A viral quasispecies is a
population structure of
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
es with a large number of variant
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s (related by mutations). Quasispecies result from high
mutation rate
In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates ...
s as mutants arise continually and change in relative
frequency
Frequency is the number of occurrences of a repeating event per unit of time. It is also occasionally referred to as ''temporal frequency'' for clarity, and is distinct from ''angular frequency''. Frequency is measured in hertz (Hz) which is eq ...
as
viral replication
Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome an ...
and
selection
Selection may refer to:
Science
* Selection (biology), also called natural selection, selection in evolution
** Sex selection, in genetics
** Mate selection, in mating
** Sexual selection in humans, in human sexuality
** Human mating strateg ...
proceeds.
The theory predicts that a viral
quasispecies
The quasispecies model is a description of the process of the Darwinian evolution of certain self-replicating entities within the framework of physical chemistry. A quasispecies is a large group or "cloud" of related genotypes that exist in an en ...
at a low but
evolutionarily neutral
Evolution is change in the heredity, heritable Phenotypic trait, characteristics of biological populations over successive generations. These characteristics are the Gene expression, expressions of genes, which are passed on from parent to ...
and highly connected (that is, flat) region in the
fitness landscape
Fitness may refer to:
* Physical fitness, a state of health and well-being of the body
* Fitness (biology), an individual's ability to propagate its genes
* Fitness (cereal), a brand of breakfast cereals and granola bars
* ''Fitness'' (magazine), ...
will outcompete a quasispecies located at a higher but narrower fitness peak in which the surrounding mutants are unfit.
This phenomenon has been called 'the quasispecies effect' or, more recently, the 'survival of the flattest'.
The term quasispecies was adopted from a theory of the
origin of life
In biology, abiogenesis (from a- 'not' + Greek bios 'life' + genesis 'origin') or the origin of life is the natural process by which life has arisen from non-living matter, such as simple organic compounds. The prevailing scientific hypothes ...
in which primitive
replicons consisted of mutant distributions, as found experimentally with present-day
RNA virus
An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses ...
es within their
host
A host is a person responsible for guests at an event or for providing hospitality during it.
Host may also refer to:
Places
* Host, Pennsylvania, a village in Berks County
People
*Jim Host (born 1937), American businessman
* Michel Host ...
.
The theory provided a new definition of
wild type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
when describing viruses, and a conceptual framework for a deeper understanding of the
adaptive potential of RNA viruses than is offered by classical studies based on simplified
consensus sequence
In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...
s.
The quasispecies model is most applicable when the genome size is limited and the mutation rate is high, and so is most relevant to
RNA viruses (including important
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s) because they have high
mutation rate
In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates ...
s (approx one error per round of
replication),
though the concepts can apply to other biological entities such as reverse translating DNA viruses like hepatitis B. In such scenarios, complex distributions of closely related variant genomes are subjected to
genetic variation
Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, ...
, competition and
selection
Selection may refer to:
Science
* Selection (biology), also called natural selection, selection in evolution
** Sex selection, in genetics
** Mate selection, in mating
** Sexual selection in humans, in human sexuality
** Human mating strateg ...
, and may act as a
unit of selection
A unit of selection is a biological entity within the hierarchy of biological organization (for example, an entity such as: a self-replicating molecule, a gene, a cell, an organism, a group, or a species) that is subject to natural selection. ...
. Therefore, the evolutionary trajectory of the viral infection cannot be predicted solely from the characteristics of the fittest sequence. High mutation rates also place an
upper limit compatible with inheritable information. Crossing such a limit leads to RNA
virus extinction, a transition that is the basis of an antiviral design termed
lethal mutagenesis
Error catastrophe refers to the cumulative loss of genetic information in a lineage of organisms due to high mutation rates. The mutation rate above which error catastrophe occurs is called the error threshold. Both terms were coined by Manfred ...
, and of relevance to antiviral medicine.
The relevance of quasispecies in virology has been the subject of extended debate. However, standard clonal analyses and
deep sequencing
Coverage (or depth) in DNA sequencing is the number of unique reads that include a given nucleotide in the reconstructed sequence. Deep sequencing refers to the general concept of aiming for high number of unique reads of each region of a sequence. ...
methodologies have confirmed the presence of myriads of mutant genomes in viral populations, and their participation in
adaptive processes.
History
![Viral quasispecies Figure 1](https://upload.wikimedia.org/wikipedia/commons/1/1e/Viral_quasispecies_Figure_1.png)
Quasispecies theory was developed in the 1970s by
Manfred Eigen
Manfred Eigen (; 9 May 1927 – 6 February 2019) was a German Biophysical chemistry, biophysical chemist who won the 1967 Nobel Prize in Chemistry for work on measuring fast chemical reactions.
Eigen's research helped solve major problems in ...
and
Peter Schuster
Peter K. Schuster (born 7 March 1941) is a theoretical chemist known for his work with the German Nobel Laureate Manfred Eigen in developing the quasispecies model. His work has made great strides in the understanding of viruses and their replica ...
to explain self-organization and adaptability of primitive
replicons (a term used to refer to any replicating entity), as an ingredient of
hypercyclic organizations that link
genotypic
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
and
phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
information, as an essential step in the origin of life.
