An endogenous viral element (EVE) is a DNA sequence derived from a

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 ...

, and present within the

germline In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...

of a non-viral organism. EVEs may be entire viral genomes ( proviruses), or fragments of viral genomes. They arise when a viral DNA sequence becomes integrated into the

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 ...

of a

germ cell Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually * Germ layer, a primary layer of cells that forms during embry ...

that goes on to produce a viable organism. The newly established EVE can be inherited from one generation to the next as an

allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...

in the host species, and may even reach fixation. Endogenous retroviruses and other EVEs that occur as proviruses can potentially remain capable of producing

infectious An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

virus in their endogenous state. Replication of such 'active' endogenous viruses can lead to the proliferation of viral insertions in the germline. For most non-retroviral viruses, germline integration appears to be a rare, anomalous event, and the resulting EVEs are often only fragments of the parent virus genome. Such fragments are usually not capable of producing infectious virus, but may express

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

and even

cell surface receptors Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral me ...

Diversity and distribution

EVEs have been identified in

animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...

s and

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

. In

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

s EVEs derived from

retrovirus 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 transcriptase ...

es ( endogenous retroviruses) are relatively common. Because retroviruses integrate into the

nuclear genome Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...

of the

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 ...

cell as an inherent part of their replication cycle, they are predisposed to enter the host germline. In addition, EVEs related to parvoviruses,

filoviruses ''Filoviridae'' () is a family of single-stranded negative-sense RNA viruses in the order ''Mononegavirales''. Two members of the family that are commonly known are Ebola virus and Marburg virus. Both viruses, and some of their lesser known re ...

bornavirus ''Bornaviridae'' is a family of negative-strand RNA viruses in the order '' Mononegavirales''. Horses, sheep, cattle, rodents, birds, reptiles, and humans serve as natural hosts. Diseases associated with bornaviruses include Borna disease, a f ...

es and circoviruses have been identified in vertebrate genomes. In plant genomes, EVEs derived from pararetroviruses are relatively common. EVEs derived from other, non-retrotranscribing virus families, such as ''

Geminiviridae ''Geminiviridae'' is a family of plant viruses that encode their genetic information on a circular genome of single-stranded (ss) DNA. There are 520 species in this family, assigned to 14 genera. Diseases associated with this family include: bri ...

'', have also been identified in plants. Moreover, EVEs related to

giant viruses A giant virus, sometimes referred to as a girus, is a very large virus, some of which are larger than typical bacteria. All known giant viruses belong to the phylum ''Nucleocytoviricota''. Description While the exact criteria as defined in the s ...

(aka GEVEs) of

phylum In biology, a phylum (; plural: phyla) is a level of classification or taxonomic rank below kingdom and above class. Traditionally, in botany the term division has been used instead of phylum, although the International Code of Nomenclature f ...

Nucleocytoviricota ''Nucleocytoviricota'' is a phylum of viruses. Members of the phylum are also known as the nucleocytoplasmic large DNA viruses (NCLDV), which serves as the basis of the name of the phylum with the suffix - for virus phylum. These viruses are refe ...

'' (NCLDV) similar to '' Aureococcus anophagefferens virus'' (AaV) have been found in 2019/2020.

Identification

EVEs are traditionally identified by similarity to known viruses. In 2021, it has been demonstrated that the

k-mer In bioinformatics, ''k''-mers are substrings of length k contained within a biological sequence. Primarily used within the context of computational genomics and sequence analysis, in which ''k''-mers are composed of nucleotides (''i.e''. A, T, G ...

composition of endogenous RNA virus resemble that of their exogenous counterparts. As a result, it is now possible to identify novel groups of endogenous RNA viruses whose exogenous relatives have become extinct.

Use in paleovirology

EVEs are a rare source of retrospective information about ancient viruses. Many are derived from germline integration events that occurred millions of years ago, and can be viewed as viral

fossil A fossil (from Classical Latin , ) is any preserved remains, impression, or trace of any once-living thing from a past geological age. Examples include bones, shells, exoskeletons, stone imprints of animals or microbes, objects preserved ...

s. Such ancient EVEs are an important component of paleovirological studies that address the long-term

evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...

of viruses. Identification of

orthologous Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...

