group was estimated to
Biebricher and colleagues (12,24±27) is the broad            have emerged more than 1000 years ago (before the
reach through sequence space which is provided by            North and South American equine encephalitis virus
RNA virus replicase error rates poised at the threshold      divergence) by a very rare recombination event
of error catastrophe. Finally, it should be noted that, as   between eastern equine encephalitis virus and a
in all evolution, rapid emergences of new RNA                sindbis virus-like progenitor (6,18,34).
variants are counterbalanced by rapid extinctions of             Another example of slow versus rapid evolution
others.                                                      can be observed with vesicular stomatitis virus (VSV)
                                                             in both laboratory and natural settings. VSV Indiana
                                                             serotype has been observed to undergo extremely
Extremely High Mutation Rates Do Not                         rapid evolution under conditions of persistent infec-
Necessitate Rapid Evolution                                  tion in cell culture and relative genomic stasis under
                                                             conditions of repeated dilute passages in the same
Although, it is intuitively obvious that high rates of       cells (35). In nature, VSV in its enzootic focus in
RNA virus mutation facilitate rapid evolution, it            Panama has undergone very little evolution over
seems counterintuitive that RNA viruses sometimes            recent decades (36). In contrast extensive evolution
can exhibit rather long periods of relative evolu-           was observed for strains isolated farther north. The
tionary stasis. In general, RNA viruses evolve rapidly       farther north the strains were isolated, the greater was
but rates can vary considerably, and relative stasis is      the sequence diversity from the genetically stable
not uncommon. For example, evolutionary rates for            ( presumed ancestral) strains in enzootic foci in
many RNA viruses can be as high as 10 À 2 to 10 À 3          Panama and Costa Rica (36). The greatest divergence
base substitutions per nucleotide site per year              was found in strains from the extreme northern range
(1,6,18,20±23), but rates of evolution of arthropod-         of VSV in the United States. Thus, there is a
borne viruses can be orders of magnitude slower.             geographic clock rather than a molecular clock as
Transovarial passage of the Phlebovirus toscana virus        would be expected from neutral evolutionary theory.
in sand¯y vectors showed extreme genome stability            This apparent punctuated equilibrium evolution was
during 2 years transmission time and over 12 sand¯y          postulated to be due to different selective ecological
generations (28). Likewise, alphaviruses in the eastern      factors operating to drive virus evolution in diverse
equine encephalitis complex evolved at rates nearly as       geographic areas and different insect vector/hosts are
low as 10 À 4 base substitutions ®xed per site per year      probably important among these (36). These extre-
(29,30). This low rate of evolution occurred despite         mely unequal rates of evolution within a single virus
normally high rates of mutation and was attributed to        species and serotype dramatically con®rm the role of
stabilizing selection for the ability to replicate           selection in driving virus evolution. They also
16     Holland and Domingo

dramatically emphasize the fact that high (and            populations are small in asexual populations, there
probably rather constant) mutation rates can be           can be an inexorable accumulation of deleterious
consistent with both rapid rates of evolution (mutation   mutations leading to a ratchet-like decline in
®xation) or with evolutionary stasis. Relative stasis     replicative ®tness. Chao (43) convincingly demon-
(equilibrium) is favored under more constant selective    strated the operation of Muller's ratchet in the
conditions in the environment-precisely as is pre-        tripartite RNA bacteriophage f6. Chao et al. (44)
dicted by quasispecies theory (see section above).        also showed that sexual crossing could often reverse
   Another remarkable example of a single virus           the effects of Muller's ratchet. Quantitation of ®tness
species exhibiting either evolutionary stasis or          losses during repeated small population transfers
extremely rapid evolution is provided by the thorough     ( plaque-to-plaque genetic bottleneck transmissions)
extensive studies of Webster and coworkers (20,37±        of VSV and food-and-mouth disease virus con®rmed
39) of in¯uenza virus in natural avian hosts or in        that variable, stochastic, often-profound ®tness
mammalian hosts including humans. In aquatic wild         decreases occur rather regularly (45±49). Clearly,
birds, in¯uenza virus is apparently completely-           genetic bottlenecks have the capacity to disturb virus
adapted to intestinal replication and shedding with       adaptive equilibrium and thereby to drive stochastic
no signs of disease and with very little selection for    evolutionary changes. The number of virus particles
evolutionary change. Rapid evolution is the norm          which constitute an effective genetic bottleneck can
when in¯uenza viruses emerge into mammalian hosts         vary greatly from only several particles to tens of
(20,37,38). Immunity and other selective factors          particles depending upon initial virus population
apparently drive the extreme rates of in¯uenza virus      ®tness (50,51).
evolution exhibited during adaptation to mammals.             The opposite effect on ®tness occurs during
Overall, the work of Webster and colleagues indicates     repeated transfers of very large numbers (105 to 106)
that ducks and other waterfowl are the original hosts     of infectious virus particles. Under these large dose
for in¯uenza viruses. Rare genome segment reassort-       transmission conditions, regular exponential increases
ment events or transfers of entire in¯uenza virus         in virus replicative ®tness occur and previous ®tness
genomes initiate emergence into mammalian species,        decreases due to Muller's ratchet are reversed
but it is the destabilizing selective forces in mammals   (48,50,51). Unquestionably, virus population trans-
which drives the ensuing rapid evolution. This is         mission size can affect virus evolution very
another good example of punctuated equilibrium in         profoundly, and this inevitably must also occur
virus evolution. There are theoretical reasons (based     during natural virus outbreaks. Transmission of large
upon expected movements between adaptive peaks in         doses of infectious virus particles often occurs during
adaptive landscapes) to expect that evolution will        transmissions involving close contact (e.g., sexual,
frequently exhibit punctuated equilibrium (40). Plant     kissing); during transfusions or other medical/dental
viruses, such as the tobamoviruses can also exhibit       blood/tissue transmission; intravenous drug abuse,
genetic stability for long periods, again due to strong   some insect vector or animal bite transmissions; and
environmental selective pressures restricting quasis-     during some very close respiratory droplet transmis-
pecies diversi®cation (41).                               sions, some fecal-oral transmissions, etc. Genetic
                                                          bottleneck transmissions inevitably occur during
                                                          many rather distant virus transmissions during
Effects of Virus Population Transmission Size on          respiratory droplet inhalations. This is clear from
Selection, Fitness and Evolution                          quantitative studies of both experimental and natural
                                                          virus aerosol transmissions (52±54). After sneezing
Whenever viruses become extremely-well-adapted to         and coughing of infected people in a room, the volume
host environments and evolutionary stasis is reached,     of room air which must be sampled to obtain a single
this equilibrium obviously can be upset readily           infectious particle can be very large (53,54). For
( punctuated) by host or vector switching or by drastic   example, 15 men in bed infected with adenovirus type
environmental changes. Another, less obvious              4 and coughing frequently in a barracks room led to
mechanism involves changes in the size (dose) of          recovery of one tissue culture infective unit per 2820
virus particle transmission. In 1964, Muller (42)         sq. ft. (54). Thus, genetic bottleneck transmissions
postulated that whenever mutation rates are high and      must be frequent and unavoidable for respiratory
Origin and Evolution of Viruses       17

viruses although large population transfers must also         account for 50% or more of the plants nuclear
occur often during close contact. Similar considera-          DNA! Large blocks of reiterated retrotransposons
tions apply to fecal-oral spread, spread from                 inserted within each other are found in gene-
inanimate objects (fomites) and from insect vector            containing regions as intergenic segments (56,57).