The theory portrayed early replicon populations as organized mutant spectra dominated by a master sequence, the one endowed with the highest
fitness (replicative capacity) in the distribution. It introduced the notion of a mutant ensemble as a unit of selection, thus emphasizing the relevance of
intra-population interactions to understand the response to
selective constraints. One of its corollaries is the
error threshold relationship, which marks the maximum mutation rate at which the master (or dominant) sequence can stabilize the mutant ensemble. Violation of the error threshold results in loss of dominance of the master sequence and
drift
Drift or Drifts may refer to:
Geography
* Drift or ford (crossing) of a river
* Drift, Kentucky, unincorporated community in the United States
* In Cornwall, England:
** Drift, Cornwall, village
** Drift Reservoir, associated with the village
...
of the population in
sequence space
In functional analysis and related areas of mathematics, a sequence space is a vector space whose elements are infinite sequences of real or complex numbers. Equivalently, it is a function space whose elements are functions from the natural num ...
.
The core quasispecies concepts are described by two fundamental equations: replication with production of error copies, and the error threshold relationship. They capture two major features of RNA viruses at the population level: the presence of a mutant spectrum, and the adverse effect of an increase of mutation rate on virus survival, each with several derivations.
![Viral quasispecies Figure 2](https://upload.wikimedia.org/wikipedia/commons/4/44/Viral_quasispecies_Figure_2.png)
The existence of a mutant spectrum was experimentally evidenced first by clonal analyses of
RNA bacteriophage Qβ populations whose replication had been initiated by a single virus particle. Individual genomes differed from the consensus sequence in an average of one to two mutations per individual genome.
Fitness of biological clones was inferior to that of the parental, uncloned population, a difference also documented for
vesicular stomatitis virus
''Indiana vesiculovirus'', formerly ''Vesicular stomatitis Indiana virus'' (VSIV or VSV) is a virus in the family ''Rhabdoviridae''; the well-known ''Rabies lyssavirus'' belongs to the same family. VSIV can infect insects, cattle, horses and pigs ...
(VSV).
The
replicative capacity of a population ensemble need not coincide with that of its individual components. The finding that a viral population was essentially a pool of mutants came at a time when mutations in general genetics were considered rare events, and virologists associated a viral genome with a defined
nucleotide sequence
A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usu ...
, as still implied today in the contents of
data bank In database management and information architecture, a data bank or databank is a repository of information about one or more subjects, that is, a database which is organized in a way that facilitates local or remote information retrieval and is abl ...
s. The cloud nature of Qβ was understood as a consequence of its high mutation rate, calculated in 10
−4 mutations introduced per nucleotide copied,
together with
tolerance of individual genomes to accept an undetermined proportion of the newly arising mutations, despite fitness costs. The error rate estimated for bacteriophage Qβ has been confirmed, and is comparable to values calculated for other RNA viruses.
High mutation rates and quasispecies were verified for other RNA viruses based on dissection of viral populations by molecular or biological cloning, and sequence analysis of individual clones. John Holland and colleagues were the first to recognize that a rapidly evolving RNA world inserted in a DNA-based biosphere had multiple evolutionary and medical implications.
Genome plasticity of RNA viruses had been suspected for many decades. Key early observations were variations in viral traits described by Findley in the 1930s, the studies of Granoff on transitions of
plaque
Plaque may refer to:
Commemorations or awards
* Commemorative plaque, a plate or tablet fixed to a wall to mark an event, person, etc.
* Memorial Plaque (medallion), issued to next-of-kin of dead British military personnel after World War I
* Pla ...
morphology of
Newcastle disease virus Newcastle usually refers to:
*Newcastle upon Tyne, a city and metropolitan borough in Tyne and Wear, England
*Newcastle-under-Lyme, a town in Staffordshire, England
*Newcastle, New South Wales, a metropolitan area in Australia, named after Newcastle ...
, or the high frequency of conversions between
drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
and dependence in
Coxsackie A9 virus, among other studies with animal and plant viruses in the middle of the 20th century.
When put in the context of present-day knowledge, we realize that these observations on phenotypic changes were the tip of the iceberg of an extremely complex reality of viral populations. High mutation rates and population heterogeneity characterize RNA viruses, with consequences for viral pathogenesis and the control of viral disease. Detailed studies on quasispecies dynamics ''in vivo'' have been performed with
human immunodeficiency virus type 1
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabe ...
(HIV-1) and
hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepato ...
.
Current scope
The first mathematical formulation of quasispecies was deterministic; it assumed steady state mutant distributions in
genetic equilibrium without perturbations derived from modifications of the environment or
population size
In population genetics and population ecology, population size (usually denoted ''N'') is the number of individual organisms in a population. Population size is directly associated with amount of genetic drift, and is the underlying cause of effect ...
.
These conditions are common in initial theoretical formulations of complex phenomena because they confer mathematical tractability. Since then, several extensions of the theory to non-equilibrium conditions with stochastic components have been developed, with the aim of finding general solutions for multi-peak
fitness landscape
Fitness may refer to:
* Physical fitness, a state of health and well-being of the body
* Fitness (biology), an individual's ability to propagate its genes
* Fitness (cereal), a brand of breakfast cereals and granola bars
* ''Fitness'' (magazine), ...
s. These objectives approximate quasispecies to the real case of RNA viruses, which are compelled to deal with dramatic variations in population size and environment. Research on quasispecies has proceeded through several theoretical and experimental avenues that include continuing studies on evolutionary optimization and the origin of life,
RNA-RNA interactions and replicator networks, the error threshold in variable fitness landscapes, consideration of chemical mutagenesis and proofreading mechanisms,
evolution of tumor cells, bacterial populations or
stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s,
chromosomal instability
Chromosomal instability (CIN) is a type of genome instability, genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increas ...
