ISSN 20790864, Biology Bulletin Reviews, 2015, Vol. 5, No. 6, pp. 527–537. © Pleiades Publishing, Ltd., 2015.

Original Russian Text © S.V. Shestakov, E.A. Karbysheva, 2015, published in Uspekhi Sovremennoi Biologii, 2015, Vol. 135, No. 2, pp. 115–127.

The Role of Viruses in the Evolution of Cyanobacteria

S. V. Shestakova, b and E. A. Karbyshevab
a
Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia
b
Moscow State University, Moscow, Russia
email: karbisheva@mail.ru
Received November 14, 2014

Abstract—Cyanophages play an important role in the evolution of cyanobacteria. They control cyanobacte
rium abundance, population dynamics, and the structure of natural communities. Cyanophages are a global
reservoir of genetic information. They act as vectors that transfer genes, endow cyanobacteria with novel
properties, and affect the rate and direction of evolutionary processes. Lysogeny makes a significant contri
bution to the maintenance of the gene pool and ecological adaptation of cyanobacteria. The integration of
many cyanobacterial genes into cyanophage genomes indicates that a genetic transfer occurs between hosts
and phages. Such a gene transfer performs the driving functions in adaptive microevolution. Analysis of the
molecular base of cyanophage–host interactions strongly supports the concept of the coevolution of
cyanophages and cyanobacterial genomes.

Keywords: evolution, genomics, cyanobacteria, cyanophages, horizontal gene transfer

DOI: 10.1134/S2079086415060079

INTRODUCTION genomes) serve as vectors for intrapopulational and

Bacteriophages, or, simply, phages, are viruses that
infect bacteria. They play an important role in the
ecology and evolution of microbial communities,
which determine the biogeochemistry of the Earth
(Fuhrman, 1999; Hambly and Suttle, 2005). The
interaction between phages and their hosts imple
ments this role.
First, phages control the microbial population size
and furnish the environment with sources of carbon,
nitrogen, and micronutrients by degrading prokary
otic cells. The concentration of phage particles in oce
anic ecosystems reaches 106–109 per mL. These parti
cles lyse 20–40% of prokaryotic biomass daily (Suttle,
2007). By regulating bacterium “mortality,” phages
not only influence the turnover of matter and energy in
the biosphere but also drive microbe diversification,
modify ecosystem structures (Weinbauer and Rassou
lzadegan, 2004), and modulate the rates of food web
processes.
Second, phage genomes are greatly variable. Thus,
they store a huge volume of genetic information in the
biosphere (Clokie et al., 2011). Metagenomic studies
of oceanic ecosystems revealed hundreds of thousands
of phage genotype, most of which have no similar
sequences in genomic databases (Angly et al., 2006).
The presence of identical genomic segments in phages
sampled from different regions of the ocean and ter
restrial ecosystems points to a broad circulation of
phages in the biosphere.
Third, phages and viruslike particles (derivatives
of defective phages bearing fragments of host
interspecific gene transfer (Kristensen et al., 2010).
Horizontal gene transfer among prokaryotic taxa can
be mediated by gene transfers between phages and host
cells, in which phages undergo mutational and recom
binational events. Phages supply host cells with
genetic information that can alter the evolution rate
and direction (Filee et al., 2003). In nature, lytic
phages evolve towards higher virulence, and host cells
strengthen their defense, in particular, restriction–
modification systems, mechanisms associated with
clustered regularly interspaced short palindromic
repeats (CRISPRs) that arrest phage gene expression
(Sorec et al., 2008; Stern and Sorec, 2010), and muta
tions in phage receptors (Labrie et al., 2010). The flex
ibility of systems mediating the interaction between
phages and hosts underlies the permanent antagonistic
coevolution of phages and their victims (Buckling and
Rainey, 2002). The viral pursuit of wellbeing leads to
responded host genome variability in response. This
mutual dependence is figuratively described as an arms
race (Comeau and Krisch, 2005; Stern and Sorec, 2010)
in which each contestant strives to leave the rival behind.
The evolution of cyanobacteria, whose contribu
tion to gene and metabolic networks of various ecosys
tems is of global significance, is discussed in the con
text of these three types of phage involvement in eco
logical and evolutionary processes.
CYANOBACTERIAL VIRUSES
Cyanobacterial viruses, or cyanophages, belong to
the order Caudovirales. They have linear double

