Viruses and Genetic Diversity

Zehra Nur Koyuncu^T., Ebru Kavaklı^E.

Genetic variation is the fundamental mechanism of evolution and provides a basis for organisms to overcome environmental challenges¹. When these factors are considered, genetic variations essential for all biological systems are shaped within the framework of five basic mechanisms². These mechanisms represent the concepts of mutation, recombination, natural selection, genetic drift, and migration regarding determining genetic structure and evolutionary processes in biological populations³. Mutations are considered a series of events that direct evolution and occur spontaneously. Mutations represent a change in the genomic sequences or the process underlying the change in an organism. The types of mutations vary, including point mutations in a single base pair, deletions, insertions, duplications, or inversions in megabase pairs⁴. Conversely, recombination is a key factor that creates genetic variation by generating new allele combinations from broken or repaired DNA (deoxyribonucleic acid) chains^5,6. When recombination produces effects that strengthen adaptation, it is considered positive, but when it separates meaningful combinations of alleles, it is considered negative (harmful)⁵. Natural selection is a selective event that occurs when variants that adapt to selected conditions increase in frequency in the population or when the frequencies of non-adaptive variants decrease, shaped by the combined process of directional selection³. Migration and genetic drift represent the regional dynamics of populations that are shaped by different regions and demographic patterns, with varying levels of stability and differences⁷. Within the framework of genetic variation, there are three basic formation theories that suggest viruses, which are a rich variable in terms of genetic variation, are formed based on pre-cellular (pericellular), intracellular parasitic, or cellular genetic elements. These theories cannot fully explain the fact that viruses share a common ancestor⁸.

Viruses are biological structures that cause numerous diseases in humans, animals, and other organisms, and require a host to replicate⁹. Additionally, viruses can infect vital organisms across all domains of the ecosystem¹⁰. They are also defined as nano-scale agents that have systematically evolved to transfer viral genetic material efficiently¹¹. The evolution of viruses is a parallel and inseparable process with their relationships to target cells. Different evolutionary methods are developed within the scope of the lytic cycle involving lysing cells or the lysogenic cycle in which the virus genetic material is inserted into the host genome. Viruses exert selective pressure on cells, prompting them to evolve countermeasures to avoid infection, which in turn directs the virus to evolve strategies against the host’s protection mechanism^10,12. This is a dynamic and long-term co-evolution process between the virus and the host¹³. The evolutionary changes of viruses also differentiate the units of their reproductive-based mechanisms. The first of these, the intracellular stage, involves the virus reprogramming by producing viral particles (virions); the second stage is called the extracellular process, where virions maintain their continuity away from the infected cell¹⁴. The replication of viruses on specific cells they infect involves transferring metabolic and biosynthetic materials to produce proteins encoded by the viruses (virus-encoded)¹⁵.

In the classification of viruses, the vast majority have an RNA (ribonucleic acid) genome, while a significant minority have a DNA genome¹⁶. Depending on the genome architecture, they can be single-stranded (ss) or double-stranded (ds), and depending on the genome form, they can be circular, linear, or segmented^15,17. The genomic materials are surrounded by a protein-based layer called the capsid, and the capsid complex containing the genome is called the nucleocapsid¹⁸. Pathogenic viruses circulating in most humans have a lipid-based envelope structure. The viral envelope induces fusion between the virus and host cell membranes, forming a basis for infecting the target cell¹⁹. Another important structural component is glycoproteins, which facilitate interactions between the virus surface and the host (Figure 1)²¹.

Figure 1. Illustration of components belonging to the virus structure on the basic diagram²¹. The basic diagram shows the genomic material belonging to the virus structure, which is housed within the genome; the capsid; and, while not being the primary material seen in every virus form, the lipid envelope typically seen in viruses that cause human-based infections.

Of DNA and RNA viruses, DNA viruses have a single nucleic acid molecule (monopartite), whereas RNA viruses consist of multiple parts (multipartite) ²². In addition, single-stranded virus genomes with functional mRNA of the same polarity and gene coding capacity are present in the positive (+) form. Forms that do not primarily have gene coding capacity can subsequently be in the negative (-) form, where the spiral is transcribed^{22, 23}. The life cycle of viruses includes stages based on the genome, such as binding to the host cell, the passage of the virus genome into the host cell, and replication of the virus genome, followed by stages involving the synthesis of virus proteins, assembly of virus particles, and the release of new virions from the host cell (Figure 2) ²⁴.

