Genetic change and Selection

Populations of organisms change over generations in evolution. Evolution is a process

that results in changes in the genetic material of a population over time. Genetic variations
underlie these changes. Genetic variations can arise from gene variants (mutations) or from a
normal process in which genetic material is rearranged as a cell is getting ready to divide
(genetic recombination). Genetic variations that alter gene activity or protein function can
introduce different traits in an organism.

If a trait is advantageous and helps the individual survive and reproduce, the genetic
variation is more likely to be passed to the next generation (natural selection). Over time, as
generations of individuals with the trait continue to reproduce, the advantageous trait becomes
increasingly common in a population, making the population different than an ancestral one.
Sometimes the population becomes so different that it is considered a new species.

Evolution is not influenced by all variants. Only hereditary variants, which occur in egg
or sperm cells, can be passed to future generations and potentially contribute to evolution. Some
variants occur during a person’s lifetime in only some of the body’s cells and are not hereditary,
hence natural selection cannot play a role. Many genetic changes have also no impact on the
function of a gene or protein and are not helpful or harmful.

In addition, the environment in which a population of organisms lives is integral to the

selection of traits. Some differences introduced by variants may help an organism survive in one
setting but not in another. For example, resistance to a certain bacteria is only advantageous if
that bacteria is found in a particular location and harms those who live there.Some harmful traits,
like genetic diseases, persist in populations instead of being removed by natural selection. There
are several possible explanations, but in many cases, the answer is not clear. For some
conditions, such as the neurological condition Huntington disease, signs and symptoms occur
later in life, typically after a person has children, so the gene variant can be passed on despite
being harmful.

For other harmful traits, a phenomenon called reduced penetrance, in which some
individuals with a disease-associated variant do not show signs and symptoms of the condition,
can also allow harmful genetic variations to be passed to future generations. For some
conditions, having one altered copy of a gene in each cell is advantageous, while having two
altered copies causes disease. The best-studied example of this phenomenon is sickle cell
disease: Having two altered copies of the HBB gene in each cell results in the disease, but having
only one copy provides some resistance to malaria. This disease resistance helps explain why the
variants that cause sickle cell disease are still found in many populations, especially in areas
where malaria is prevalent.

Biomolecular basis of viral variation

Genetic variation is an essential feature of all living organisms. It provides the resource
for natural selection and for the progressive adaptation of the population to a changing
environment. Viruses face continuous environmental change as they pass from host to host. The
most obvious and significant of these is the defensive or immunological response. Evasion of the
host defences is a central feature of the survival strategy of all viruses. However, allelic
variations in host genes or differences in their pattern of expression also present a changing
environmental landscape that can determine susceptibility to infection or efficiency of
replication.

Viral variation can be generated by a number of mechanisms. Major rearrangements in

genome structure and organisation can occur by genetic recombination. Gene duplications, gene
exchanges and gene adoptions also occur. However, the most common form of variation is
mutation by nucleotide substitution. This occurs as a consequence of polymerase error in reading
the template during replication. As viruses replicate rapidly and prodigiously, viral variation has
significant implications for diagnosis and epidemiology.

Genetic variation in RNA and DNA viruses

From a genetic perspective, viruses can be classified according to whether the genome
comprises RNA or DNA. RNA viruses are inherently hypervariable as RNA polymerases, which
replicate the viral genome, lack proof reading and error editing functions that occur in cellular
DNA polymerases. The resulting rate of nucleotide misincorporation in RNA viruses (10-3-10-4)
is at least 1000 times that of bacteria or eukaryotes, causing one or more base substitutions each
time the viral genome replicates.
Some mutations are lethal as they truncate or distort the resulting protein, rendering it non-
functional. However, many mutations result in viable genomes that continue to replicate and
contribute to the virus population. In this way, RNA viruses continually refine their genetic
structure to accommodate the changing environment. Some RNA viruses may also undergo
genetic rearrangements that allow exchange of corresponding genes or gene segments during
mixed infections. These recombination and reassortment events allow the most efficient and
environmentally adapted combinations of genes to emerge from the available genetic pool,
increasing the potential for viral survival.

Viruses are continuously changing as a result of genetic selection. They undergo subtle
genetic changes through mutation and major genetic changes through recombination. Mutation
occurs when an error is incorporated in the viral genome. Recombination occurs when
coinfecting viruses exchange genetic information, creating a novel virus.