527
528 SHESTAKOV, KARBYSHEVA
stranded DNA genomes (Ackermann, 2003) and are
divided into three large families: myoviruses (Myovir
idae), which are similar to phage T4 and possess a long
contractile tail; tailless podoviruses (Podoviridae); and
λlike siphoviruses (Siphoviridae), which possess a
long noncontractile tail. The notion of species
assumed for prokaryotes is not applicable to cyanoph
ages. Classification inside a family is based on the abil
ity of phages to infect cells of certain species or strains
of host cyanobacteria (Safferman et al., 1983). Strains
and isolates are designated alphanumerically with
indication of the ecologic origin. The classical marker
16S rRNA used in the phylogenetical analysis of
prokaryotes cannot be applied to viruses, since they
have no ribosomes. Studies of cyanomyoviruse
genomic diversity often use the relatively conservative
marker gene g20, which encodes one of capsid pro
teins (Zhong et al., 2002; Dorigo et al., 2004; Wilhelm
et al., 2006; Jing et al., 2014). The differences between
strains in this marker reach 50%, and the differences
between isolates are seldom greater than 0.5%.
Cyanophages infecting filamentous freshwater
cyanobacteria were discovered in 1960s (Safferman
and Morris, 1963). Phages infecting unicellular
marine cyanobacteria were extensively studied in
1990s (Waterbury and Valois, 1993; Wilson et al.,
1993). Analysis of cyanophage genomes showed their
broad diversity in size (10 to 380 kb) and sequence.
Metagenomic studies of marine ecosystems revealed a
great diversity of virus genotypes, including cyanoph
ages (Bench et al., 2007; Williamson et al., 2008). This
great variability is related to the species and strain
specificity of the interaction between cyanophages
and host cyanobacteria that inhabit different habitats
in different regions of the globe. Most cyanophages
can infect only certain cyanobacterium species or
strains. For example, one of podovirus groups is spe
cific to Prochlorococcus HL strains adapted to high
insolation (Sullivan et al., 2003). Cyanophages with
wide host ranges also exist. Some cyanomyoviruses
infect LL strains of Prochlorococcus and many Syn
echococcus strains sharing the same ecozone (Sullivan
et al., 2003). For example, both cyanobacterium gen
era are hosts of cyanophage Syn9 (Weigele et al.,
2007).
Cyanobacteria displaying high phylogenetic prox
imity according to basic sets of genes and synteny may
differ significantly in the presence of auxiliary opera
tional genes, which are often located on the same
genome islands (Coleman et al., 2006) as genes con
trolling fitness traits, including virus resistance.
Cyanobacterial genes from such islands have been
found in cyanophage genomes (Labrie et al., 2013).
This discovery is indicative of a gene transfer between
viruses and hosts and the putative involvement of the
islands in cyanophagemediated horizontal gene
transfer (Dufresne et al., 2008; Millard et al., 2009). It
is the transfer of auxiliary genes, including genes for
cyanophages resistance, that determines the genetic
BIOLOGY BULLETIN REVIEWS
heterogeneity of natural cyanobacterial populations,
which underlies the ecological diversification of
strains in microevolution.
Genomic studies of cyanomyoviruses lysing Syn
echococcus and Prochlorococcus reveal a great similar
ity of many basic genes encoding replication and tran
scription proteins to functionally similar genes of
phage T4 (Clokie et al., 2010). In addition, cyanoph
age genomes contain many metabolic genes with
functions typical of cyanobacteria: psbA, mazG, phoH,
cobS, etc. (Clokie et al., 2010; IgnacioEspinoza and
Sullivan, 2012).
THE ECOLOGIC AND GENETIC
SIGNIFICANCE OF CYANOPHAGES
Cyanophages are among the key factors determin
ing the rate and direction of evolution in cyanobacte
rial populations. Cyanobacteria need viruses as
genetic information stores and carriers (Hambly and
Suttle, 2005). Cyanophages also regulate the sizes and
genetic diversity of cyanobacterial populations.
Viruses need hosts to reproduce their genomes. This
mutually profitable partnership determines popula
tion histories in communities and provides grounds for
the coevolution of cyanophages and cyanobacteria
(Marston et al., 2012).
Lytic cyanophages destroy cyanobacterial cells.
The degree of lysis depends on the ratio between the
amounts of virulent cyanophage particles and cyano
bacterial cells sensitive to viral infection (Mann,
2003). This ratio depends on the population structure,
availability of nutrient and energy sources, competi
tion with other ecosystem members, and various envi
ronmental factors, particularly seasonal factors.
(Mühling et al., 2005; McDaniel et al., 2008). The
degree of lysis is negligible in oligotrophic marine
communities due to the low population density and
rare contacts between cyanophages and their hosts. In
tropical regions of the ocean, cyanobacteria are more
abundant; correspondingly, lysis is more intense,
though it depends on the amount of viral particles,
which rapidly die at high insolation and temperature.
Obviously, the genotype ranges of virus and host pop
ulations are the decisive factor.
The coexistence of phagesensitive and phage
resistant cyanobacterial strains supports the dynamic
balance of interests in the cyanobacterium–cyanoph
age system (Garza and Suttle, 1998; Avrani et al., 2011).
New variants of virulent cyanophages constantly arise
in nature. Concurrently, cyanobacterium strains resis
tant to strainspecific phage infection are selected.
The development of cyanophage resistance can follow
different pathways. Resistance to a certain cyanophage
may be determined, first of all, by mutations in cyano
bacterial genes, which code for cell receptors recog
nized by cyanophages. The Synechococcus marine
cyanobacterium has a group of independent mutant
strains selected for resistance against 32 cyanomyovi
Vol. 5 No. 6 2015