, drug resistance, and
conformation distributions in
prions
Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...
(a class of proteins with conformation-dependent pathogenic potential; in this case the quasispecies is defined by a distribution of conformations).
New inputs into experimental quasispecies research have come from deep sequencing to probe viral and cellular populations, recognition of interactions within mutant spectra, models of viral
population dynamics
Population dynamics is the type of mathematics used to model and study the size and age composition of populations as dynamical systems.
History
Population dynamics has traditionally been the dominant branch of mathematical biology, which has ...
related to disease progression and pathogen transmission, and new teachings from fidelity variants of viruses.
Here we summarize the main aspects of quasispecies dynamics, and recent developments relevant to virus evolution and pathogenesis.
Dynamic heterogeneity
The molecular basis of high error rates is the limited template-copying fidelity of
RNA-dependent RNA polymerase
RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes synthesis of the RNA strand complementary to a given RNA template. This is in contrast to t ...
s (RdRps) and
RNA-dependent DNA polymerases (also termed reverse transcriptases, RTs). In addition, these enzymes are defective in
proofreading
Proofreading is the reading of a galley proof or an electronic copy of a publication to find and correct reproduction errors of text or art. Proofreading is the final step in the editorial cycle before publication.
Professional
Traditional ...
because they lack a 3’ to 5’
exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end (exo) of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3′ or the 5′ end occurs. Its close relative is the ...
domain present in replicative cellular DNA polymerases.
Also, postreplicative-repair pathways, abundant to correct genetic lesions in replicating cellular DNA, appear as ineffective for double-stranded RNA or RNA-DNA hybrids. The presence of a proofreading-repair activity in
coronavirus
Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the com ...
es increases their copying accuracy in about 15-fold. This and other repair activities, that may act on standard RNA or
retroviral
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...
genomes, do not prevent the formation of mutant spectra, although their amplitude may be lower than for other RNA viruses, at least in populations close to a clonal (single genome) origin. Quasispecies dynamics will operate in any viral or cellular system in which due to high mutation rates (as a result of low fidelity nucleic acid polymerases or environmental alterations) mutant spectra are rapidly generated.
Studies with different
virus-host systems have established some general observations on the mechanisms of mutant generation, and implications of quasispecies dynamics.
In RNA virus genetics when we speak of "a mutant" the entity we handle is a cloud of mutants in which the specific mutation to which we direct our attention is present in all (or the great majority of) individual genomes. There is no such a thing as "a" wild type or "a" mutant virus. They are always clouds of mutants. Changes in the relative dominance of components of mutant spectra are particularly severe during ''in vivo''
infections
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmiss ...
, with complex dynamics of intra-host heterogeneity and variations.
Bioinformatic
Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combine ...
procedures have been developed to unveil the relationships among different but closely related genome types that may suggest some hierarchical order of mutation acquisition or identification of transmission clusters (examples are Partition Analysis of Quasispecies, PAQ or QUasispecies Evolution, Network-based Transmission Inference, QUENTIN).
Phenotypic reservoirs
![Viral quasispecies Figure 3](https://upload.wikimedia.org/wikipedia/commons/1/14/Viral_quasispecies_Figure_3.png)
The crux of the matter regarding quasispecies implications is that at any given time, the viral population includes a reservoir not only of
genotypic
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
but also of
phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
variants, conferring upon the population some adaptive
pluripotency Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta.
According to Latin terms, Pluripotentia means the ability for many thin ...
. Accumulating laboratory and clinical evidence renders untenable that minority components of mutant spectra should be dismissed on the grounds of their being
neutral
Neutral or neutrality may refer to:
Mathematics and natural science Biology
* Neutral organisms, in ecology, those that obey the unified neutral theory of biodiversity
Chemistry and physics
* Neutralization (chemistry), a chemical reaction in ...
. They can participate in selective processes and cannot be excluded from interpretations of virus behavior. Variation universally involves
point mutation
A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
s and it can also include
recombination (in its replicative and non-replicative modes), and
genome segment reassortment.
All modes of molecular variation are compatible, only restricted by the scope of mechanisms accessible to the replicative machinery, and for the need for viral genomes to remain functional. David Evans and colleagues identified many recombination events associated with
enterovirus
''Enterovirus'' is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine ('enteric' meaning intestinal).
Serologic ...
replication, and only a few recombinants made their way towards continued replication.
Recombination can mediate adaptability and
virulence
Virulence is a pathogen's or microorganism's ability to cause damage to a host.
In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ca ...
.
High mutation and recombination rates have led to the conceptual distinction between mechanistically unavoidable and evolutionarily relevant variation, in connection with the issue of clonal versus non-clonal nature of
virus evolution (microbial evolution in general).
Only a minority of the nascent variation during replication can be successfully propagated. Within limits that are set by
biological constraints, each population is made of an array of variant genomes, with a total number which is commensurate with the virus population size. To infect a plant, animal or cell culture with 10
3 infectious units can have very different consequences than to infect with 10
10 infectious units, not only because the
host defense
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
systems may be overwhelmed by the high infectious dose, but also because the mutant repertoire that engages in adaptive explorations is larger. Part of the variants of a mutant spectrum, either in isolation or in consortium with others,
may perform better than other members of the same population in the event of an environmental change. Selective pressures favor replication of some components of a mutant spectrum over others, despite all of them being interconnected by mutation. Differential performance can be at the level of viral genomes (during replication, intracellular
gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
, interaction with host factors, etc.) or viral particles (for thermal stability,
entry into or
exit from cells, to withstand neutralizing antibodies, etc.).
