About useful and harmful virus genes in our genome, how viruses are embedded in DNA and how virus sequences are related to schizophrenia and other diseases.
Usually, by "virus" we mean known diseases such as influenza and Ebola virus. They refer to so-called exogenous viruses, which we can catch from other people. But some viruses exist inseparable from us in our genome for millions of years - such viruses are called endogenous. About the traces of ancient viruses in the body of living creatures in the guide 'Viruses'
Origin of endogenous viruses
Viruses appeared in the very early stages of evolution. They do not leave any physical traces or fossils in the sedimentary rocks, but they can be detected differently by studying the virus-specific nucleotide sequences in our DNA.
Viruses that once disappeared like mammoths and dinosaurs still exist in our genomes and in the genomes of many other living things: animals, plants and fungi. Sometimes they are represented as complete viral genomes, and then they even retain the ability to cause infection: the expression (conversion of hereditary information carried by a gene into RNA or protein) of such a "viral gene" produces new viral particles. Such embedded viruses are called proviruses.
In most cases, however, endogenous viruses are fragments of a viral genome. They cannot cause an infection but RNA and proteins can often be expressive.
Endogenous retro viruses.
Retro viruses are most often endogenous. This is due to the specificity of their replication within an infected cell. Most viruses do not interact directly with the genetic material of an infected cell, which cannot be said about retro viruses. Their genome is formed by an RNA molecule that becomes a matrix for reverse transcription (synthesis) of DNA when it enters the cell. This DNA is embedded in the target cell's genome and becomes an integral part of its genetic material from now on.
As long as somatic cells, i.e. non-sexual cells, are affected by a retro virus, this remains a problem in one organism. But if the virus enters germ or sex cells, it will be passed on to future generations along with the rest of the genetic material. The viruses that get into the genome cells and are sustainably transmitted by inheritance become endogenous.
The behavior of retro viruses in germ cells is still poorly understood. The study of "cell immunity" against retro virus KoRV-A, which occurs in the wild population of Australian koalas and is "endogenized" in their genome, has helped us to make significant progress in understanding these processes. This is due to the fact that it somehow managed to penetrate their germ cells, and therefore is now inherited in some groups of koalas.
By studying this virus, the geneticists were able to detect a cellular mechanism that prevents the assembly of viral particles from the KoRV-A genetic material contained in the genome of koalas. Small RNA molecules known as pyriRNA differentiate koala DNA from the genetic material in the retrovirus and then block the synthesis of the virus particles. It is likely that all modern organisms whose genome contains endogenous viruses have gone through such a process.
In some cases, viral elements give advantage to those individuals in whose genome they have been integrated. For example, they can protect against infection caused by related viruses by inhibiting their replication. How do they do this?
The fact is that a viral particle is a puzzle of viral and sometimes cellular proteins that wrap up its genetic material. Endogenous retroviruses in our genome can insert their "unsuitable" parts into this puzzle, resulting in a faulty design that prevents the replication of viral copies. There is another way to prevent an exogenous virus from settling in an infected organism: endogenous viruses in the genome can "clog" vacancies in cell receptors with their proteins, so that another virus will not be able to dock and thus enter the cell.
In addition, the presence of endogenous retro viruses in the genome trains the cell to identify retro viral sequences within its genetic material and suppress their expression. In order for the mechanism to work, our genetic material must have "preset training sequences".
How viruses are embedded in the genome
In vertebrates, endogenous retro viruses are quite common. It is not difficult to detect them in the genome because all families of endogenous retro viruses have characteristic nucleotide sequences. In addition, due to the mechanism of insertion, they are limited to short direct repetitions in DNA from both edges - specific nucleotide sequences for virus integration into the genome.
According to some estimates, endogenous retro viruses can represent between 7 and 9% of the vertebrate genome. Most often, such genetic material is "trash" and does neither benefit nor harm. This is due to the fact that cells have mechanisms to protect against the incorporation of retro viral genetic material: for example, they can cover their DNA with a protein that inhibits the expression of viral genes.
It is not the genes that make up the bulk of the human genome, but the so-called intergenic spaces. Once there, the endogenous retro virus is likely to be repressed, accumulate mutations and wait for its time to come in handy for the cell. Of course, only a small part of the range of endogenous retro virus sequences is used in the end and the rest are in a state of recycling.