 THE ROLE OF VIRUSES IN THE EVOLUTION OF CYANOBACTERIA
ral isolates (Stoddard et al., 2007). Most mutations are
related to the restriction of cyanophage adhesion.
Many mutants selected for resistance to a particular
cyanophage isolate show crossresistance to other,
though not all, cyanophages. In addition, the control
of cyanophage resistance involves various metabolic
genes responsible for the biosynthesis of certain carbo
hydrates and lipids and for transferase activities (Mar
ston et al., 2012). These data indicate a broad range of
cyanobacterial genetic diversity in natural communi
ties with regard to phage resistance.
Most mutations conferring phage resistance occur
in hypervariable genome islands, where many genes
mediating adaptation to stress impacts are clustered.
These islands are intensely engaged in horizontal gene
transfer (Avrani et al., 2011). The variability in island
composition and polymorphism is produced by
genomic rearrangements in the course of multiple
infection events. It manifests itself in the formation of
subpopulations differing in cyanophage resistance.
With the absence of viruses, phageresistant cells con
stitute as little as 0.01–0.2% of a population (Garza
and Suttle, 1998). These cells grow more slowly than
phagesensitive ones and lose the competition (pay
ment for resistance) but ensure the preservation of the
basic gene pool of hosts (Lennon et al., 2007). The
coexistence and interaction of resistant and sensitive
cells capable of gene transfer is the tool with which
viruses control population composition and support
the balance of genetic diversity (Bouvier and del Gior
gio, 2007; Buckling and Rainey, 2012). This is how
cyanobacteria adapt to new conditions in particular
econiches.
One of the mechanisms controlling phage resis
tance in cyanobacteria may be associated with the
CRISPR system. The system is conjugated with the
function of Cas proteins, which arrest virus replication
in host cells (Breitbart, 2012). Genomic analysis of
two thermostable Synechococcus isolates from hot
springs revealed two types of CRISPR repeats specific
to each of the strains. The viral metagenome of the
same habitat contained genome variants that are capa
ble of evading the CRISPR resistance mechanism
(Heidelberg et al., 2009). Cyanobacteria apparently
produce mutant variants with altered CRISPR arrays,
ensuring immunity against mutant cyanophages.
Thus, coevolution as the strategic principle of the
virus–host interaction is clearly implemented in this
system as well.
The possibility of rapid antagonistic coevolution in
the twocomponent cyanobacterium–cyanophage
system was proven in experiments (Marston et al.,
2012). After six months of cyclic cocultivation of Syn
echococcus WH7803 with lytic cyanomyovirus RIM8,
the culture contained new cyanophage variants with
altered host ranges and phenotypically new (resistant
to the cyanophage) cyanobacterial isolates.
BIOLOGY BULLETIN REVIEWS Vol. 5 No. 6 2015
529
LYSOGENY IN CYANOBACTERIA
Lysogeny is an important mechanism by which
cyanobacteria resist phage infection. It involves the
integration of temperate cyanophage genomes into
chromosomes or plasmids of some cyanobacterium
strains (Mann, 2003). The resulting prophages repli
cate with the host genome without causing lysis. They
prevent host infection by genetically related virus
strains, thereby ensuring homoimmunity. Stress fac
tors, such as heat shock, intense illumination, UV
irradiation, heavy metal ions, etc., can induce the
prophage, causing virus development and host cell
lysis.
Lysogeny was discovered in filamentous freshwater
cyanobacteria (Cannon et al., 1971). There is indirect
evidence for lysogeny in senescent cultures of unicel
lular freshwater cyanobacteria Synechocystis aquatilis,
Microcystis aeruginosa, and Anacystis nidulans
(Goryushin et al., 1976). Later, lysogeny was found in
natural populations of marine unicellular cyanobacte
ria (Sode et al., 1994; Ohki and Fujita, 1996;
McDaniel et al., 2002). Lysogeny in cyanobacteria is
confirmed by their ability to produce phage particles in
response to mitomycin C (Cannon et al., 1971;
McDaniel et al., 2002; Ortmann et al., 2002). How
ever, little is known about the mechanisms governing
the lysogenic cycle in cyanobacteria and the function
of their prophages.
The evolutionary significance of lysogeny involves
the control of cyanobacterial population size, mainte
nance of the cyanobacterial gene pool in an ecosys
tem, and support of the virus reproductive potential.
High levels of lysogeny and poor prophage induction
efficiency in a population are related to low concen
trations of cells sensitive to a particular cyanophage
type. The probability of the lysogenic cycle is lower at
higher concentrations of sensitive cells (Mann, 2003).
The proportion of lysogenic cells is limited under con
ditions favoring phototrophic growth, but it increases
with shortage of nutrients, phosphorus, or iron. The
worse the living conditions of marine cyanobacteria
are, the higher is the selection probability of cells
housing inserted prophages in the population (Paul,
2008). This tendency is clearly seen in the seasonal
habit of lysogeny. In winter, when daytime is short,
populations of marine cyanobacteria contain large
proportions of lysogenic cells, which bear prophages
responsible for immunity and regulation of adaptive
response to stresses. The proportions of prophage
bearing cyanobacterial cells are higher in anoxic water
ecosystems and oligotrophic lakes of Antarctica (Lay
bournParry et al., 2007). Metagenomic analysis of the
virosphere of marine plankton demonstrates an asso
ciation between prophage induction and the activity of
genes encoding integrases, which are involved in
prophage formation (Paul, 2008; McDaniel et al.,
2008). The possibility of the lysogenic cycle in some
cyanophages in principle is indicated by the presence
530 SHESTAKOV, KARBYSHEVA