EVE insertions enables the calibration of long-term evolutionary timelines for viruses, based on the estimated time since

divergence In vector calculus, divergence is a vector operator that operates on a vector field, producing a scalar field giving the quantity of the vector field's source at each point. More technically, the divergence represents the volume density of the ...

of the ortholog-containing host species groups. This approach has provided minimum ages ranging from 30 to 93 million years for the ''

Parvoviridae Parvoviruses are a family of animal viruses that constitute the family ''Parvoviridae''. They have linear, single-stranded DNA (ssDNA) genomes that typically contain two genes encoding for a replication initiator protein, called NS1, and the pr ...

'', ''

Filoviridae ''Filoviridae'' () is a family of single-stranded negative-sense RNA viruses in the order ''Mononegavirales''. Two members of the family that are commonly known are Ebola virus and Marburg virus. Both viruses, and some of their lesser known re ...

'', ''Bornaviridae'' and ''

Circoviridae ''Circoviridae'' is a family of DNA viruses. Birds and mammals serve as natural hosts. There are 101 species in this family, assigned to 2 genera. Diseases associated with this family include: PCV-2: postweaning multisystemic wasting syndrome; ...

'' families of viruses, >100 million years in the ''

Flaviviridae ''Flaviviridae'' is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors (mainly ticks and mosquitoes). The family gets its name from the yellow fever virus ...

'', and 12 million years for the

Lentivirus ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...

genus of the ''Retroviridae'' family. EVEs also facilitate the use of

molecular clock The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory when two or more life forms diverged. The biomolecular data used for such calculations are usually nucleoti ...

-based approaches to obtain calibrations of viral evolution in

deep time Deep time is a term introduced and applied by John McPhee to the concept of geologic time in his book ''Basin and Range'' (1981), parts of which originally appeared in the ''New Yorker'' magazine. The philosophical concept of geological time w ...

Co-option and exaptation by host species

EVEs can sometimes provide a selective advantage to the individuals in which they are inserted. For example, some protect against infection with related viruses. In some mammal groups, including higher primates, retroviral

envelope An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card. Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a shor ...

proteins have been exapted to produce a protein that is expressed in the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...

syncytiotrophoblast Syncytiotrophoblast (from the Greek 'syn'- "together"; 'cytio'- "of cells"; 'tropho'- "nutrition"; 'blast'- "bud") is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nut ...

, and is involved in fusion of the

cytotrophoblast "Cytotrophoblast" is the name given to both the inner layer of the trophoblast (also called layer of Langhans) or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo ...

cells to form the

syncytial A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus) ...

layer of the placenta. In humans this protein is called

syncytin Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene ( endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized ...

, and is encoded by an endogenous retrovirus called (

ERVWE1 Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene ( endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized ...

) on chromosome seven. Remarkably, the capture of syncytin or syncytin-like genes has occurred independently, from different groups of endogenous retroviruses, in diverse mammalian lineages. Distinct, syncytin-like genes have been identified in

primates Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...

rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...

lagomorph The lagomorphs are the members of the taxonomic order Lagomorpha, of which there are two living families: the Leporidae (hares and rabbits) and the Ochotonidae (pikas). The name of the order is derived from the Ancient Greek ''lagos'' (λαγ� ...

carnivore A carnivore , or meat-eater (Latin, ''caro'', genitive ''carnis'', meaning meat or "flesh" and ''vorare'' meaning "to devour"), is an animal or plant whose food and energy requirements derive from animal tissues (mainly muscle, fat and other sof ...

s, and

ungulates Ungulates ( ) are members of the diverse clade Ungulata which primarily consists of large mammals with hooves. These include odd-toed ungulates such as horses, rhinoceroses, and tapirs; and even-toed ungulates such as cattle, pigs, giraffes, cam ...

, with integration dates ranging from 10 to 85 million years ago.

Diversity and distribution

Identification

Use in paleovirology

Co-option and exaptation by host species

See also