Figure 2. Penetration of the virus into the host cell membrane²⁴. The figure shows the penetration of the virus into the host cell, along with the subsequent stages of entry into the host cell. The virus particle that enters the host cell carries specific receptors that aid in its penetration. Once inside the host cell, the virus particle utilizes the host cell’s metabolic functions to replicate the genetic material and protein synthesis.

Infections that occur in the cycle of life typically begin with receptor-mediated endocytosis or micropinocytosis²⁵, in which large amounts of extracellular fluid and components are transported between the infection, virus, and host cell^26,27. After penetration, transcription, translation, and the viral genome’s replication are supported²⁶. Once the virus has completed its entry into the cell, it has two basic processes: the replication of the virus genome by synthesizing new viral particles and the synthesis of viral proteins for the assembly of new virus particles²⁴. Viral genes are divided into two stages: early (E) and late (L)²⁸. The early stage is the transcription where the relevant proteins are encoded by genetic material. In the late stage, structural proteins associated with the morphogenesis of new viral strains are encoded²⁹. Although cellular components are released along with the viral genome and enter the nucleus, most RNA viruses remain in the cytoplasm^27,30. The relationship between viruses and hosts is shaped by the host’s energy requirements, the formation of a ribosomal system for the synthesis of viral proteins from viral mRNA during protein synthesis, and the requirements for structural components of the cell³¹. Negative-strand RNA viruses (NSVs), which are RNA forms, create a structure with a genomic viral skeleton RNA and a helical configuration by forming numerous viral nucleoprotein copies^{31, 32}.

There are two major groups of NSVs. These are segmented RNA viruses that encode their genomes in two or more molecules³² and non-segmented RNA viruses that contain all RNA segments in a single virus particle^{33, 34}. All NSVs are catalyzed by RNA-dependent RNA polymerase (RdRp) in the context of viral ribonucleoprotein (vRNP) complexes^{35, 36}. RdRp is a multifunctional enzyme essential for the replication and transcription of RNA viruses³⁷. The first task of NSVs seen within cells is to create a positive RNA helix in a matching structure, reaching a double-stranded structure. Both strands of the double-stranded structure are used as templates, with the positive-stranded helix being used to synthesize the negative-stranded helix in the next generation. The negative-stranded helix is used as a template for the mRNA function of positive-stranded RNAs^{24, 32}.

Positive-sense RNA viruses (PSVs) replicate in the cytoplasm and associate with numerous membrane-bound viral replicase complexes (VRCs)³⁸. The expression of replication-associated proteins is followed by translation steps for the formation of genomic RNA. The replication complex initiates the synthesis of complementary RNA strands and, in the meantime, reshapes the host membrane to form cytoplasmic components³⁹. Cytoplasmic components are intracellular components that host viral replication organelles and are called viral factories. They are necessary for the maturation and assembly of new virions⁴⁰. Retroviruses, which are RNA viruses, copy genetic material by integrating their RNA genome into the host DNA with their own DNA polymerase and reverse transcriptase (RT) enzyme⁴¹. In DNA viruses, the genome structure and replication strategy progress in a coordinated manner. While smaller DNA viruses use almost all of the host’s replication system, larger forms code for their own DNA polymerase enzyme during replication⁴². dsDNA viruses have two consecutive stages for the production of the viral gene. Early and immediate-early genes are viral genes that undergo transcription and translation⁴³. The complementary and parallel progression of early and late stages is essential for producing transcription factors and packaging new virions⁴⁴. The products coded by viral operations induce the expression of viral genes, viral DNA replication, and cell cycle continuity by blocking host cell metabolism⁴⁵.

In DNA viruses, the nucleocapsid structure must pass into the cytoplasm. The viruses interact with the nuclear pore complex (NPC) to reach the nucleus using the host cell’s cytoskeleton and motor proteins⁴⁶. The viral genome replicates through DNA polymerase bound to DNA (DdDp)⁴². The viral DNA replication starts at the L phase; along with gene expression, structural proteins are coded, and viral materials come together before the virion is released⁴⁵. DNA viruses mostly use the host’s RNA polymerase II enzyme to synthesize viral mRNA⁴⁶. It has been found that DNA viruses evolve more slowly in the traditional context, and single-stranded DNA viruses evolve faster than double-stranded ones⁴⁷. Viral proteins, which are another component, are structurally characterized and used to form the basis of the capsid or complementary elements of the virion⁴⁸. Other non-structural proteins are involved in the assembly of virion particles and viral processes such as nucleic acid replication, transcription, translation, and inhibition of natural host immunity. Various viral enzymes, such as replicases, transcriptases, proteases, helicases, and ligases, are also present⁴⁸.