Adaptability of RNA viruses is linked to parameters that facilitate exploration of sequence space: genome size (1.8 to 33 Kb), population size (variable but that can attain an impressive 10
12 individual genomes in an infected host at a given time), replication rate, mutation rate, fecundity (yield of viral particles per cell), and number of mutations required for a phenotypic change (surprisingly low for several relevant traits
).
Mutant spectrum dynamics has been depicted in different ways, and we have chosen one that encompasses frequent events in natural populations and research designs, such as
virus isolation
Viral culture is a laboratory technique in which samples of a virus are placed to different cell lines which the virus being tested for its ability to infect. If the cells show changes, known as cytopathic effects, then the culture is positive.
...
from an infected host, adaptation to cell culture for studies on experimental evolution, or adaptation to alternative hosts in vivo. The reality is even more complex, given the large population sizes, with an indeterminate proportion of genomes actively replicating at any given time (sometimes equated with the effective population size in general genetics), and harboring multiple mutations per genome. The scenarios suggested by current experimental data defy our imagination. The relative frequency of individual mutations fluctuates in an unceasing exploration of sequence space,
with phenotypic changes (not only genotypic changes) being far more frequent than previously thought. The
experimental evolution
Experimental evolution is the use of laboratory experiments or controlled field manipulations to explore evolutionary dynamics. Evolution may be observed in the laboratory as individuals/populations adapt to new environmental conditions by natura ...
design that consists of passaging viral populations for long time periods (many sequential infections) is often extremely revealing. In
foot-and-mouth disease virus
''Foot-and-mouth disease virus'' (FMDV) is the pathogen that causes foot-and-mouth disease. It is a picornavirus, the prototypical member of the genus ''Aphthovirus''. The disease, which causes vesicles (blisters) in the mouth and feet of cattl ...
(FMDV) such a design led to a remarkable phenotypic diversification into subpopulations of colonizers and competitors, that modulated virulence of the mutant ensemble.
In HCV such a design unveiled continuous mutation waves and a more accurate understanding of the types of fitness landscapes occupied by high fitness viruses.
Limitations and indeterminacies
The nucleotide sequence of an individual genome from a population (no matter which the degree of population complexity might be), can be determined either following a biological or molecular cloning event or by deep sequencing of entire viral genomes, in a manner that mutation linkage (assignment of different mutations to the same genome molecule) can be established. Each of these procedures implies some limitations: biological cloning can bias the representation in favor of infectious genomes, while molecular cloning can introduce non-infectious (defective) genomes in the analysis.
Whole genome quasispecies description is still technically challenging due to the artifactual introduction of mutations. Most current deep sequencing platforms yield sequences of short reads for a given amplicon (sequence under analysis); minority mutations in an amplicon cannot be reliably linked to mutations in a different amplicon of the same genome; at most, statistical inferences on linkage can be proposed. Despite these limitations, control experiments and improvements of bioinformatic procedures support that the majority of sequence heterogeneity analyzed in viral populations indeed reflects differences in the natural template populations. If mutation linkage can be solved on a routine basis, a new wave of molecular information relevant to epistatic interactions will enter the picture.
There are additional levels of indeterminacy in the sequential analysis of viral populations, in particular those replicating in vivo. Components of the mutant spectrum represented at a given time in the sample taken for sequencing may differ from those in the next time point, due either to sampling uncertainties or bona fide fluctuations of genome frequencies. It is not justified to accept a rough similarity because even a single mutation in a given sequence context may affect biological properties.
In the words of John Holland and colleagues: "It is important to remember that every quasispecies genome swarm in an infected individual is unique and "new" in the sense that no identical population of genomes has ever existed before and none such will ever exist again".
On top of the fleeting nature of any mutant distribution, the standard methods available for quasispecies characterization provide genomic sequences of a minority of the population (estimated in 10
−8 to 10
−13 for molecular cloning-Sanger sequencing, and in 10
−6 to 10
−11 for deep sequencing).
We can only have an approximate representation of viral populations and their dynamics, as evidenced by many experimental studies.
Non-consensus-based descriptors
The points summarized in previous sections fully justifies addressing analytical tools towards the mutant spectrum rather than ignoring it or considering its presence a side issue. Use of consensus sequences to describe the genome of a virus isolate, despite being warranted by the difficulties of conveying the information recapitulated in a mutant spectrum, blurs and enfeebles biological interpretations. Experimental results have demonstrated that minority genomes from a mutant spectrum (that cannot be identified by examining the consensus sequence) can include mutations that confer resistance to
antiviral inhibitors,
neutralizing antibodies
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic.
Neutralizing antibod ...
or
cytotoxic T cells
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...
, or that can alter the capacity to induce
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...
(IFN) or to respond to IFN, virulence or particle stability, among other phenotypic traits.
Mutant spectra can also mediate cyclical adaptation to different cell types.
A mutant spectrum defines a consensus but the consensus is an abstraction; it may not be represented in the population. Many events in viral pathogenesis and evolution are due to mutant spectrum modifications or interactions which cannot be properly interpreted solely on the basis of consensus sequences.
Collective response
Mutant spectra are not mere aggregates of mutants acting independently. They are often engaged in collective responses.