of genes for recombinases, integrases, and antirepres
sors responsible for prophage switchon and induction
in their genomes (Yoshida et al., 2008; Huang et al.,
2012; Sullivan et al., 2009; Labrie et al., 2013).
It should be mentioned that prophage genes con
trol not only the suppression of the lytic cycle but also
some metabolic processes in the host cell. Prophages
possess genes for transcription regulators, including
repressors, which arrest the activity of unnecessary
metabolic pathways in slowly growing cells. This phe
nomenon saves energy and macronutrients in chal
lenging environments. Prophages act as modulators of
phenotypic variability, which determines the course of
selection in populations. Insertion of a prophage
inside a gene or operon can influence the manifesta
tion of the corresponding trait significantly. A proph
age can be a target for recombination–transposition
systems performing genome rearrangements that
affect gene expression. The specific mechanisms by
which prophage genes suppress metabolism in
lysogenic cyanobacterial cells in response to stress are
unknown. However, it is reasonable to suggest that the
key role is played by sensory systems and mediated by
various histidine and serine–threonine protein
kinases. In particular, cyanophage SSM1 utilizes the
PhoR/PhoB regulatory system of Synechococcus cells
for induction of the expression of phage genes pstS and
phoH against a background of phosphate deficiency
(Zeng and Chisholm, 2012). Thus, the presence and
activity of prophages are an adaptive feature that
assists host cell survival under adverse conditions.
They are beneficial for both parties of the cyanobacte
rium–cyanophage system. Hence, prophages should
not be considered solely as a dangerous timebomb
(Paul, 2008). The relationships between a cyanophage
and its host assume the possibility of pseudolysogeny,
in which the viral genome exists in the infected cell as
an inactive particle that does not cause lysis rather
than as a prophage (Mann, 2003; Clokie et al., 2011).
It is conceivable that pseudolysogeny also provides the
conditions for genetic transfer between the cyanoph
age and host cell.
In the lytic phase, after prophage induction, the
probability of gene transfer between cyanobacterial
cells increases due to the appearance of cyanophages
acting as vectors. The result is an opportunity for
genetic diversification of strains and selection of
clones with mutations that confer virus resistance and
affect DNA repair and recombination processes.
These processes control genetic variability, which
determines microevolution in populations. Although
the role of lysogeny in cyanobacteria attracts scientists’
interest, information on prophages and their genomes
is scarce. No prophages were found in the genomes of
cultivated marine strains of Synechococcus and
Prochlorococcus (Kettler et al., 2007; Labrie et al.,
2013). Only a single cell of one Prochlorococcus isolate
of the HL ecotype contained a defective prophage
similar to the genome of podovirus PSSP7 (Malm
BIOLOGY BULLETIN REVIEWS
strom et al., 2013). Prophagelike elements were
found in genomes of freshwater cyanobacteria Syne
chococcus PCC 6301 (Huang et al., 2012) and Syne
chocystis PCC 6714 (Kopf et al., 2014).
Little is known about the mechanisms by which
cyanophages transfer cyanobacterial genes. No repro
ducible transduction systems have been developed for
cyanobacteria (Flores et al., 2008; Hess, 2008),
although there is indirect evidence of the possibility of
gene transfer by common transduction. A study of
DNA from cyanomyovirus SPM2, which infected
Synechococcus, detected a cyanobacterial DNA frag
ment with the Kmr marker gene in encapsulated
cyanophage particles (Clokie et al., 2003). It was
deduced from PCR data that one of the 105 phage par
ticles contained a packed fragment of cyanobacterial
DNA of the same size as the phage genome. With
regard to the presence of DNA from degraded phage
particles in the aquatic environment, gene transfer by
transfection of cyanobacterial cells may be suggested.
CYANOBACTERIAL GENES
IN CYANOPHAGE GENOMES
The presence of homologs of bacterial genes in
cyanophage genomes (see table) is indicative of gene
transfer between viruses and their hosts (Lindell et al.,
2004; Zeidner et al., 2005; Sullivan et al., 2006; Clokie
et al., 2010; IgnacioEspinoza and Sullivan, 2012).
Coinfection of cyanobacteria by different cyanophage
strains capable of infecting both Synechococcus and
Prochlorococcus is accompanied by recombination
between the genomes of different cyanophage strains
(Zeidner et al., 2005). This is how gene transfer
between genera may occur. Through recombination of
viruses acting as vectors, cyanobacterial genes cap
tured by cyanophages are drawn into gene transfer. In
the case of closely related cyanophage strains,
intragenic homologous recombination produces
mutations and allelic variants. However, amino acid
replacement happens very rarely because of tough sta
bilizing selection (Marston and Amrich, 2009).
Homologous recombination between genetically dis
tant cyanophage strains or between a virus and the
host genome produces mosaic genes, which consist of
segments from different partners (Marston and
Amrich, 2009). In nonhomologous (illegitimate)
recombination, cyanobacteria acquire “alien” genes
of adaptive significance, which can alter the direction
of evolutionary processes in bacterial populations
(Shestakov, 2007). Some cyanophage genes, e.g.,
phoH, talC, and hsp20, are highly similar to genes of
some heterotrophic bacteria. It appears that cyano
bacteria that had received these genes from genetically
distant donors were intermediate hosts for corre
sponding cyanophages. It is likely that agents perform
ing gene transfer in the nature include viruses whose
overlying host ranges have not been established.
Vol. 5 No. 6 2015
 THE ROLE OF VIRUSES IN THE EVOLUTION OF CYANOBACTERIA 531