Mutations

Mutations arise by the effects of physical mutagens (UV light, x-rays) on nucleic acids,
the natural behavior of the bases that make up nucleic acids (resonance from keto to enol and
from amino to imino forms), and through the fallibility of the enzymes that replicate the nucleic
acids. The first two mechanisms act similarly in all viruses; hence, the effects of physical
mutagens and the natural behavior of nucleotides are relatively constant. However, viruses differ
markedly in their mutation rates, which is due primarily to differences in the fidelity with which
their enzymes replicate their nucleic acids. Viruses with high-fidelity transcriptases have
relatively low mutation rates and vice versa.

Mutation Rates and Outcomes

DNA viruses have mutation rates similar to those of eukaryotic cells because, like
eukaryotic DNA polymerases, their replicatory enzymes have proofreading functions. The error
rate for DNA viruses has been calculated to be 10-8 to 10-11 errors per incorporated nucleotide.
With this low mutation rate, replication of even the most complex DNA viruses, which have 2 ×
105 to 3 × 105 nucleotide pairs per genome, will generate mutants rather rarely, perhaps once in
several hundred to many thousand genome copies. The RNA viruses, however, lack a
proofreading function in their replicatory enzymes, and some have mutation rates that are many
orders of magnitude higher—10-3 to 10-4 errors per incorporated nucleotide. Even the simplest
RNA viruses, which have about 7,400 nucleotides per genome, will generate mutants frequently,
perhaps as often as once per genome copy.

Not all mutations that occur persist in the virus population. Mutations that interfere with
the essential functions of attachment, penetration, uncoating, replication, assembly, and release
do not permit misreplication and are rapidly lost from the population. However, because of the
redundancy of the genetic code, many mutations are neutral, resulting either in no change in the
viral protein or in replacement of an amino acid by a functionally similar amino acid. Only
mutations that do not cripple essential viral functions can persist or become fixed in a virus
population.

Phenotypic Variation by Mutations

Mutations that alter the viral phenotype but are not deleterious may be important. For
example, mutation can create novel antigenic determinants. A mutation in the hemagglutinin
gene of influenza A virus can give rise to a hemagglutinin molecule with an altered antigenic site
(epitope). Provided the attachment function of the new hemagglutinin is intact, the mutant virus
may be able to initiate an infection in an individual immune to viruses expressing the previous
hemagglutinin. For example, from 1968 to 1979, mutations altered 10 percent of the amino acids
in the influenza virus hemagglutinin serotype H3 molecule. This relatively modest mechanism of
antigenic change through mutation, called antigenic drift, may allow a virus to outflank host
defenses and cause disease in previously immune individuals.

Vaccine Strains from Mutations

Mutation has been a principal tool of virologists in developing attenuated live virus
vaccines. For example, the Sabin vaccine strains of poliovirus were developed by growing
polioviruses in monkey kidney cells. Mutation and selection produced variant polioviruses that
were adapted for efficient replication in these cells. Some of the mutations in these variants
affected the genes coding for the poliovirus coat proteins in such a way as to produce mutants
unable to attach to human neural cells but still able to infect human intestinal cells.
 Infection of human intestinal cells does not produce paralytic disease but does induce
immunity. Poliovirus vaccine strains 1 and 2 have multiple mutations in the coat proteins and are
very stable. The type 3 vaccine strain is less stable and is subject to back-mutations (reversions)
that restore neural virulence. This vaccine strain therefore causes paralytic disease in one out of
every several million vaccinated individuals. Despite the possibility of back-mutations, the
generation and selection of attenuated viral mutants remains an important mechanism for
producing viral vaccines.

Recombination

Viral recombination occurs when viruses of two different parent strains coinfect the same
host cell and interact during replication to generate virus progeny that have some genes from
both parents. Recombination generally occurs between members of the same virus type (e.g.,
between two influenza viruses or between two herpes simplex viruses). Two mechanisms of
recombination have been observed for viruses: independent assortment and incomplete linkage.
Either mechanism can produce new viral serotypes or viruses with altered virulence.

Recombination by Independent Assortment

Independent assortment occurs when viruses that have multipartite (segmented) genomes
trade segments during replication. These genes are unlinked and assort at random.
Recombination by independent assortment has been reported, for example, for the influenza
viruses and other orthomyxoviruses (8 segments of single-stranded RNA) and for the reoviruses
(10 segments of double-stranded RNA). The frequency of recombination by independent
assortment is 6 to 20 percent for orthomyxoviruses.