transmissions (55). Whenever large virus population           Clearly, these are involved in determining gene
transmissions occur repeatedly, selection can operate         expression, genome size and genome organization,
repeatedly to select the best of the best of the best . . .   so that the distinction between host and sel®sh
in terms of virus ®tness in a constant host species.          parasitic genes is blurred beyond recognition.
Conversely, repetitive genetic bottleneck transmis-              Although RNA riboviruses cannot interact with
sions interrupt selective forces and allow stochastic         host DNA genomes as directly, nor as frequently as do
changes in ®tness and in evolutionary directions.             DNA viruses and retroviruses/retroelements, RNA
These stochastic changes will usually be in the               recombination is equally common and important
direction of ®tness loss (and perhaps loss of virulence)      among them as evolutionary events. The mechanisms
but rarely, by chance, the converse will be true.             and importance of recombination in riboviruses and
Virulence is a multifactorial, multigenic trait which         retroviruses are reviewed in (58,59). Riboviral RNA
may or may not correlate with replicative ®tness and          recombines with both cellular and viral RNAs and
transmission ef®ciency. The major insight to be               acquisition of genes and gene segments from both can
gained from experimental studies of virus ®tness is           be very important in ribovirus evolution and
that RNA viruses are phenotypically quasispecies as           emergence. Homologous recombination occurs fre-
well as genetic quasispecies. Thus, all phenotypic            quently during every replication of most positive
characteristics, including virulence, will be highly          sense riboviruses (58,60) but is extremely rare among
variable among the numerous mutants present in a              negative sense riboviruses in which non-homologous
complex quasispecies swarm. Therefore, chance                 recombination events usually generate defective
sampling events such as genetic bottlenecks may               genomes (some quite bizarre), most of which are
profoundly affect virulence traits (and other traits)         dependent upon non-defective helper viruses for
during an epidemic. Likewise, repetitive large                replication (61). Very rarely, helper-dependent,
population transmissions can preserve and enhance             bizarre, defective RNA virus genomes are probably
virulence or other traits which had been sampled by           involved in major virus evolutionary events via RNA
chance during earlier genetic bottleneck events. This         recombination with non-defective helper viruses.
can, of course, in¯uence disease severity and outcome         Because their helper viruses provide all vital
in infected individuals and in small local host cohorts       replication functions, defective viral genomes are
infected by such sampling of the quasispecies swarm.          largely unconstrained by selective forces and can
                                                              undergo extremely rapid, massive evolution. Thus,
                                                              they could (very rarely) donate extensively-mutated
Recombination, Reassortment and Gene                          and rearranged genome segments back to the helper
Duplication in Virus Evolution                                viruses from which they arose (61).
                                                                 Among the segmented-genome viruses, reassort-
As outlined in the chapters on virus origins,                 ment of segments provides a ready mechanism for
recombination has long been recognized as a central           generating new viruses. The best-known examples, of
mechanism in the evolution of DNA bacteriophages              course, involve the periodic antigenic shifts of
and/or DNA viruses and retroviruses of animals and            in¯uenza A viruses which usually occur at multi-
plants. Recombination with, and insertion into, and           decade intervals to initiate new human pandemics
excision from, cellular DNA allows intimate genetic           (37±39). The gene segment reassortment events which
interactions with host genomes, episomes and                  cause emergence of new in¯uenza A viruses are very
plasmids. Just as the frequent acquisition of cellular        rare events because only certain permutations of avian
genes can help shape virus evolution, so can the              and mammalian gene segments will be highly
frequent acquisition of virus and retroelement genes          infectious and ®t, and because reassortment requires
help to shape host evolution. A remarkable example is         rare dual infection (by appropriate progenitor viruses)
provided by maize in which many dozens or even                of appropriate mixing vessel hostsÐmost often
many hundreds of diverse retroelement families                probably swine or humans (37±39). Once a ®t new
18     Holland and Domingo

reassortant emerges into the human population very        generally evolve to achieve and maintain optimal
rapid evolution ensues (37±39). Reassortment events       function. They often tend to produce inapparent and
are important in the evolution of many other              silent latent infections, to co-evolve slowly with their
segmented genome RNA viruses. For example,                hosts over geologic time periods, and even to
bunyaviruses can evolve by reassortment in doubly-        in¯uence the evolution of their host species (68,70±
infected mosquitoes (62) and naturally-occurring Sin      73). Nevertheless, many DNA viruses can exhibit
Nombre hantavirus reassortants have been observed         considerable genetic plasticity (74) and this can be
in Peromyscus deer mice in Nevada and Eastern             manifested via antiviral drug resistance and other
California (63). No reassortants were observed            clinical problems. This is not surprising because DNA
between Sin Nombre and other hantaviruses indi-           viruses can have host recombination systems avail-
genous to their region, suggesting that reassortants      able to them in addition to intrinsic viral mechanisms.