Two major types are those that depend on the presence of sets of variants, and those that rely on intra-mutant spectrum interactions.
Variants that drive responses to selective constraints
Behavior of reconstructed quasispecies
In some cases of
sweeping selection (very strong selection for a trait), an individual (or a limited number of individuals) that encodes signatures prone to be selected, may approach dominance while becoming the founder of a mutant cloud (because formation of a cloud is inherent to replication). Conditions for dominance (in this case in response to selection) are that the genome senses the selective sweep and that its replication in the new selective environment is permitted. In other cases, a collection of mutants is selected. This was illustrated with a FMDV quasispecies that was reconstructed in the laboratory with multiple antigenic variants (each at low frequency) that belonged to two different categories, and shared resistance to the same
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
.
One category included mutants with an amino acid substitution that affected
receptor recognition (since the antigenic determinant overlapped with the
integrin receptor
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
recognition site); in the other category, the substitutions affected the antigenic determinant but not the receptor recognition site. Passages of the virus in absence of the monoclonal antibody resulted in dominance of antigenic variants that maintained the receptor recognition capacity, but the dominant variants were surrounded by a cloud of mutants of the other antigenic variant category. Conversely, passages in the presence of the antibody led to selection of variants with altered receptor recognition, surrounded by a cloud of antigenic variants that maintained receptor recognition. The results underlined the role of mutant clouds in selective events, and unveiled a new mechanism of antigenic flexibility.
Quasispecies memory
Quasispecies memory is a type of molecular memory dependent on the recent history of the evolutionary lineage and the integrity of the mutant spectrum.
The search for memory was prompted by the complex adaptive system behavior of a viral quasispecies, suggested by the presence of core information (considered the one that defines viral identity) despite variation of constitutive elements (the mutant spectrum). A well-known example is
memory in the immune system that mobilizes and expands minority components in response to stimuli previously faced by the system.
In the experiments designed to identify memory in viral quasispecies, members of the mutant spectrum increased in frequency as a consequence of their replication during a selection event that drove them towards dominance. When the selective constraint was withdrawn, memory genomes remained at levels that were 10- to 100-fold higher than the basal levels attributable solely to their generation by mutation, as documented with independent FMDV genetic markers, and with HIV-1 ''in vivo''.
Thus, memory is a history-dependent, collective property of the quasispecies that confers a selective advantage to respond to environmental changes previously experienced by the same evolutionary lineage. It can be manifested only if the mutant spectrum maintains its completeness, since memory is lost when the population undergoes a
bottleneck
Bottleneck literally refers to the narrowed portion (neck) of a bottle near its opening, which limit the rate of outflow, and may describe any object of a similar shape. The literal neck of a bottle was originally used to play what is now known as ...
event that excludes minorities. A relevant example of the consequences of memory occurs in antiviral pharmacology with the administration for a second time of the same or a related antiviral agent (capable of evoking shared resistance mutations) used in a previous treatment. The second intervention may face inhibitor-resistant memory genomes from the earlier treatment, thus contributing to virus escape.
This is an aspect that has not received adequate attention in the planning of antiviral interventions for patients who fail a first treatment and have to be subjected to a second treatment.
Intra-mutant spectrum interactions for interference, complementation or cooperation
Individual genomes surrounded by a cloud of related mutants can be either suppressed to be kept at low frequency, or helped to be maintained in the population. The two alternative fates are dependent on several factors, one being the surrounding mutant spectrum in those steps of the infectious cycle in which an effective competition among variants is established, for example within replication complexes. This important concept was first derived theoretically,
and then approached experimentally with several viruses. In an early study, Juan Carlos de la Torre and John Holland described suppression of high fitness VSV by mutant spectra of inferior fitness.
Suppressive effects have since been documented with standard and mutagenized viral populations. Some examples are:
* Suppression of high fitness antigenic variants of FMDV by low fitness antibody-escape mutants.
* Suppression of virulent
poliovirus
A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species ''Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3.
Poliovirus is composed of an ...
(PV) by attenuated virus in
poliovirus vaccines.
* Suppression of pathogenic
lymphocytic choriomengitis virus (LCMV) (that cause growth hormone deficiency in mice) by non-pathogenic LCMV variants.
* Suppression of FMDV by a mutagenized FMDV population.
* Suppression of FMDV by capsid and polymerase FMDV mutants.
* Suppression of drug-resistant viral mutants during antiviral therapy.
Opposite to suppression is maintenance of a mutant either by a favorable position in a fitness landscape or by interactions of
complementation or
cooperation
Cooperation (written as co-operation in British English) is the process of groups of organisms working or acting together for common, mutual, or some underlying benefit, as opposed to working in competition for selfish benefit. Many animal a ...
with members of the mutant spectrum. The position in a fitness landscape influences vulnerability to mutations, as popularized with the terms "advantage of the flattest" or "survival of the flattest", indicating that a variant located at the top of a sharp fitness peak has higher probability to decrease fitness as a result of new mutations than the same variant located at a
fitness plateau.
Survival of the flattest has been also proposed as an ingredient in some models of the error threshold.
Collective behavior of viruses was documented with mutant RNA viruses resistant to nucleotide analogues. The study of this class of mutants has been instrumental for the understanding of the molecular basis of template copying fidelity, and the consequences of fidelity alterations in the adaptive capacity and pathogenic potential of RNA viruses.
In the first mutant studied, amino acid substitution G46S in the PV polymerase resulted in about four-fold increase in template-copying fidelity. This modification reduced PV adaptability and infective potential in vivo.