Cyanophage genes homologous to cyanobacterial ones

Gene Encoded protein Cyanophage Cyanobacterium
psbA Protein D1 FSII PSSM4 (M) Prochlorococcus
(photosystem II) PSSP7 (P) Prochlorococcus
SPM2 (M) Synechococcus
psbD Protein D2 FSII PSSM4 (M) Prochlorococcus
(photosystem II) SPM2 (M) Synechococcus
psaEF Proteins FSI Metagenomic Prochlorococcus
(photosystem I) clones Synechococcus
hli Photoprotective proteins PSSM2 (M) Prochlorococcus
PSSP7 (P) Prochlorococcus
SPM2 (M) Synechococcus
SCBS2 (S) Synechococcus
pebS Phycoerythrobilin synthase PSSM2 (M) Prochlorococcus
pcyA Ferredoxin oxidoreductase PSSM4 (M) Prochlorococcus
cpeT Regulation of phycoerythrin PRSM4 (M) Prochlorococcus
synthesis SPM2 (M) Synechococcus
speD SAdenosylmethionine PSSM4 (M) Prochlorococcus
decarboxylase SPM2 (M) Synechococcus
nblA Phycobilisome PaVLD Planktothrix
degradation MaLMM01 Microcystis
tal C Transaldolase PRSM4 (M) Prochlorococcus
PSSP7 (P) Prochlorococcus
SRSM2 (M) Synechococcus
petF Ferredoxin PSSM2 (M) Prochlorococcus
SSM2 (M) Synechococcus
petE Plastocyanin PSSM2 (M) Prochlorococcus
SRSM2 (M) Synechococcus
ho1 Heme oxidase PSSM2 (M) Prochlorococcus
pto Plastoquinone PSSM4 (M) Prochlorococcus
terminal oxidase Syn9 (M) Synechococcus
gnd 6Phosphogluconate dehydrogenase Syn9 (M) Synechococcus
zwf Glucose6phosphate dehydrogenase Syn9 (M) Synechococcus
cp12 Regulator of C metabolism PSSM2 (M) Prochlorococcus
SSM2 (M) Synechococcus
pstS ABCtype phosphate transport PSSM4 (M) Prochlorococcus
SSM2 (M) Synechococcus
phoH Phosphate metabolism PSSM2 (M) Prochlorococcus
regulation SPM2(M) Synechococcus
MaLMM01(M) Microcystis
cobS Cobalamin synthase PSSM2 (M) Prochlorococcus
cobO (vitamin B1 synthesis) SRSM4 (M) Synechococcus
SCBS2 (S) Synechococcus
nrdA Subunits α and β PSSP7 (P) Prochlorococcus
nrdB of ribonucleotide reductase PSSM2 (M) Prochlorococcus
PSS2 (S) Prochlorococcus
SPM2 (M) Synechococcus
MaLMM01(M) Microcystis