between distantly-related hantaviruses are rare or non-   Also, DNA ®delity is limited for viruses which
viable, and/or that host species speci®cities greatly     replicate via single-stranded DNA because mismatch
limit reassortment. Again, generation of ®t reassor-      repair/excision repair systems are unavailable for
tants between distantly-related and different-host-       single-stranded DNA genomes. But, even bacter-
adapted virus strains is generally a rare event in        iophage T7, a classic double-stranded DNA virus
nature.                                                   exhibited rapid evolution of replicating ®tness in
   A major mechanism observed in the evolution of         single plaques (75). It should be noted that some DNA
all life formsÐgene duplicationÐis sometimes              viruses such as the canine/feline parvoviruses evolve
important in virus evolution. For example, beet           in nature at least as rapidly as the slower-evolving
yellows virus, a ®lamentous RNA virus, contains a         RNA viruses and can change host species speci®cities
coat protein gene duplication (64) and two rabies-        very readily as well (76). This is in marked contrast to
related rhabdoviruses, Adelaide river virus (65) and      the primate papillomaviruses, for example. Van Ranst
bovine ephemeral fever virus (66) each contain two        et al. (77) estimated primate papillomavirus mutation
consecutive glycoprotein genes of differing size and      rates to be of the order of 3 Â 10 À 8 base substitutions
sequence. Both glycoprotein genes are expressed in        per site per year in the EG gene. This is only about 20±
each of these viruses; via monocistronic mRNAs in         30 times faster than the rate of evolution of their
the case of bovine ephemeral fever virus and              primate host species and about a million-fold lower
polycistronic mRNAs for Adelaide virus. Gene              than rates of evolution of the most rapidly evolving
duplication of this kind occurs by recombination          RNA riboviruses (29±35,78).
events, probably via intra- or inter-molecular copy
choice replicase leaps (58,67).
   Finally, a very simple, effective mechanisms for       Implications of RNA Virus Quasispecies for
creation of new virus gene products involves acquired     Disease and Disease Emergence
usage of alternative reading frames of an existing gene
to create overlapping genes. This overprinting            Some investigators have stated that quasispecies
mechanism is common in virus evolution as outlined        mutant swarms are not really necessary for disease
in the review of Gibbs and Kease (4).                     processes during RNA virus infections. Of course, this
                                                          could be argued quantitatively in terms of the minimal
                                                          mutation rate which quali®es to produce a quasis-
Do DNA Viruses Evolve as Quasispecies?                    pecies. However, this misses the essence of RNAvirus
                                                          biology. RNA viruses have been the most abundant
DNA viruses generally do not form complex                 and successful parasites since the appearance of
quasispecies mutant swarms to the extent that RNA         cellular life (see the ®rst chapter) and this has been
viruses do because they generally have genomic            achieved by maintaining error rates very near the error
mutation rates about 300-fold lower than those of         threshold (12). This allows maximal variability and
RNA riboviruses and roughly 30-fold lower than            adaptability (21±27) This great adaptability allows
retroviruses (23,68). Proofreading and mismatch           ®tness to be increased rapidly in changing environ-
repair (69) of DNA can provide ®delity for even           ments and the intact animal, human, plant or insect
very large DNA virus genomes. Hence, DNA viruses          vector organism always confronts invading microbes
Origin and Evolution of Viruses        19

with multiple, challenging and changing environ-           remember that myocarditis due to Coxsackie viruses
ments. RNA virus quasispecies frequently undergo           is rare relative to the number of human infections.
major or minor changes in composition in response to       Virulence is a trait which is seldom selected except
in¯ammatory and immune responses (20,37,38,79) to          when it correlates with replicative ®tness. Immune
different host cell types within individual infected       de®cits arising from selenium de®ciency regularly
organisms, to widely differing conditions in verte-        allowed expansion of the Coxsackievirus B3 quasis-
brate versus insect vector hosts (80), to antiviral drug   pecies mutant swarm and colonization of myocardial
treatments (81,82), to inadequate vaccine programs,        cells to cause disease. The cardiovirulent variants
etc. Different subsets of the lymphocytic choriome-        selected in heart muscle cells established a new
ningitis virus quasispecies swarm are involved in          quasispecies distribution which was cardiovirulent for
lymphoid cell infection with immune suppression as         normal mice after it was deliberately isolated from the
contrasted with neuronal cell infection with runting       total whole animal wild type quasispecies swarm. It is
syndrome (growth hormone de®ciency syndrome)               beyond question in this outstanding study that it is
(83,84).                                                   those quasispecies subsets normally buried within the
    Perhaps the involvement of quasispecies in disease     total circulating quasispecies population which have
is best illustrated by the propensity of polioviruses to   the potential to cause viral myocarditis (89,90). This is
cause paralytic disease in a small percentage of           likely a rather typical situation with regard to RNA
infected individuals (60), and for some Coxsackie          virus disease potential.
viruses to cause cardiomyopathy in a small percentage         Finally, the role of RNA virus quasispecies in
of infected humans. Microevolution of the quasis-          future emerging diseases of humans, domestic
pecies population present in the type 3 Sabin oral         animals and crops is obvious. Most emerging human
poliovirus vaccine seed stocks (85) can cause              diseases in recent years have been RNA virus
paralytic disease in a very small percentage of vaccine    diseases; from AIDS to Ebola hemorrhagic fever to
recipients and can even initiate outbreaks of polio-       hantavirus pulmonary syndrome. Most new or
myelitis in unvaccinated populations (60,86). Clearly,     emergent virus diseases in the future will also be
the quasispecies nature of the vaccine seed stocks and     RNA viruses because of the rapid evolution potential
of their progeny is responsible for this rare but          of their quasispecies. This trend will be accelerated so
unfortunate disease complication of an otherwise           long as the human population continues to expand
excellent vaccine. An endemic cardiomyopathy               exponentially. For example, the recent rapid growth of
affecting thousands in China has been associated           human populations in tropical areas has been matched
with both selenium de®ciency and isolation of              by an equally-rapid increase in dengue fever, dengue
Coxsackieviruses from patients (87,88). Beck et al.        hemorrhagic fever and dengue shock syndrome, and
in a remarkable study of selenium de®cient mice (89)       by an increasing rate of evolution of dengue viruses
showed that infection by a normally non-virulent           (91±93). All of us and our domestic animals (94) are
clone of Coxsackie B3 virus induced signi®cant             potential incubators for the rapid exploration of
myocarditis in the Se-de®cient mice, and virus             previously-unexplored sequence space by evolving
recovered from the hearts of these myocarditic mice        RNA viruses. Sequence space is a v-dimensional
regularly caused myocarditis in normal Se-adequate         hypercube in which v is the genome length in bases or
mice! Complete sequence analysis of the recovered          base pairs (12). For a 10 kb RNA virus genome there
myocarditic strain of Coxsackievirus B3 revealed six       are 410,000 sequence permutations and combinations
speci®c nucleotide changes, all of which had appeared      which must be explored before all viable and adaptive
in four separate isolates from the initial myocarditic     virus sequences have been testedÐeven if we assume
mouse examined and from 3 individual follow-up             a constant genome size restriction (which never
mice (89). This study agrees with the sequence studies     happens). There is not enough space-time in countless
of Chapman et al. (90) who also found that speci®c         imaginable universes to test even a minuscule fraction
changes at these six nucleotide sites are associated       of such incomprehensibly vast dimensions. Hence,
with the cardiovirulent phenotype (89,90) of               new sequence spaces will be explored increasingly
Coxsackievirus B3. Nothing could more clearly              rapidly in future decades. New RNA viruses and
illustrate the importance of quasispecies mutant           new diseases will emerge with increasing rapidity as
swarms in RNA virus disease. It is important to            long as human population growth remains in an
20       Holland and Domingo

exponential phase. Planet earth has a ®nite human                           Animal Virus Genetics. Academic Press, New York, 1981,
carrying capacity, but its dimensions are uncertain and                     pp. 363±384.