The mutant in isolation did not replicate efficiently in the brain of susceptible mice, but it did when its mutant spectrum was broadened by
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...
mutagenesis or when it was co-inoculated with wild type PV.
Complementation (often occurring when a functional protein encoded by a set of genomes is used by another set of genomes whose encoded protein is not functional) may underlie some collective responses of quasispecies such as fitness of individuals isolated from a population being inferior to fitness of the population.
Complementation was described between two truncated FMDV genomic forms.
The genomes with internal deletions became detectable upon high multiplicity passage of a clonal population of standard FMDV, a virus with a monopartite single stranded RNA genome. Infectivity was generated by complementation of the two truncated forms, in absence of standard, full length FMDV genomes. For complementation to be effective, prior exploration of sequence space through point mutations was a requirement.
The system underwent a remarkable evolutionary transition akin to genome segmentation. Drastic genetic lesions in viral genomes are difficult to observe unless a mechanism such as complementation comes into the rescue of the deviant genomes. Additional examples of complementation among RNA viruses have been reported.
Complementation is a means to maintain defective genomes at detectable frequencies in viral populations.
A distinction has been made between complementation and cooperation, in which two different genomes give rise to a new phenotype through the interaction between two variant proteins.
An example of cooperation was characterized during studies with measles virus on membrane fusion which is essential for virus entry into cells. For this virus fusion is mediated by two proteins termed H and F. A truncated H was deficient in cell fusion but the activity was regained when the truncated H was accompanied by two forms of F but not one of the forms individually.
Therefore, complementation, cooperation,
interference
Interference is the act of interfering, invading, or poaching. Interference may also refer to:
Communications
* Interference (communication), anything which alters, modifies, or disrupts a message
* Adjacent-channel interference, caused by extr ...
and suppression can emerge from interactions among components of mutant spectra that have their origin in random mutations. Selection acts on whatever sets of mutants can provide a useful trait, to turn random occurrences into biological meaning.
Bottlenecks
![Viral quasispecies Figure 4](https://upload.wikimedia.org/wikipedia/commons/7/75/Viral_quasispecies_Figure_4.png)
A means to interrupt the participation of individual genomes in interactions with their mutant spectrum is for the quasispecies swarm to undergo drastic reductions in population size that isolate one or few individual genomes from their surroundings. Such reductions are termed bottlenecks, and they have an important participation in shaping evolutionary lineages for all kinds of organisms, and also for viruses. They occur frequently not only upon host-to host transmission but also inside infected hosts,
and they can perturb positive and negative selection events in processes that are difficult to identify and characterize.
Drastic bottleneck events have been reproduced with laboratory populations of viruses in the form of plaque-to-plaque transfers.
This design served to verify experimentally the operation of
Müller’s ratchet
In evolutionary genetics, Muller's ratchet (named after Hermann Joseph Muller, by analogy with a ratchet effect) is a process through which, in the absence of recombination (especially in an asexual population), an accumulation of irreversible ...
, or fitness decrease by the irreversible incorporation of mutations in asexual organisms in absence of compensatory mechanisms.
The serial bottleneck transfers unveiled the presence rare mutations, not seen in standard laboratory or natural viral populations. In absence of forced bottleneck events, such rare mutations would be lost by negative selection because of their fitness cost.
The investigation of how FMDV clones debilitated by Müller’s ratchet regained replicative fitness revealed several alternative molecular pathways for fitness recovery.
The implications of this observation went largely unnoticed until recent results with
hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepato ...
(HCV) have also suggested the accessibility of multiple pathways for fitness gain.
Also, extensive passage of a biological clone of FMDV in
BHK-21 cells conferred the capacity to infect several human cell lines in addition to the expected fitness increase for multiplication in BHK-21 cells.
Thus, several lines of evidence suggest that fitness gain in a specific environment may paradoxically broaden the phenotypic potential of a virus. It will be interesting to investigate whether focused adaptation of other viruses to a specific environment may also entail a broadening of diversity, with many phenotypic variants attaining similar fitness levels. If generalized, this broadening of phenotypic space would provide a new interpretation of the molecular basis of adaptation, and explain why adaptation to alternative environments may not lead to
attenuation
In physics, attenuation (in some contexts, extinction) is the gradual loss of flux intensity through a medium. For instance, dark glasses attenuate sunlight, lead attenuates X-rays, and water and air attenuate both light and sound at variable att ...
.
Deprivation of an individual virus from possible suppression, complementation or cooperation, may represent a liberation to initiate a new evolutionary process, or a condemnation to extinction. If liberated from suppression, the isolated genome must replicate and be able to reconstruct a mutant cloud to regain adaptive capability. This has led to the suggestion that high mutation rates evolved to allow such mutant spectrum recovery following bottlenecks. Other models attribute high mutation rates to adaptive optimization independent of bottlenecks, or to a mechanistic consequence of rapid replication.
Whatever their ultimate origins, high mutation rates serve the purpose of adaptation in multiple circumstances, not only following bottlenecks. A founder virus can introduce a different phenotype for the ensuing evolution. Evolution of viruses in nature and as disease agents can be viewed as succession of mutant spectrum alterations, subjected to expansions and reductions of population size in a continuous interplay of positive and negative selection and random drift. While short-term (for example, intra-host) evolution is observable and measurable, viruses may appear to be relatively static in the long term for decades (as seen with antigenic variants of FMDV
) or longer. Intra-host evolution is generally more rapid than inter-host evolution, as documented with viruses
and other biological systems.