Independent assortment between an animal and a human strain of influenza virus during a
mixed infection can yield an antigenically novel influenza virus strain capable of infecting
humans but carrying animal-strain hemagglutinin and/or neuraminidase surface molecules. This
recombinant can infect individuals that are immune to the parent human virus. This mechanism
results in an immediate, major antigenic change and is called antigenic shift. Antigenic shifts in
influenza virus antigens can give rise to pandemics (worldwide epidemics) of influenza. Such
antigenic shifts have occurred relatively frequently during recent history.
 The number of different serotypes of hemagglutinin and neuraminidase are limited, a
given strain reappears from time to time. For example, the H1N1 influenza virus strain was
responsible for the 1918 to 1919 influenza pandemic that caused 20 million deaths. The same
virus also caused pandemics in 1934 and in 1947, then disappeared after 1958 and reappeared in
1977. The reappearance of virus strains after an absence is believed to be the result of
recombinational events involving the independent assortment of genes from two variant viruses.

Recombination of Incompletely Linked Genes

Recombination also occurs between genes residing on the same piece of nucleic acid
(Fig. 43-3). Genes that generally segregate together are called linked genes. If recombination
occurs between them, the linkage is said to be incomplete. Recombination of incompletely linked
genes occurs in all DNA viruses that have been studied and in several RNA viruses.

In DNA viruses, as in prokaryotic and eukaryotic cells, recombination between

incompletely linked genes occurs by means of a break-rejoin mechanism. This mechanism
involves the actual severing of the covalent bonds linking the bases of each of the two DNA
strands in a DNA molecule. The severed DNA strands are then rejoined to the DNA strands of a
different DNA molecule that has been broken in a similar site. Recombination rates for
herpesviruses, which are DNA viruses that replicate in the nucleus of infected cells, approximate
those expected for a eukaryotic genome of the size of the herpesvirus genome. Herpesviruses
have an average recombination frequency of 10 to 20 percent for any two loci. However, the rate
of recombination between a specific pair of genetic loci depends on the distance between them
and varies from less than 1 percent to approximately 50 percent. Measurement of the
recombination frequencies for different loci can be used to map the virus genome. In this type of
genetic map, loci with high recombination frequencies are far apart and loci with low
recombination frequencies are close together.

Recombination has been shown to occur in several positive-sense single-stranded RNA

virus groups: retroviruses, picornaviruses, and coronaviruses. That is initially surprising, as
recombination between RNA molecules has not been observed in prokaryotic or eukaryotic cells.
In retroviruses, recombination actually occurs at the point in replication when the retrovirus
genome is in a DNA form and takes place by the same break-rejoin mechanism as in cells and
DNA viruses.
 Recombination can occur both between two related retroviruses and between the
retrovirus DNA and the host cell DNA. Recombination between two retroviruses gives rise to
novel viral progeny with reassorted genes. Recombination between retroviruses and the host cell
can give rise to novel viral progeny that carry nonviral genes. If these host genes code for growth
factors, growth factor receptors, or a number of other specific cellular proteins, the recombinant
retroviruses may be oncogenic.

In picornaviruses and coronaviruses, recombination takes place at the level of the

interaction of the viral RNA genomes and is not believed to occur by a break-rejoin mechanism.
The mechanism is currently believed to be a copy-choice mechanism. Copy-choice may occur in
these RNA viruses because the viral RNA polymerase binds to only a few bases of the template
RNA at any one time. Such a weak interaction of the polymerase with the template RNA would
permit the polymerase, carrying its RNA strand, to disassociate from the original template
nucleic acid strand and then associate with a new template RNA strand. Recombination
frequencies in the range of 0.2 to 0.4 percent have been reported. Therefore, the efficiency of this
mechanism of recombination is low.

Phenotypic Variation from Recombination

As mentioned above, viral recombination is important because it can generate novel

progeny viruses that express new antigenic and/or virulence characteristics. For example, the
novel progeny viruses may have new surface proteins that permit them to infect previously
resistant individuals; they may have altered virulence characteristics; they may have novel
combinations of proteins that make them infective to new cells in the original host or to new
hosts; or they may carry material of cellular origin that gives them oncogenic potential.
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