                                                                      12.   Eigen M. and Biebricher C.K. in Domingo E., Holland J.J., and
will be affected by human choices concerning quality                        Ahlquist P. (eds), RNA Genetics. CRC Press, Inc., Boca Raton,
of life, economics, environmental values, etc. (95).                        1988, pp. 211±245.
But beyond human choice are the evolutionary paths                    13.   Kaufmann S.A., The Origins of Order. Self Organization and
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Reflection paper 1

  • 1. Virus Genes 16:1, 13±21, 1998 # 1998 Kluwer Academic Publishers, Boston. Manufactured in The Netherlands. Origin and Evolution of Viruses JOHN HOLLAND1* & ESTEBAN DOMINGO2 1 Department of Biology and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093±0116 USA E-Mail: jholland@ucsd.edu. 2 Centro de Biologia Molecular Severo Ochoa Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain E-Mail: edomingo@mvax.cbm.uam.es. Virus Origins in the cases of bacteriophage Mu (which is both a virus and a transposon) and retroviruses (which are The origin(s) of viruses can not be known with retrotransposons containing a functional envelope certainty. PCR and other sensitive molecular techni- gene). As Temin pointed out (10), non-viral retroid ques will reveal some viral genome sequences from elements can become retroviruses only when such the relatively recent past, but very ancient viral retrotransposing protoviruses acquire envelope genes genomes will remain a matter for speculation. from another viral or cellular source by recombina- Numerous theories have been advanced regarding tion. DNA viruses and (non-retrovirus) RNA virus origins (reviewed in 1) and all necessarily riboviruses may also arise by recombinational (or involve speculation. However, comparative sequence reassortment) reshuf¯ing of cellular and viral or analysis strongly suggests that both RNA (2) and plasmid/episome/transposon mobile element genes. DNA (3) viruses have deep, archaic evolutionary Botstein (11) theory of modular evolution of DNA roots both for genome structural organization and as viruses is quite plausible. It envisions virus evolution regards certain genomic and protein domains. It is by recombinational arrangement of interchangeable also clear that both DNA and RNAviruses can emerge genetic elements or modules. The advantage of such and evolve by a variety of mechanisms including modular evolution is obvious. It allows virus genes, mutation, recombination and reassortment. This can protein domains, regulatory systems, etc. to evolve involve point mutation, insertions and deletions, independently under a wide variety of selective acquisition or loss of genes (and gene domains, or conditions. Thus, one module might have undergone sets of genes), rearrangement of genomes and its most recent evolution as part of an integrated utilization of alternate reading frames or inverted episome, another as part of a transposon, a third as a reading frames (1±6). plasmid element, yet another as part of a cellular gene Recombination can create new viruses by cap- or an integrated defective virus, etc. Such modular turing genes or gene segments or sets of genes either mobility obviously can relax evolutionary constraints from cellular nucleic acids or from other viruses. The which would prevail if all were required to co-evolve presence of cellular genes within virus genomes has within a single genomic unit. Of course, it will be an long been recognized (5). Likewise, the resemblance extremely rare event which could bring about a of viruses to plasmids, episomes and other mobile fortuitous compatible recombination of indepen- DNA or RNA replicons such as transposons or dently-evolving modules to create a new virus retrotransposons is obvious (1,7±9). The only clear having good biological adaptive capacity. But distinction between many such mobile elements and signi®cant virus emergences are likewise extremely viruses is the maturation of the latter within capsids rare occurrences and the probabilities for emergence (and envelopes) to affect ef®cient transmission and of a drastically different virus solely by mutational target cell receptor speci®city. This is well-illustrated changes within a single genome are generally orders
  • 2. 14 Holland and Domingo of magnitude less probable. Sequence space as date from great antiquity and continue to the present. elaborated by Eigen and colleagues (12) has incom- Presently, of course, nearly all new viruses emerge via prehensibly vast dimensions, and distant, previously evolution of old viruses. This is compatible with the unexplored regions of sequence space can best be deep evolutionary trees deduced for both DNA and reached (and mutationally explored) by the evolu- RNA viruses (4) and with the long-recognized tionary leaps which recombination or reassortment capacity of viruses to acquire genetic elements from afford. See Kauffman (13) for detailed discussion of host cell nucleic acids and form other mobile this point. Finally, it should be emphasized that replicons (1). ordinary RNA viruses (riboviruses), in additional to DNA viruses and retroviruses, can undergo such modular evolution via RNA recombination (and Virus Evolution reassortment). The essence of all viruses is obligate intracellular parasitism coupled with the capacity for The evolution of existing viruses, as for all living intimate genetic interactions with the DNA and RNA things, proceeds via a variety of mechanisms of their hosts and of cohabiting mobile elements. including mutation, recombination, reassortment and The nature of the earliest viruses can never be environmental selection. Space limitations prevent determined, but it is likely that they arose very early extensive discussion of virus evolution in this short during the evolution of life on earth. It seems review, so only major points will be discussed here. extremely likely that elemental life forms involved For an excellent recent overview of the molecular RNA replicons (14) and these might have borne basis of virus evolution, see (4). More concise resemblance to present-day RNA replicons such as coverage is provided in review articles (1,18±22). viroids, virusoids or viruses. In fact, Robertson (15) has suggested that very early, primitive autono- mously-replicating, self-cleaving RNA replicons RNA Virus Mutation Rates are Very High akin to present-day viroids might have acquired additional genes to form conjoined replicons which It is now clear that all or nearly all RNA viruses have later evolved into mosaic DNA-based entities. extremely high mutation rates (18±23). Mutation rates Hepatitis D virus was suggested as a present day at individual base sites may vary considerably, but example of such a conjoined viroid-like RNA average nucleotide base misincorporation rates are of replicon. It contains an open reading frame encoding the order of 10 À 4 to 10 À 5 (reviewed in 21±23). This the delta antigen protein joined to the viroid-like results in