In the human genome, most endoviruses are more than 25 million years old: they were built into the genome of our ancestors even before the evolutionary line of the great apes was separated from other monkeys. But there are also younger viral genes that we received afterwards, but they have not preserved the ability to replicate and infect other cells. This human genome is different from mouse, cat and pig genomes: they have younger viral sequences that can generate new virions.
Humans have a stronger antiviral immunity. Special antiviral proteins identify the viral genetic material and make chemical modifications to it. As a result, the virus is embedded in our genome with many mutations that prevent it from further multiplying inside the cell. But that's not all: the viral genes are then subjected to protective methylation (i.e. introduction of a methane and hydrogen derivative into the genes) and blocked chemically. At the same time, the virus genes are inactivated and become susceptible to mutations, which reduces the risk of a sudden awakening of this viral sequence.
Viruses in the human genome
In total, there are thousands of virus sequences in the human genome. Until recently, 17 viral fragments were known to exist in the human genome that preserved intact (i.e. without critical mutations) the main retro viral proteins encoding the shell, reverse transcriptase into DNA, and "skeleton" of the viral particle. But in 2016, American geneticists from Tufts University and the University of Michigan Medical School studied the genomes of 2500 subjects and added 19 more intact retro viral fragments.
Many endoviruses in the human genome are considered "trash", but in 2000 American and French geneticists found an example of successful "domestication" of retroviral genome. The researchers found two very similar genes that resemble most of all the proteins in the retro virus shell. Now, the cells in our bodies are not using these proteins to create new viruses, but to regulate the placenta. The protein sincitine controls the fusion of cells in the outer layer of the placenta - sincity. The resulting multi-core cells seem to be a stronger barrier against aggressive substances. Surprisingly, these proteins, called sincitins, have also been found in other mammals: ungulates, hares, rodents and predators, with the only difference that they have sincitins from other groups of retro viruses.
There are other viral sequences that have been "domesticated" to protect human health. In 2015, Joanna Wysock, an American professor of developmental biology, and her colleagues at Stanford University found such functions in the endogenous virus HERVK. Scientists have found that the cells of the three-day human embryo produce a lot of protein encoded by the virus genes. These proteins affect the activity of other genes in the embryo. One of them increases the IFITM1 level, a protein in the membrane that prevents other viruses from entering the embryo. In other words, the endogenous virus prevents other viruses from infecting the human embryo.
Other endogenous viruses, on the contrary, try to "domesticate" us. Scientists have known before about viruses that can influence the behavior of their hosts, but recently such viruses have also been discovered in humans. In 2009, Russian geneticists from the cell signal system genome analysis group at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences discovered that endogenous retroviruses can influence the regulation of neighboring genes both at the transcription level and through anti-sense RNAs (specific single-chain RNAs). People with and without insertions of endogenous retrovirus sequences differ in the regulation of neighboring genes. And this can affect the functions of these cells and entire organisms.
For example, in 2018, researchers at the University of Oxford and Athens found that the endogenous virus HERV-K HML-2 (HML-2) may increase the propensity for addiction. It is located close to the genes responsible for the brain systems important for dopamine production and is able to regulate their work.
The team of Russian scientists has discovered an endogenous retrovirus that affects the propensity for schizophrenia. The hsERVPRODH virus element enhances the expression of the gene responsible for the production of prolindehyrogenase in the human brain. Proline is both an important independent neurotransmitter and a link in the biosynthesis of GABA (gamma-aminobutyric acid), another important neurotransmitter that determines whether a person will have schizophrenia. In primates, such changes in the genome have not been detected, so the change in the regulation of this gene can be considered one of the very important events in the evolution of the human brain. But it has also led to the emergence of a new pathology, which primates do not have.
New endoviruses
So far, no endoviruses other than retroviruses have been found in mammals. Hepadnaviruses and some herpes-viruses are also able to embed into the genome of our cells, but it is reported that they have not yet managed to enter the genome of germ-line cells and fix themselves there for transmission to the next generation.
The human immunodeficiency virus may become a new endovirus. No case is known yet where HIV has penetrated into human genome cells or into cells of the human embryo. This was considered impossible because HIV refers to lentiviruses, which are replicated only in non-divided cells. However, lentiviruses have recently been found in the germ cells of European rabbits and Madagascar lemurs - the latter are primates, like us. We don't know if HIV will ever become a part of our body, yet.