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532 SHESTAKOV, KARBYSHEVA

Table (Contd.)
Gene Encoded protein Cyanophage Cyanobacterium
mazG Regulation of the level PSSM4 (M) Prochlorococcus
of guanosine3',5'bispyrophosphate SRSM4 (M) Synechococcus
hsp Heat shock proteins Syn9 (M) Prochlorococcus
SPM2 (M) Synechococcus
prnA Tryptophan halogenase PSSM2 (M) Prochlorococcus
SPM2 (M) Synechococcus
rpoS RNA polymerase PSS2 (S) Prochlorococcus
sigma factor III SCBS4 (S) Synechococcus
thy1 Thymidylate synthase PSSM4 (M) Prochlorococcus
SPM2(M) Synechococcus
PSS2 (S) Prochlorococcus
SCBS2 (S) Synechococcus
dcd CTP deaminase PSS2 (S) Prochlorococcus
SCBS2 (S) Synechococcus
prm DNA primase PSS2 (S) Prochlorococcus
SCBS2 (S) Synechococcus
SPM2 (M) Synechococcus
ssb Singlestrand PSS2 (S) Prochlorococcus
DNAbinding protein SCBS2 (S) Synechococcus
SPM2 (M) Synechococcus
pep Peptidase SCBS2 (S) Synechococcus
Abbreviations: (M), myovirus; (P), podovirus; (S), siphovirus.

The evolutionary histories of phage genes of cyano
bacterial origin shown in the table are different. They
depend primarily on the mode of the interaction
between the particular virus strain and the host cyano
bacterium and on ecophysiological conditions. One
transcription cluster in the genome of a cyanophage
can combine bacterial genes that are involved in a sin
gle metabolic pathway but are located in different
cyanobacterial genome segments. Clusterization of
this sort, e.g., psbA with psbD in cyanomyovirus SPM2
(Millard et al., 2004), is a result of multiple recombi
nation events in the phage genome. It allows gene
coexpression (Lindell et al., 2007).
Among genes of the basic set, psbA and psbD most
often occur in the genomes of myo and cyanopodovi
ruses but not in cyanosiphoviruses. These genes
encode photosystem II proteins. The genomes of 88%
of marine cyanophages contain psbA, and 50% of them
have psbD as well (Sullivan et al., 2006). The psbA gene
has been found in all cyanomyoviruses and in clade B
of cyanopodoviruses infecting Prochlorococcus
(DekelBird et al., 2013). The difference in the psbA
sequence between freshwater and marine cyanophages
points to different evolutionary histories of these
cyanophage groups. Differences in psbA have been
found between cyanophages infecting Prochlorococcus
and Synechococcus, between groups of cyanomyovi
ruses and cyanopodoviruses, and between isolates
from different ocean regions. This psbA diversity is
related to the host strain specificity, which determines the
nature of cyanophage interaction in particular habitats
(Chenard and Suttle, 2008). Cyanobacteria extract and
preserve those psbA variants from the natural cyanoviral
gene pool that optimize photosynthesis.
What is the biological significance of the preserva
tion of the psbA and psbD genes in the genomes of
cyanophages, where photosynthesis is impossible? At
early stages of infection, many genes, including psbA
and psbD, terminate their operation, but the transcrip
tion of phage genes is activated, together with synthe
sis of the corresponding polypeptides of the photosys
tem (Sullivan et al., 2006). A high level of protein D1,
which is rapidly inactivated by light, is maintained in
an infected cell, and it supports the stability of the
photosystem, which provides energy for phage
genome replication. The cyanophage takes care of its
own reproduction by using the resources of the host
cell, which is sentenced to death. The photosynthetic
genes of cyanophages favor infection development and
increase the rate of virus reproduction, particularly, in
a challenging environment (Bragg and Chisholm,
2008; Hellweger, 2009).