the generation of quasispecies mutant domain. Recently (16), it was shown that liver cells swarms even when the virus population has just express a cellular homolog of the delta antigen, arisen from a clone (21,22,24). A clonal quasispecies suggesting that hepatitis D virus may have arisen by virus population is a diverse mixture of virus mutants the capture of a cellular RNA transcript by a viroid- differing from each other at one or several genomic like RNA. A copy choice template transfer sites, and can be envisioned as a cloud in sequence mechanism was proposed for the recombinational space. A consensus sequence will represent the capture event. Robertson (15) suggested that such average sequence at each genome site and the events occurring early in the primitive RNA world master sequence(s) represent the most ®t member(s) could later have given rise to mosaic DNA modules, of the swarm in any particular de®ned selective and might even be responsible for the present environment. When the selective environment widespread prevalence of split genes and introns and changes the master sequence(s) and the overall RNA-catalyzed cleavage and ligation splicing sys- composition of the quasispecies swarm will also tems (17). In general, it is quite plausible that not only change. viroid-like, but plasmid-like transposon-like, retro- Obviously, the generation of quasispecies mutant transposon-like and virus-like autonomously- swarms can provide RNA viruses with great adapt- replicating RNA and DNA elements (replicons) ability under conditions in which there is have been intimately involved in nearly all evolution environmental change, and in complex mammalian of life on earthÐboth in precellular and cellular eras. hosts, viruses always encounter changing conditions Therefore, it is probable that the origins of viruses (e.g., different cell types, in¯ammatory responses,
  • 3. Origin and Evolution of Viruses 15 immune responses, fever temperatures, interferons, ef®ciently in two very disparate hosts; vertebrates etc.). It should be emphasized that, whereas the most- and invertebrate insects (31). Despite this relatively adapted master sequence(s) and closely-related var- slow rate of evolution, alphaviruses such as eastern iants will be the most abundant and most important equine encephalitis virus (and other arboviruses) variants under rather constant environmental condi- undergo signi®cant evolutionary change over the tions, the opposite will be true under rapidly changing centuries. For example, it was estimated that the conditions (e.g., adaptation to a new mammalian host North and South American antigenic varieties of or a new arthropod vector). Variants at the periphery eastern equine encephalitis virus diverged about 1000 of the quasispecies mutant distribution (i.e., those years ago and the two South American groups most distantly-related to the previous master diverged about 450 years ago (30). Venezuelan and sequence) will usually offer the best opportunity for eastern equine encephalitis alphavirus complexes rapid adaptation to the new conditions. Selected diverged about 1400 years ago (30) while the Old peripheral variants from the previous mutant distribu- and New World alphavirus groups diverged roughly tion will frequently also be peripheral variants in the 2000 to 3000 years ago (32). Even today, new new distribution as the quasispecies moves through epidemic/epizootic strains of Venezuelan encephalitis sequence space to optimize adaptability in the new emerge from enzootic strains in South America by environment and generate new master sequences. The rather minor mutational change (33). Finally, the very essence of the quasispecies theory of Eigen, western equine encephalitis group was estimated to Biebricher and colleagues (12,24±27) is the broad have emerged more than 1000 years ago (before the reach through sequence space which is provided by North and South American equine encephalitis virus RNA virus replicase error rates poised at the threshold divergence) by a very rare recombination event of error catastrophe. Finally, it should be noted that, as between eastern equine encephalitis virus and a in all evolution, rapid emergences of new RNA sindbis virus-like progenitor (6,18,34). variants are counterbalanced by rapid extinctions of Another example of slow versus rapid evolution others. can be observed with vesicular stomatitis virus (VSV) in both laboratory and natural settings. VSV Indiana serotype has been observed to undergo extremely Extremely High Mutation Rates Do Not rapid evolution under conditions of persistent infec- Necessitate Rapid Evolution tion in cell culture and relative genomic stasis under conditions of repeated dilute passages in the same Although, it is intuitively obvious that high rates of cells (35). In nature, VSV in its enzootic focus in RNA virus mutation facilitate rapid evolution, it Panama has undergone very little evolution over seems counterintuitive that RNA viruses sometimes recent decades (36). In contrast extensive evolution can exhibit rather long periods of relative evolu- was observed for strains isolated farther north. The tionary stasis. In general, RNA viruses evolve rapidly farther north the strains were isolated, the greater was but rates can vary considerably, and relative stasis is the sequence diversity from the genetically stable not uncommon. For example, evolutionary rates for ( presumed ancestral) strains in enzootic foci in many RNA viruses can be as high as 10 À 2 to 10 À 3 Panama and Costa Rica (36). The greatest divergence base substitutions per nucleotide site per year was found in strains from the extreme northern range (1,6,18,20±23), but rates of evolution of arthropod- of VSV in the United States. Thus, there is a borne viruses can be orders of magnitude slower. geographic clock rather than a molecular clock as Transovarial passage of the Phlebovirus toscana virus would be expected from neutral evolutionary theory. in sand¯y vectors showed extreme genome stability This apparent punctuated equilibrium evolution was during 2 years transmission time and over 12 sand¯y postulated to be due to different selective ecological generations (28). Likewise, alphaviruses in the eastern factors operating to drive virus evolution in diverse equine encephalitis complex evolved at rates nearly as geographic areas and different insect vector/hosts are low as 10 À 4 base substitutions ®xed per site per year probably important among these (36). These extre- (29,30). This low rate of evolution occurred despite mely unequal rates of evolution within a single virus normally high rates of mutation and was attributed to species and serotype dramatically con®rm the role of stabilizing selection for the ability to replicate selection in driving virus evolution. They also