Apparent invariance may be the result of selection for long-term survival of populations that have previously frenziedly tested evolutionary outcomes in short-term processes.
Viral disease
Soon after quasispecies was evidenced for viruses, some medical implications were made explicit.
Several specific and general points below.
* High mutation rates and population heterogeneity endow viruses with the potential to escape immune pressures (including those due to
vaccination
Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
) and antiviral inhibitors used in therapy. It is an open question if vaccination can promote long-term evolution of antigenic determinants.
* Attenuated RNA virus vaccines can revert to virulent forms. RNA viruses released in nature for
pest control
Pest control is the regulation or management of a species defined as a pest; any animal, plant or fungus that impacts adversely on human activities or environment. The human response depends on the importance of the damage done and will range ...
purposes can mutate to new phenotypes.
* Virus attenuation and virulence is dependent on viral genetic traits. Variant forms of a given virus may display increased virulence or atypical disease.
* Components of a mutant spectrum can exhibit a different
cell tropism
Endothelial cell tropism or endotheliotropism is a type of tissue tropism or host tropism that characterizes an pathogen's ability to recognize and infect an endothelial cell. Pathogens, such as viruses, can target a specific tissue type or multipl ...
or
host range
In biology and medicine, a host is a larger organism that harbours a smaller organism; whether a parasitic, a mutualistic, or a commensalist ''guest'' (symbiont). The guest is typically provided with nourishment and shelter. Examples include a ...
than most genomes in the same population, with implications for the emergence and re-emergence of viral disease.
* Viral pathogenesis is influenced by
microevolution
Microevolution is the change in allele frequencies that occurs over time within a population. This change is due to four different processes: mutation, selection (natural and artificial), gene flow and genetic drift. This change happens over a r ...
ary processes in which some viral subpopulations are replaced by others to persist or to invade new cell types, tissues or organs.
* The larger the actively replicating (effective) population size and the replication rate, the most effective is exploration of sequence space for phenotypic expansions that favor survival and persistence.
* There is a connection between four parameters that characterize viruses during infection processes: replication rate (the rate at which viral RNA or DNA is synthesized intracellularly for viral progeny production), viral load (the total amount of virus quantified in an infected host or host compartment), genetic heterogeneity, and replicative fitness (the yield of infectious particles that can contribute to the next generation). They can influence disease progression, and any of them can be targeted for disease control.
In all interactions conductive to disease, the host cells individually and as groups in tissues and organs play decisive roles. The consequences of a viral infection are always host-dependent. However, the virus itself poses a major challenge that a deeper understanding of quasispecies dynamics is helping to confront.
Antiviral strategies
There is an increasing perception that Darwinian principles should
assist in the planning of antiviral designs.
The aim of vaccination is to evoke a protective response that either prevents virus replication or disease. The aim of an antiviral pharmacological intervention is to inhibit virus replication to provide the immune system with an opportunity to clear the virus. Expressed simply, the direct danger for vaccination and treatment is that the virus can escape through selection of mutants resistant to vaccine-triggered defense components or to the externally administered inhibitors. This has led to several proposals to confront viral disease, that can be summarized below.
Vaccine exposure of multiple B cell and T cell epitopes
Vaccines should include repertoires of
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
and
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
epitopes to evoke an ample
immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
. The broad response should minimize selection of escape mutants that may be present as minority components in mutant spectra, as repeatedly documented experimentally.
With the current types of available vaccines, those that best comply with the multiple
epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
requirement are, in the order of expected efficacy to confer protection against highly variable viruses:
attenuated >
inactivated whole virus > several expressed proteins >
one expressed protein >
multiple synthetic peptide antigens > single peptide antigen. The scarcity of effective synthetic vaccines for RNA viral pathogens despite huge scientific and economic efforts is a reflection of the underlying problems.
Antiviral agents used in combination
Antiviral
monotherapy
Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
(use of a single antiviral agent) is to be avoided. The following recommendations have been made and in some cases successfully implemented:
* Inhibitors used in combination should target different viral gene products.
* Splitting a treatment into two steps: first an induction regimen, and a second maintenance regimen. Drugs administered in the two steps should be different.
* Targeting of cellular functions needed for the virus life cycle.
* Use of innate immune response-stimulating drugs (for example, inhibitors of enzymes involved in pyrimidine biosynthesis).
* Combined use of
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
and
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
.
* Lethal mutagenesis or virus extinction by excess of mutations introduced during viral replication.
These strategies have as their main objective to avoid selection of treatment-escape mutants by multiple selective constraints that cannot be surmounted by the virus.
Control is effective either because exploration of sequence space cannot reach the required multiple mutations (even when recombination is available) or because the multiple mutations inflict a severe fitness cost.
Vaccines exposing multiple epitopes and combination therapies follow the same strategy whose aim is to limit possible escape routes to viral quasispecies in the face of the suppressive constraint.
Lethal mutagenesis
Lethal mutagenesis
Error catastrophe refers to the cumulative loss of genetic information in a lineage of organisms due to high mutation rates. The mutation rate above which error catastrophe occurs is called the error threshold. Both terms were coined by Manfred ...
is the process of virus extinction at the error rate at which a virus can no longer maintain its genetic information.