Virus Variation Mechanisms

Variations occurring within genetic materials contain numerous strategies and formation mechanisms that increase the diversity of viruses, with their basic functioning being based on molecular mechanisms¹⁵. Viruses use the exact molecular genetic variation mechanisms as other life forms⁴⁹. These mechanisms include point mutations⁴⁹, which are single nucleotide differences in DNA sequences, insertions and deletions of different lengths, hypermutation⁵⁰, which represents the highest observed mutation rate, recombination, and rearrangement of genome segments (pseudorecombination)². Mutations create a pool of genetic traits that can either provide an advantage or result in negative consequences when transferred between lineages⁵¹. Mutant viruses continuously become dominant within viral populations. They also differentiate by chance within viral populations or by exhibiting selective behavior⁵². The rate of random mutations among viruses is very high. RNA viruses mutate more quickly than DNA viruses, and the mutation rate of single-stranded viruses is faster than that of double-stranded viruses. Genome size and mutation rate are inversely proportional⁵³. Insertions, deletions, and point mutations that match virus genome mutation profiles reveal permanent differences among viruses⁵⁴. Recombination is a common process that creates differences in most viruses⁵⁵. Viral recombination provides a major opportunity for adaptation processes, particularly those involving changes in hosts. Increased adaptation to new hosts is responsible for strengthening both therapeutic resistance and evasion from the immune system among viruses⁵⁶.

As a result of adaptation, successful host switching between species enables pathogens to increase their infection success⁵⁷. For new genetic variants to arise as a result of recombination, at least two mutations must be effective on the virus, and the recombination mechanism must continue to exist within the same cell. Recombination allows for the emergence of new species, primarily through gene transfer, even in cases where it is rarely observed⁵⁸.      The rearrangement caused by recombination in segmented RNA viruses leads to the formation of new forms, moving away from origin genetic-based formations⁵⁹. The faster evolution of RNA viruses makes it more likely for genes to be transferred and recombination to occur, which provides a basis for selection or genetic drift among populations⁵⁹. As the mutation rate of RNA viruses is high, their ability to specialize and become characterized also increases. Due to the rapid and extreme cause-effect relationship, treatment options are limited against viruses that gain resistance to antiviral drugs and easily pass to other hosts^{60, 61}.

In DNA viruses, mutations serve as a driving force for evolutionary shifts⁵⁵. Factors that cause mutation are accompanied by repair mechanisms possessed by bacterial infecting viruses and DNA viruses, which detect the accuracy of DNA copies and mutant phenotypes. It is seen that the detected phenotypes are inactive. In addition, when the control of DNA recombination stages is provided, the virus functions that control it are expressed as an indicator of the ability of viruses to adapt to complex situations⁵². The entry, replication, and spread of the virus to the host cell cause tissue damage, leading to the formation of an immune response. In most diagnostic methods, clinical signals and symptoms are detected to identify the virus that causes the disease, and other forms are eliminated⁴⁸. Viral infections that cause mild to acute common diseases can sometimes have fatal consequences. After viral infection, immune system elements, physical barriers, phagocytic cells, and interferons (IFN) constitute the first line of defense for viral clearance⁶². The genetic differences and mutations observed in viruses also affect the process of disease formation and treatment methods. Treatment methods are negatively affected by drug resistance and the risk of dynamic genetic heterogeneity⁶³.

The viral process is related to parallel molecular evolution, which is defined as the independent evolution of the same genotype and phenotype from different ancestors. Parallel adaptation is studied on the same system as drug resistance and immune escape, which are compatible with viral infection properties⁶⁴. Therefore, the evolution of viruses and their genetic differences are proven to be repeatable through this definition⁶⁴. One of the processes that allow viruses to have genetic differences is due to the involvement of host cells in the evolutionary process when viruses continue to survive depending on the host⁶⁵. Although there is not enough data suitability yet for the parallel tracking of the evolutionary processes between viruses and host cells, it is still being studied on the possibility that the host cell stands out due to virus adaptation and differences⁶⁵.

Genetic variations, one of the fundamental mechanisms of evolution, provide a basis for lineages to gain new characters, and thus change population dynamics. Mutations in viruses increase their tolerance to environmental sources, host selection, and external environmental dynamics. The differentiation processes occurring in virus forms and functions make it possible for them to easily avoid drugs, needles, and treatments that will be created against them. The rapid adaptation abilities of viruses also make their classification and detection difficult.

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