  • 4. 16 Holland and Domingo dramatically emphasize the fact that high (and populations are small in asexual populations, there probably rather constant) mutation rates can be can be an inexorable accumulation of deleterious consistent with both rapid rates of evolution (mutation mutations leading to a ratchet-like decline in ®xation) or with evolutionary stasis. Relative stasis replicative ®tness. Chao (43) convincingly demon- (equilibrium) is favored under more constant selective strated the operation of Muller's ratchet in the conditions in the environment-precisely as is pre- tripartite RNA bacteriophage f6. Chao et al. (44) dicted by quasispecies theory (see section above). also showed that sexual crossing could often reverse Another remarkable example of a single virus the effects of Muller's ratchet. Quantitation of ®tness species exhibiting either evolutionary stasis or losses during repeated small population transfers extremely rapid evolution is provided by the thorough ( plaque-to-plaque genetic bottleneck transmissions) extensive studies of Webster and coworkers (20,37± of VSV and food-and-mouth disease virus con®rmed 39) of in¯uenza virus in natural avian hosts or in that variable, stochastic, often-profound ®tness mammalian hosts including humans. In aquatic wild decreases occur rather regularly (45±49). Clearly, birds, in¯uenza virus is apparently completely- genetic bottlenecks have the capacity to disturb virus adapted to intestinal replication and shedding with adaptive equilibrium and thereby to drive stochastic no signs of disease and with very little selection for evolutionary changes. The number of virus particles evolutionary change. Rapid evolution is the norm which constitute an effective genetic bottleneck can when in¯uenza viruses emerge into mammalian hosts vary greatly from only several particles to tens of (20,37,38). Immunity and other selective factors particles depending upon initial virus population apparently drive the extreme rates of in¯uenza virus ®tness (50,51). evolution exhibited during adaptation to mammals. The opposite effect on ®tness occurs during Overall, the work of Webster and colleagues indicates repeated transfers of very large numbers (105 to 106) that ducks and other waterfowl are the original hosts of infectious virus particles. Under these large dose for in¯uenza viruses. Rare genome segment reassort- transmission conditions, regular exponential increases ment events or transfers of entire in¯uenza virus in virus replicative ®tness occur and previous ®tness genomes initiate emergence into mammalian species, decreases due to Muller's ratchet are reversed but it is the destabilizing selective forces in mammals (48,50,51). Unquestionably, virus population trans- which drives the ensuing rapid evolution. This is mission size can affect virus evolution very another good example of punctuated equilibrium in profoundly, and this inevitably must also occur virus evolution. There are theoretical reasons (based during natural virus outbreaks. Transmission of large upon expected movements between adaptive peaks in doses of infectious virus particles often occurs during adaptive landscapes) to expect that evolution will transmissions involving close contact (e.g., sexual, frequently exhibit punctuated equilibrium (40). Plant kissing); during transfusions or other medical/dental viruses, such as the tobamoviruses can also exhibit blood/tissue transmission; intravenous drug abuse, genetic stability for long periods, again due to strong some insect vector or animal bite transmissions; and environmental selective pressures restricting quasis- during some very close respiratory droplet transmis- pecies diversi®cation (41). sions, some fecal-oral transmissions, etc. Genetic bottleneck transmissions inevitably occur during many rather distant virus transmissions during Effects of Virus Population Transmission Size on respiratory droplet inhalations. This is clear from Selection, Fitness and Evolution quantitative studies of both experimental and natural virus aerosol transmissions (52±54). After sneezing Whenever viruses become extremely-well-adapted to and coughing of infected people in a room, the volume host environments and evolutionary stasis is reached, of room air which must be sampled to obtain a single this equilibrium obviously can be upset readily infectious particle can be very large (53,54). For ( punctuated) by host or vector switching or by drastic example, 15 men in bed infected with adenovirus type environmental changes. Another, less obvious 4 and coughing frequently in a barracks room led to mechanism involves changes in the size (dose) of recovery of one tissue culture infective unit per 2820 virus particle transmission. In 1964, Muller (42) sq. ft. (54). Thus, genetic bottleneck transmissions postulated that whenever mutation rates are high and must be frequent and unavoidable for respiratory
  • 5. Origin and Evolution of Viruses 17 viruses although large population transfers must also account for 50% or more of the plants nuclear occur often during close contact. Similar considera- DNA! Large blocks of reiterated retrotransposons tions apply to fecal-oral spread, spread from inserted within each other are found in gene- inanimate objects (fomites) and from insect vector containing regions as intergenic segments (56,57). transmissions (55). Whenever large virus population Clearly, these are involved in determining gene transmissions occur repeatedly, selection can operate expression, genome size and genome organization, repeatedly to select the best of the best of the best . . . so that the distinction between host and sel®sh in terms of virus ®tness in a constant host species. parasitic genes is blurred beyond recognition. Conversely, repetitive genetic bottleneck transmis- Although RNA riboviruses cannot interact with sions interrupt selective forces and allow stochastic host DNA genomes as directly, nor as frequently as do changes in ®tness and in evolutionary directions. DNA viruses and retroviruses/retroelements, RNA These stochastic changes will usually be in the recombination is equally common and important direction of ®tness loss (and perhaps loss of virulence) among them as evolutionary events. The mechanisms but rarely, by chance, the converse will be true. and importance of recombination in riboviruses and Virulence is a multifactorial, multigenic trait which retroviruses are reviewed in (58,59). Riboviral RNA may or may not correlate with replicative ®tness and recombines with both cellular and viral RNAs and transmission ef®ciency. The major insight to be acquisition of genes and gene segments from both can gained from experimental studies of virus ®tness is be very important in ribovirus evolution and that RNA viruses are phenotypically quasispecies as emergence. Homologous recombination occurs fre- well as genetic quasispecies. Thus, all phenotypic quently during every replication of most positive characteristics, including virulence, will be highly sense riboviruses (58,60) but is extremely rare among variable among the numerous mutants present in a negative sense riboviruses in which non-homologous complex quasispecies swarm. Therefore, chance recombination events usually generate defective sampling events such as genetic bottlenecks