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 THE ROLE OF VIRUSES IN THE EVOLUTION OF CYANOBACTERIA
The cyanophage genes of photosystem II are, as a
rule, similar in structure to the homologous host
genes. This similarity reflects the coevolution of
cyanoviral and cyanobacterial genomes. The demand
for psbA and psbD expression is determined by the
duration of the lag phase at the beginning of infection.
Cyanophages with lag phases lasting 2–3 h require
photosynthesis genes, because the degrading host cell
is already short on energy. Cyanophages with short lag
phases, such as cyanopodovirus P60, have no photo
synthesis genes. This difference is also of ecological
significance. The psbA gene is characteristic of group B
cyanopodoviruses inhabiting the surface layer of olig
otrophic ocean, but it is absent from group A cyanop
odoviruses, which inhabiting coastal zones and estuar
ies (DekelBird et al., 2013; Zheng et al., 2013).
The relationship between coevolution processes in
cyanophages and cyanobacteria is also illustrated by
the fact that the psbA gene present in cyanomyovirus
SPM2 of Synechococcus and in the phage metage
nome of sea ecosystems has an intron that is excised at
the early infection stage by a specific endonuclease,
which is encoded by a gene linked to psbA. This splic
ing, which ensures the formation of active protein D1,
is regulated by an antisense miniRNA, and the synthe
sis of this miniRNA is coregulated by psbA and the
endonuclease gene (Millard et al., 2010). The stabili
zation of photosystem II may involve the product of the
speD cyanophage gene for Sadenosylmethionine
decarboxylase, which is the key enzyme in the synthesis
of the polyamines protecting mRNA (Mann et al., 2005).
Genes of photosystem I are also found in metage
nomic analysis of cyanophages. Six psa genes are clus
tered together, although they are dispersed over differ
ent genome regions of cyanobacteria (Sharon et al.,
2009). The modified complex of photosystem I genes
is likely to be associated with the respiratory chain of
electron transport and to support the reduction poten
tial. Cyanomyoviruses PSSM2 and PSSM4, which
infect Prochlorococcus, contain genes pebS for phyco
erythrobilin synthase and pcyA for ferredoxin oxi
doreductase. These genes are involved in the synthesis
of phycobilisomes, which are lightgathering com
plexes that assist photosynthesis and protect it from
photoinactivation (Dammeyer et al., 2008). The
cyanophage pebS gene encodes a new protein that per
forms the same functions as those performed by two
cyanobacterial proteins: PsbA and PsbB. It is one
more example of rearrangements in the cyanophage
genome in the course of coevolution of the virus and host.
Some cyanophages possess the cpeT gene, which regu
lates phycoerythrin production. Cyanophage SPM2
induces phycoerythrin synthesis in infected Synechoc
occus cells (Shan et al., 2008).
Cyanophage genomes contain a number of genes
supporting the photosynthesis machinery. They
include hli genes, which encode the family of chloro
phyllassociated HLIP proteins. These proteins pro
tect photosynthesis systems and cells from photoinac
BIOLOGY BULLETIN REVIEWS Vol. 5 No. 6 2015
533
tivation (Bhaya et al., 2002). These proteins absorb the
excess of excitement energy. They are induced by high
insolation and expressed in conjugation with ribonu
cleotide reductase genes psbA and nrdAB at early stages
of infection (Lindell et al., 2007). Cyanobacteria have
multiple copies of hli genes, which are located mainly
in genomic islands. It appears that these genes were
recurrently transferred by cyanophages. The cyanoph
age pto (ptoX) gene encodes plastoquinone terminal
oxidase, which is responsible for electron flux switch,
and also contributes to the optimization of energy sys
tems (Sullivan et al., 2003; Weigele et al., 2007; Mill
ard et al., 2009).
In the absence of photosynthesis, the pentose
phosphate pathway (PPP) provides energy for virus
replication. Its key steps are controlled by cyanophage
genes. The genomes of many cyanophages contain the
cp12 gene (Thompson et al., 2011; IgnacioEspinoza
and Sullivan, 2012). Its product inhibits the Calvin
cycle and switches C metabolism to PPP, which is
conjugated with the functions of the zwf gene for glu
cose6phosphate dehydrogenase and gnd gene for
phosphogluconate dehydrogenase, which is found in
Syn9 (Weigele et al., 2007) and some other cyanoph
ages (Millard et al., 2009; Clokie et al., 2010; Sullivan
et al., 2010; Labrie et al., 2013). PPP activation pro
motes the production of deoxyribonucleoside triphos
phates and increases the level of NADPH, which is
required for this process. Infected cells demonstrate
coordinated expression of the zwf, gnd, and cp12
genes, together with the talC gene for transaldolase, a
PPP enzyme (Thompson et al., 2011). Thus,
cyanophages not only serve as vectors for the men
tioned genes but also modulate C metabolism in host
cells in order to optimize their own reproduction.
Many cyanophages bear hsp genes, which encode
proteins inducible by heat stress (Mann et al., 2005;
Weigele et al., 2007; Maaroufi and Tanguay, 2013).
These genes, borrowed from hosts, participate in the
assembly of phage capsids. Marine and freshwater
cyanomyoviruses have phoH and pstS genes, which
control the phosphorus metabolism (Sullivan et al.,
2005; Yoshida et al., 2008; Clokie et al., 2010). These