Application of lethal mutagenesis as an antiviral strategy deserves attention in the context of the present article because its origins lie in quasispecies theory, in the form of the error threshold relationship. Both the error threshold and lethal mutagenesis are highly fitness landscape-dependent, but both can occur in complex fitness landscapes as those pertinent to viral populations.
The term lethal mutagenesis was coined by Lawerence Loeb and colleagues,
and it is now widely used to describe the antiviral activity of base and nucleoside analogues that increase the viral mutation rate. Although several models have been proposed to account for virus extinction by excess mutations,
an extension of the violation of the error threshold stands as a likely mechanism.
Interestingly, some antiviral agents licensed for human use, initially thought to act only as inhibitors of viral replication, may actually exert their antviral activity against some RNA viruses at least partially by lethal mutagenesis. This is the case of
favipiravir (T-705; 6-fluoro-3-hydroxy-2-pirazinecarboxamide) and
ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
(1-β-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) that are currently being intensively investigated as lethal mutagens.
Defense mechanisms based on genome modification of invading genetic parasites such as editing cellular activities that are recruited as part of the innate immune response (
ADAR
Adar ( he, אֲדָר ; from Akkadian ''adaru'') is the sixth month of the civil year and the twelfth month of the religious year on the Hebrew calendar, roughly corresponding to the month of March in the Gregorian calendar. It is a month of 29 d ...
,
APOBEC
image:Apobec.J.Steinfeld.D.png, 300px, upExample of a member of the APOBEC family, APOBEC-2. A cytidine deaminase from ''Homo sapiens''.; ; rendered usinPyMOL
APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide") is a family o ...
,
RIP
Rest in peace (RIP), a phrase from the Latin (), is sometimes used in traditional Christian services and prayers, such as in the Catholic, Lutheran, Anglican, and Methodist denominations, to wish the soul of a decedent eternal rest and peace.
...
, etc.)
represent a natural counterpart of the principle utilized by lethal mutagenesis. Applicability to pathogenic cellular elements is a real possibility, and lethal mutagenesis to control tumor cells is an active field of investigation.
Thus, the recognition of quasispecies dynamics has suggested some fundamental guidelines for disease prevention and control that are gradually permeating clinical practice. This is in line with the recognized need to apply Darwinian principles to the control of infectious disease.
Error threshold
This may be defined as "The inability of a genetic element to be maintained in a population as the fidelity of its replication machinery decreases beyond a certain threshold value".
In theory, if the mutation rate was sufficiently high, the viral population would not be able to maintain the genotype with the highest fitness, and therefore the ability of the population to adapt to its environment would be compromised. A practical application of this dynamic is in antiviral drugs employing lethal mutagenesis. For example, increased doses of the mutagen
ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pegin ...
reduces the infectivity of poliovirus.
However, these models assume that only the mutations that occur in the fittest sequence are deleterious, and furthermore that they are non-lethal. It has been argued that, if we take into account the deleterious effect of mutations on the population of variants and the fact that many mutations are lethal, then the error threshold disappears, i.e. the fittest sequence always maintains itself.
Empirical data on the effect of mutations in viruses is rare, but appears to correspond with this scenario.
Possible evolutionary consequences
Mutational robustness
The long-term evolution of the virus may be influenced in that it may be a better evolutionarily stable strategy
An evolutionarily stable strategy (ESS) is a strategy (or set of strategies) that is ''impermeable'' when adopted by a population in adaptation to a specific environment, that is to say it cannot be displaced by an alternative strategy (or set of ...
to generate a broad quasispecies with members of approximately equal fitness than to have a sharply defined 'most fit' single genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
(with mutational neighbours substantially less fit). This has been called 'survival of the flattest' - referring to the fitness profiles of the two strategies respectively.
Over the long-term, a flatter fitness profile might better allow a quasispecies to exploit changes in selection pressure
Any cause that reduces or increases reproductive success in a portion of a population potentially exerts evolutionary pressure, selective pressure or selection pressure, driving natural selection. It is a quantitative description of the amount of ...
, analogous to the way sexual organisms use recombination to preserve diversity in a population. At least in simulations, a slower replicator can be shown to be able to outcompete a faster one in cases where it is more robust and the mutation rate is high.
However, whether mutational robustness
In evolutionary biology, robustness of a biological system (also called biological or genetic robustness) is the persistence of a certain characteristic or trait in a system under perturbations or conditions of uncertainty. Robustness in developm ...
evolved or is intrinsic to genetic systems is unconfirmed, because the basic mechanism behind robustness would depend upon the peculiarities of each system.
Cooperation
Experimental manipulation of poliovirus
A poliovirus, the causative agent of polio (also known as poliomyelitis), is a serotype of the species ''Enterovirus C'', in the family of ''Picornaviridae''. There are three poliovirus serotypes: types 1, 2, and 3.
Poliovirus is composed of an ...
to give them a higher-fidelity polymerase
A polymerase is an enzyme ( EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base- ...
– and hence reduce their mutation rate – showed these variants to have lower pathogenicity
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ge ...
than wild-type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
sequences. Pathogenicity could then be restored by mutagen application. This was interpreted to mean lower mutation rates had reduced the adaptability (or breadth) of the quasispecies. The mutant viruses extracted from brain tissue were not themselves pathogenic, and the authors speculate that there may be complementation between variant members of the quasispecies that could enable viruses to colonize different host tissues and systems.
References
{{Reflist
External links
Video: Using fitness landscapes to visualize evolution in action
contains an example of "survival of the flattest"
Microbial population biology
Virology
Infraspecific virus taxa