may genomes (some quite bizarre), most of which are profoundly affect virulence traits (and other traits) dependent upon non-defective helper viruses for during an epidemic. Likewise, repetitive large replication (61). Very rarely, helper-dependent, population transmissions can preserve and enhance bizarre, defective RNA virus genomes are probably virulence or other traits which had been sampled by involved in major virus evolutionary events via RNA chance during earlier genetic bottleneck events. This recombination with non-defective helper viruses. can, of course, in¯uence disease severity and outcome Because their helper viruses provide all vital in infected individuals and in small local host cohorts replication functions, defective viral genomes are infected by such sampling of the quasispecies swarm. largely unconstrained by selective forces and can undergo extremely rapid, massive evolution. Thus, they could (very rarely) donate extensively-mutated Recombination, Reassortment and Gene and rearranged genome segments back to the helper Duplication in Virus Evolution viruses from which they arose (61). Among the segmented-genome viruses, reassort- As outlined in the chapters on virus origins, ment of segments provides a ready mechanism for recombination has long been recognized as a central generating new viruses. The best-known examples, of mechanism in the evolution of DNA bacteriophages course, involve the periodic antigenic shifts of and/or DNA viruses and retroviruses of animals and in¯uenza A viruses which usually occur at multi- plants. Recombination with, and insertion into, and decade intervals to initiate new human pandemics excision from, cellular DNA allows intimate genetic (37±39). The gene segment reassortment events which interactions with host genomes, episomes and cause emergence of new in¯uenza A viruses are very plasmids. Just as the frequent acquisition of cellular rare events because only certain permutations of avian genes can help shape virus evolution, so can the and mammalian gene segments will be highly frequent acquisition of virus and retroelement genes infectious and ®t, and because reassortment requires help to shape host evolution. A remarkable example is rare dual infection (by appropriate progenitor viruses) provided by maize in which many dozens or even of appropriate mixing vessel hostsÐmost often many hundreds of diverse retroelement families probably swine or humans (37±39). Once a ®t new
  • 6. 18 Holland and Domingo reassortant emerges into the human population very generally evolve to achieve and maintain optimal rapid evolution ensues (37±39). Reassortment events function. They often tend to produce inapparent and are important in the evolution of many other silent latent infections, to co-evolve slowly with their segmented genome RNA viruses. For example, hosts over geologic time periods, and even to bunyaviruses can evolve by reassortment in doubly- in¯uence the evolution of their host species (68,70± infected mosquitoes (62) and naturally-occurring Sin 73). Nevertheless, many DNA viruses can exhibit Nombre hantavirus reassortants have been observed considerable genetic plasticity (74) and this can be in Peromyscus deer mice in Nevada and Eastern manifested via antiviral drug resistance and other California (63). No reassortants were observed clinical problems. This is not surprising because DNA between Sin Nombre and other hantaviruses indi- viruses can have host recombination systems avail- genous to their region, suggesting that reassortants able to them in addition to intrinsic viral mechanisms. between distantly-related hantaviruses are rare or non- Also, DNA ®delity is limited for viruses which viable, and/or that host species speci®cities greatly replicate via single-stranded DNA because mismatch limit reassortment. Again, generation of ®t reassor- repair/excision repair systems are unavailable for tants between distantly-related and different-host- single-stranded DNA genomes. But, even bacter- adapted virus strains is generally a rare event in iophage T7, a classic double-stranded DNA virus nature. exhibited rapid evolution of replicating ®tness in A major mechanism observed in the evolution of single plaques (75). It should be noted that some DNA all life formsÐgene duplicationÐis sometimes viruses such as the canine/feline parvoviruses evolve important in virus evolution. For example, beet in nature at least as rapidly as the slower-evolving yellows virus, a ®lamentous RNA virus, contains a RNA viruses and can change host species speci®cities coat protein gene duplication (64) and two rabies- very readily as well (76). This is in marked contrast to related rhabdoviruses, Adelaide river virus (65) and the primate papillomaviruses, for example. Van Ranst bovine ephemeral fever virus (66) each contain two et al. (77) estimated primate papillomavirus mutation consecutive glycoprotein genes of differing size and rates to be of the order of 3 Â 10 À 8 base substitutions sequence. Both glycoprotein genes are expressed in per site per year in the EG gene. This is only about 20± each of these viruses; via monocistronic mRNAs in 30 times faster than the rate of evolution of their the case of bovine ephemeral fever virus and primate host species and about a million-fold lower polycistronic mRNAs for Adelaide virus. Gene than rates of evolution of the most rapidly evolving duplication of this kind occurs by recombination RNA riboviruses (29±35,78). events, probably via intra- or inter-molecular copy choice replicase leaps (58,67). Finally, a very simple, effective mechanisms for Implications of RNA Virus Quasispecies for creation of new virus gene products involves acquired Disease and Disease Emergence usage of alternative reading frames of an existing gene to create overlapping genes. This overprinting Some investigators have stated that quasispecies mechanism is common in virus evolution as outlined mutant swarms are not really necessary for disease in the review of Gibbs and Kease (4). processes during RNA virus infections. Of course, this could be argued quantitatively in terms of the minimal mutation rate which quali®es to produce a quasis- Do DNA Viruses Evolve as Quasispecies? pecies. However, this misses the essence of RNAvirus biology. RNA viruses have been the most abundant DNA viruses generally do not form complex and successful parasites since the appearance of quasispecies mutant swarms to the extent that RNA cellular life (see the ®rst chapter) and this has been viruses do because they generally have genomic achieved by maintaining error rates very near the error mutation rates about 300-fold lower than those of threshold (12). This allows maximal variability and RNA riboviruses and roughly 30-fold lower than adaptability (21±27) This great adaptability allows retroviruses (23,68). Proofreading and mismatch ®tness to be increased rapidly in changing environ- repair (69) of DNA can provide ®delity for even ments and the intact animal, human, plant or insect very large DNA virus genomes. Hence, DNA viruses vector organism always confronts invading microbes
