11 July 2008

Viruses have regulated humans

Так выглядит типичный ретровирусWhen millions of years ago ancient retroviruses introduced parts of their DNA into the primate genome, these aggressors unwittingly made a significant contribution to the development of the mechanism of self-regulation of the human body at the gene level. According to scientists from the University of California, it was these distant relatives of HIV that gave rise to one of the most important mechanisms for regulating gene expression – the protein encoded by the p53 gene.

(Gene expression is synthesis based on information encoded in DNA, matrix RNAs (transcription) and further proteins (translation). The stages at which intracellular regulation of gene expression occurs are: transcription, post-transcriptional modifications, RNA transfer, degradation of matrix RNAs, translation and post-translational modifications. DNA itself or the structure of chromosomes can also undergo modification).

Nowadays, about 8% of the human genetic code consists of endogenous retroviruses – DNA remnants of these "narcissistic parasites". A study conducted at the University of California describes the process of development of the regulatory gene grid. It is known that not all genes in DNA are equal – some have the privilege to "turn off" and re-"turn on" the expression of certain DNA sites. The emergence of gene regulation mechanisms allowed better control of the expression of various genes in higher vertebrates.

Such a subtle and sensitive control of reading genetic information allows different species, even genetically as close as humans and chimpanzees, to have significant differences in biological structure and development.

Scientists have long been greatly interested in the ability of one of the main regulatory genes - p53 – to turn on and off a wide range of genes involved in the processes of cell division, DNA repair, and also to program cell death. It was also unclear how p53 single-handedly took over the head of this gene empire.

Applying modern methods of computational genomics, scientists have come to the conclusion that retroviruses are behind p53.

At one time, endogenous parasites embedded themselves in the DNA chain and distributed numerous copies of their nucleotide sequences throughout the molecule, which allowed p53 to take control of its vast areas. Currently, geneticists call p53 nothing but an emperor or a king, an autocrat among the entire kingdom of genomes – strict, but fair. Its only task is to constantly inspect the condition of cells and their development. Often, a failure in the work of p53 leads to irreversible violations in the cellular mechanism and the appearance of cancerous tumors.

Approximately half of the malignant tumors found in humans contain mutated or impaired p53.

David Haussler, professor of biomolecular engineering at the University of California, emphasizes the importance of the study from the point of view of biomedical applications, since the detected DNA changes under the influence of retrovirses occurred only in primates. Pure lines of mice – the main consumable of physicians, biologists and geneticists - do not have anything like this.

Dr. Ting Wang, the key author of the publication in the Proceedings of the National Academies of Science, emphasizes the very short duration of the evolutionary period that primates needed to develop such a structure of the gene control mechanism.

Analyzing the genetic information of various species, a group of scientists concluded about the time frame of the penetration of retroviruses into the DNA of primates, which led to the emergence of the mechanism of gene self-regulation. Individual retroviruses penetrated the heredity molecule about 40 million years ago, and their widespread distribution among primates occurred 15 million years later. Around the same time, monkeys began to transform into humans.

Researchers have been guessing about the important role of retroviruses in regulatory processes at the gene level for quite some time. More than half a century ago, Nobel laureate Barbara McClintock noticed a change in the rate of gene expression in corn cells due to the action of so–called "jumping genes" - interchangeable DNA sections. In 1971, Roy Britten and Eric Davidson put forward the theory that the often observed repeatedly repeated sections of DNA function within a common regulatory system. They made the assumption that such sites are remnants of retroviruses and can change their location in the sequence in case of activation. Now researchers from California have finally substantiated this theory.

They thoroughly studied the human genome for the presence of endogenous retrovirus residues, identified the DNA regions that p53 controls, and studied its ability to regulate the expression of the corresponding genes. It turned out that more than a third of the sites controlled by p53 are associated with retrovirus residues.

The results obtained make scientists think harder about the role of so–called "genetic garbage" - DNA sections that do not encode anything; retrovirus remnants also fall into this category. For a long time, scientists did not see the point in the existence of these sites, but a new study sheds light on the importance of the presence of such chains in the genome.

Californians hope to unearth their treasure in these "genetic garbage".

Among other things, Wang's team dared to propose a new mechanism of evolutionary development. Traditional ideas assume the occurrence of small changes in the genotype, which then undergo a "strength test" and, if successful, are fixed in the genome or destroyed together with the individual carrier of changes that have not withstood competition.

The new study suggests a different mechanism than point mutations. Instead, retroviruses are introduced into the genome and significantly change its sequence, regulating gene expression, which determines the occurrence of changes in the biological structure of a particular species. Of course, such "mixing" should pass the test of time.

Wang and his colleagues have no doubt that the work carried out will have a great impact on various branches of science and medicine. They are sure that such a mechanism is common to all species. Most likely, such an invasion of retroviruses into DNA has occurred more than once and has taken place not only in primates, and probably there are other regulatory genes that have stood on a par with p53 at the head of gene regulatory networks with the help of ancient retroviruses. They have yet to be studied.

Retroviruses are viruses with an unusual way of replicating genetic material. The reproduction cycle of this large family of viruses is characterized by a reverse flow of genetic information: instead of the usual transcription (i.e. rewriting) of deoxyribonucleic acid (DNA) into ribonucleic acid (RNA), as it happens in a cell, their genomic RNA is rewritten into DNA. This feature of retrovirus reproduction is reflected in the name: "retro" means "reverse". Members of the retrovirus family cause a number of serious diseases of animals and humans. The most studied viruses include leukemia viruses of birds, mice, cats and primates, as well as immunodeficiency viruses of cats, monkeys and humans. The human immunodeficiency virus (HIV) caused the HIV and AIDS pandemic (acquired immunodeficiency syndrome) worldwide.
The genetic information of retroviruses is presented in the form of RNA. Shortly after the retrovirus enters the cell, its RNA is rewritten into double–stranded DNA with the help of a specific viral enzyme - reverse transcriptase, capable of synthesizing DNA on the RNA matrix (viral RNA). After the synthesis is completed, the viral double-stranded DNA is transported to the cell nucleus and embedded in the structure of chromosomal DNA, where it can be permanently present in any chromosome, forming a so-called provirus. In some cases, the proviral DNA is immediately rewritten into RNA, but sometimes the provirus is in a "dormant" state for a long time, after which it is activated with the formation of daughter viral particles. During the rewriting of the proviral DNA, the genetic information of the retrovirus is transmitted using cellular enzymes in the usual, forward direction. From the resulting viral RNA and proteins, new viral particles are collected, which leave the cell, spread and infect other cells.

Alexey Petrov, "Gazeta.Ru»

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