genes are induced upon a phosphate deficiency. It is
hypothesized that these auxiliary genes, which occur
mainly in genomic islands and support adaptation to
phosphate shortage, are involved in cyanophage
mediated horizontal transfer between cyanobacteria.
The genomes of most cyanophages have the cobS
(cobO) genes for cobalamin synthase, an enzyme par
ticipating in vitamin B1 production (Sullivan et al.,
2005; Sullivan et al., 2010; Huang et al., 2012).
Cyanophages support the natural diversity of various
metabolic genes. It follows from phylogenetic analysis
that these genes may have been obtained by phages
from different original donors (Sullivan et al., 2010).
Horizontal transfer systems ensured broad dis
persal of the mazG gene, which is found in the
genomes of all cyanomyoviruses (Bryan et al., 2008).
534 SHESTAKOV, KARBYSHEVA
This conservative gene appears to be essential for
metabolism coordination at early stages of infection. It
regulates the level of guanosine3',5'bispyrophos
phate, which participates in adaptive cell responses to
stress factors. Phylogenetic analysis shows that differ
ent cyanobacteria received mazG from different
donors.
Many cyanophage genes that are supposed to have
been received from bacteria support replication (thy1,
prm, and ssb), transcription (rpoS), or translation (see
table). The genomes of some cyanophages contain
intact or modified genes for transfer RNAs, which are
presumably able to assist in reading phage information
or serve as targets for insertion of mobile elements.
The intact copies improve the efficiency of phage
genome translation by the convergence of GC con
tents and codon usage in the viral and host genomes
(specialization strategy). Cyanomyoviruses employ
the adaptation strategy. They insert their set of tRNA
genes into host cells, thereby supporting the reading of
their genes even in cyanobacteria differing in GC con
tent. In doing so, they expand their host range (Limor
Waisberg et al., 2011). Thus, the variability and horizon
tal transfer of tRNA genes are putative tools for the
coevolution of cyanoviral and cyanobacterial genomes.
In addition to metabolic genes shown in the table,
cyanophage genomes have other genes of bacterial ori
gin: methyltransferases, irondependent oxygenases,
peptidases signaling protein kinases, cell surface pro
teins (lipopolysaccharides, receptors, and transport
ers), and many hypothetical genes of unknown func
tions (Mann et al., 2005; Weigele et al., 2007; Yoshida
et al., 2008; Millard et al., 2009; Gao et al., 2012).
Some of these genes are very similar to genes of other
cyanobacteria (Gloeothece, Nostoc, and Trichodes
mium) or even heterotrophic bacteria. Cyanophages
might acquire such genes from cyanobacteria serving
as intermediate hosts; they received them by horizon
tal transfer from phylogenetically distant donors
within the same habitat.
Data on the functions of cyanobacterial genes in
cyanophage genomes are related mainly to marine
unicellular bacteria. Complete sequences are available
only for a few genomes of cyanophages infecting fresh
water or soil cyanobacteria (Xia et al., 2013). This is a
constraint on our discussion of cyanobacterial genes in
cyanoviral genomes. About 20 cyanobacterial genes have
been found in the genome of cyanophage PaVLD of the
filamentous Planktotrix cyanobacterium. Their prod
ucts are similar to proteins of various cyanobacteria:
Nostoc, Lyngbya, Cyanothece, etc. This cyanophage
possesses the nblA gene, which is involved in phycobil
isome degradation (Gao et al., 2012). A similar nblA
gene and nrd genes for ribonucleotide reductase are
present in the genome of myovirus MaLMM01,
which infects the toxic freshwater Microcystis aerugi
nosa cyanobacterium (Nakamura et al., 2014). It is
believed that the Nbl protein of cyanophages is
involved in protection of host cells from photoinacti
BIOLOGY BULLETIN REVIEWS
vation. The genome of SCRM01, which infecs
Microcystis, contains the “photosynthetic” psbA gene
(Dreher et al., 2011), which is absent from Ma
LMM01 and PaVLD.
CONCLUSIONS
By 2014, a large volume of information on com
pletely sequenced cyanobacterial and cyanoviral
genomes had been collected (http://proportal.mit.
edu/project/cyanophage/), and the Cyanobase plat
form had been updated (Nakao et al., 2010). Compar
ative genomics provides convincing evidence that hor
izontal gene transfer played an important role in
cyanobacterial evolution (Zhaxybaeva et al., 2006; Shi
and Falkowski, 2008; Yerrapragada et al., 2009; Igna
cioEspinoza and Sullivan, 2012). Cyanobacteria har
boring plasmids and mobile elements can potentially
utilize them for genetic transfer of transformation and
conjugation systems (Hess, 2008; Flores et al., 2008).
Marine cyanobacteria with small genomes, which are
devoid of mobile elements and transposases (Mikhe
eva et al., 2011), as a rule have a limited capacity for
transformation and conjugation. The ample data pre
sented in this review suggest that cyanophages provide
the main route for genetic communication among
such cyanobacteria. Investigation of the machinery
supporting the involvement of cyanophages in the
control of populational processes and gene transfer in
natural communities is an urgent task in the evolution
ary genetics of cyanobacteria.
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Translated by V. Gulevich