  • 7. Origin and Evolution of Viruses 19 with multiple, challenging and changing environ- remember that myocarditis due to Coxsackie viruses ments. RNA virus quasispecies frequently undergo is rare relative to the number of human infections. major or minor changes in composition in response to Virulence is a trait which is seldom selected except in¯ammatory and immune responses (20,37,38,79) to when it correlates with replicative ®tness. Immune different host cell types within individual infected de®cits arising from selenium de®ciency regularly organisms, to widely differing conditions in verte- allowed expansion of the Coxsackievirus B3 quasis- brate versus insect vector hosts (80), to antiviral drug pecies mutant swarm and colonization of myocardial treatments (81,82), to inadequate vaccine programs, cells to cause disease. The cardiovirulent variants etc. Different subsets of the lymphocytic choriome- selected in heart muscle cells established a new ningitis virus quasispecies swarm are involved in quasispecies distribution which was cardiovirulent for lymphoid cell infection with immune suppression as normal mice after it was deliberately isolated from the contrasted with neuronal cell infection with runting total whole animal wild type quasispecies swarm. It is syndrome (growth hormone de®ciency syndrome) beyond question in this outstanding study that it is (83,84). those quasispecies subsets normally buried within the Perhaps the involvement of quasispecies in disease total circulating quasispecies population which have is best illustrated by the propensity of polioviruses to the potential to cause viral myocarditis (89,90). This is cause paralytic disease in a small percentage of likely a rather typical situation with regard to RNA infected individuals (60), and for some Coxsackie virus disease potential. viruses to cause cardiomyopathy in a small percentage Finally, the role of RNA virus quasispecies in of infected humans. Microevolution of the quasis- future emerging diseases of humans, domestic pecies population present in the type 3 Sabin oral animals and crops is obvious. Most emerging human poliovirus vaccine seed stocks (85) can cause diseases in recent years have been RNA virus paralytic disease in a very small percentage of vaccine diseases; from AIDS to Ebola hemorrhagic fever to recipients and can even initiate outbreaks of polio- hantavirus pulmonary syndrome. Most new or myelitis in unvaccinated populations (60,86). Clearly, emergent virus diseases in the future will also be the quasispecies nature of the vaccine seed stocks and RNA viruses because of the rapid evolution potential of their progeny is responsible for this rare but of their quasispecies. This trend will be accelerated so unfortunate disease complication of an otherwise long as the human population continues to expand excellent vaccine. An endemic cardiomyopathy exponentially. For example, the recent rapid growth of affecting thousands in China has been associated human populations in tropical areas has been matched with both selenium de®ciency and isolation of by an equally-rapid increase in dengue fever, dengue Coxsackieviruses from patients (87,88). Beck et al. hemorrhagic fever and dengue shock syndrome, and in a remarkable study of selenium de®cient mice (89) by an increasing rate of evolution of dengue viruses showed that infection by a normally non-virulent (91±93). All of us and our domestic animals (94) are clone of Coxsackie B3 virus induced signi®cant potential incubators for the rapid exploration of myocarditis in the Se-de®cient mice, and virus previously-unexplored sequence space by evolving recovered from the hearts of these myocarditic mice RNA viruses. Sequence space is a v-dimensional regularly caused myocarditis in normal Se-adequate hypercube in which v is the genome length in bases or mice! Complete sequence analysis of the recovered base pairs (12). For a 10 kb RNA virus genome there myocarditic strain of Coxsackievirus B3 revealed six are 410,000 sequence permutations and combinations speci®c nucleotide changes, all of which had appeared which must be explored before all viable and adaptive in four separate isolates from the initial myocarditic virus sequences have been testedÐeven if we assume mouse examined and from 3 individual follow-up a constant genome size restriction (which never mice (89). This study agrees with the sequence studies happens). There is not enough space-time in countless of Chapman et al. (90) who also found that speci®c imaginable universes to test even a minuscule fraction changes at these six nucleotide sites are associated of such incomprehensibly vast dimensions. Hence, with the cardiovirulent phenotype (89,90) of new sequence spaces will be explored increasingly Coxsackievirus B3. Nothing could more clearly rapidly in future decades. New RNA viruses and illustrate the importance of quasispecies mutant new diseases will emerge with increasing rapidity as swarms in RNA virus disease. It is important to long as human population growth remains in an
  • 8. 20 Holland and Domingo exponential phase. Planet earth has a ®nite human Animal Virus Genetics. Academic Press, New York, 1981, carrying capacity, but its dimensions are uncertain and pp. 363±384. 12. Eigen M. and Biebricher C.K. in Domingo E., Holland J.J., and will be affected by human choices concerning quality Ahlquist P. (eds), RNA Genetics. CRC Press, Inc., Boca Raton, of life, economics, environmental values, etc. (95). 1988, pp. 211±245. But beyond human choice are the evolutionary paths 13. Kaufmann S.A., The Origins of Order. Self Organization and to be followed by exponentially-increasing quasispe- Selection in Evolution. Oxford University Press, New York, 1993. cies swarms of RNA viruses exploring humans as 14. Gesteland R.F. and Atkins J.F. (ed.), The RNA World, Cold hosts. Virus evolution is stochastic and unpredictable Spring Harbor Lab Press, Plainview, NY, 1993. (35,96), but increasing numbers of human outbreaks 15. Robertson H.D. in Holland J.J. (ed.), Genetic Diversity of RNA are inevitable. They will occur; they should be Viruses. Curr. Top. Microbiol. Immunol., 1992. anticipated and there should be reasonable preparation 16. Brazas R. and Ganem D., Science 274, 90±94, 1996. for some unpleasant outbreaks. The human carrying 17. Robertson H.D., Science 274, 66±67, 1996. 18. Strauss J.H. and Strauss E.G., Annu Rev Microbiol 42, 657± capacity of our planet may ultimately be determined, 683, 1988. not by human choice, but by RNA virus evolution. 19. Zimmern D. in Domingo E., Holland J.J., and Ahlquist P. (eds), RNA Genetics. CRC Press, Boca Raton, 1988, pp. 211±240. 20. Webster R.G., Bean W.J., Gorman O.T., Chambers T.M., and Kawaoka Y., Microbiol Rev 56, 152±179, 1992. Acknowledgments 21. Domingo E. and Holland J.J. in Morse S. (ed.), Emerging Viruses. Oxford University Press, 1994, pp. 203±218. Work in La Jolla, CA was supported by NIH Grant 22. 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