Table of contents :

• Virions => viruses
• Subviral agents or unconventional viruses
• Plasmids
• Mobile genetic elements (MGE)
• Web resources
• Bibliography

As subcellular life forms are obligate parasitic organisms, their physiology is strictly dependent on host cell biology and so often on their pathogenicity. Click here for more informations on those causing Homo sapiens diseases.
 

• capsid : the shell of protein that protects the nucleic acid of a virus; it may have helical or icosahedral symmetry and is composed of structural units, or capsomers. According to the number of subunits possessed by capsomers, they are called dimers (2), trimers (3), pentamers (5), or hexamers (6).
• capsomer / capsomere : the morphological unit of the capsid of a virus.
• helical symmetry : an arrangement of capsomers seen in viruses with a rodlike or filamentous capsid, in which subunits form a coiled structure, with each subunit forming bonds with the subunit in each of the adjoining turns to provide stability
• icosahedral symmetry : an arrangement of viral subunits in which the structure of the viral capsid is characterized by symmetry having the rotation axes of a regular polygon with 20 triangular surfaces (icosahedron); each face contains several subunits, the total number of subunits in the capsid being a multiple of 60.
• viruses share a common ancestor that existed over 3 billion years ago and may even have preceded cellular forms of life : based on a comparison of known virus types and an icosahedral virus isolated from a hot spring in Yellowstone National Park, USA, oat proteins in all viral types that inhabit the 3 domains of life—Eukarya, Bacteria, and Archaea—have conformational similarities even though the genetics underlying them is quite different. Virus genes evolve so quickly that it is very difficult to trace relationships over long evolutionary distances on the basis of sequence : to investigate evolutionary considerations, more sophisticated criteria than simple sequence similarity are required. There is this pressure upon the conservation of the structure, although the sequence is changing so very much. Many of the coat protein sequences of apparently unrelated viruses that infect all 3 domains of life (Archaea, Bacteria, and Eukarya) are compatible with the major coat protein of bacteriophage PRD1. That builds on earlier evidence that a number of viruses are descended from that bacteriophage^ref. Both are trimeric molecules with two viral jelly rolls, with each such barrel containing 8 beta strands in tandem folded back at the middle. P3, the major coat protein of bacteriophage PRD1, strikingly resembled hexon, the major coat protein of human adenovirus^ref. The reasoning behind why we believe this structural similarity is not due to convergent evolution is there are 4 different ways to fold these barrels, and there's only one used in all these viral folds. Adenovirus and PRD1 are also structurally similar in architecture, vertex recognition spikes, and genomes with inverted terminal repeats and terminal proteins. As no detectable sequence similarity now exists between these viruses, they diverged billions of years ago. X-ray crystallography, electron microscope image reconstructions, or sequence similarities suggest other relatives of this double-barrel trimer lineage include algal phycodnavirus Paramecium bursaria Chlorella virus 1 (PBCV-1), bacteriophage Bam35, insect iridovirus Chilo iridescent virus, African swine fever virus, mimivirus, and perhaps even the poxviruses. In 2004, a research team found the major coat protein of an archaeal virus, Sulfolobus turreted icosahedral virus, matched well with PRD1 P3, providing an example from the third domain of life^ref. All described viruses are icosahedral dsDNA viruses. The double-barrel trimer is an ideal building block for a protein array ideal for large surfaces. It can be used in principle to build a virus of any size. tenuous evidence existed for another virus lineage that may span all three domains consists of the herpesviruses and tailed bacteriophages, all dsDNA viruses. Also, the dsRNA reoviruses span Bacteria and Eukarya, with none yet known for Archaea. Convergent evolution can never be absolutely ruled out, but the amount of data they have makes a strong case for common ancestry. The fact the sequences diverged as much as they have suggests the lineages are ancient, a good argument that viruses emerged earlier than the emergence of the 3 domains. It argues that viruses have had a really big role in the evolution of life and had a more central role than most people might have imagined. To cement their hypothesis, we need to uncover further similarities in structure within the double-barrel trimer lineage, such as the special vertex both PRD1 and PBCV-1 have for packaging and perhaps injecting DNA. There is a lot of interest in using viral capsids as a delivery vehicle for nanotechnologies. So these findings could help learn more about the structure of these viruses, the biggest icosahedral viruses, and you could imagine them being useful someday for protein nanocontainers. Horizontal exchange of genes between viruses made determining linear ancestries extraordinarily complicated.
• DNA virus / deoxyribovirus : a virus whose genome consists of DNA
• RNA virus / ribovirus : a virus whose genome consists of RNA
• nonenveloped  or naked virus : a virus lacking an outer lipoprotein bilayer
• enveloped virus : a virus having an outer lipoprotein bilayer acquired by budding through the host cell membrane. It has been generally thought that this process is driven by interactions between the viral transmembrane proteins and the internal virion components (core, capsid, or nucleocapsid). This model was particularly applicable to alphaviruses, which require both spike proteins and a nucleocapsid for budding. However, genetic studies have clearly shown that the retrovirus core protein, i.e., the Gag protein, is able to form enveloped particles by itself. Also, budding of negative-strand RNA viruses (rhabdoviruses, orthomyxoviruses, and paramyxoviruses) seems to be accomplished mainly by internal components, most probably the matrix protein, since the spike proteins are not absolutely required for budding of these viruses either. In contrast, budding of coronavirus particles can occur in the absence of the nucleocapsid and appears to require two membrane proteins only. Biochemical and structural data suggest that the proteins, which play a key role in budding, drive this process by forming a three-dimensional (cage-like) protein lattice at the surface of or within the membrane. Similarly, recent electron microscopic studies revealed that the alphavirus spike proteins are also engaged in extensive lateral interactions, forming a dense protein shell at the outer surface of the viral envelope. Budding of enveloped viruses in general is governed by lateral interactions between peripheral or integral membrane proteins. This new concept also provides answers to the question of how viral and cellular membrane proteins are sorted during budding. In addition, it has implications for the mechanism by which the virion is uncoated during virus entry
• defective virus : one that cannot be completely replicated or cannot form a protein coat; in some cases replication can proceed if missing gene functions are supplied by other (helper) viruses
• helper virus : a virus (e.g., the Rous-associated virus (RAV)) that aids the development of a defective virus by supplying or restoring the activity of a viral gene or enabling a defective virus (e.g., the Rous sarcoma virus (RSV)) to form a protein coat.
• lytic virus : one that is replicated in the host cell and causes death and lysis of the cell
• latent or masked virus : a virus which ordinarily occurs in a noninfective state and is demonstrable by indirect methods which activate it, as by blind passage in experimental animals.
• slow virus : any virus causing a disease characterized by a very long preclinical course and very gradual progression once the symptoms appear.
• eclipse : in virology, that period of the infective cycle during which infected bacterial cells contain no detectable infective bacteriophage
• bacterial virus / bacteriophage / phage : a virus capable of producing transmissible lysis of bacteria; the virus particle attaches to the bacterial cell wall and viral nucleoprotein enters the cell, resulting in the synthesis of virus and its liberation on physical disruption of the cell. Bacterial viruses are usually specific for bacterial species, but they may be strain-specific or may infect more than one species of bacteria
• prophage : the latent stage of a phage in a lysogenic bacterium, in which the viral genome becomes inserted into a specific portion of the host chromosome and is duplicated each cell generation
• Twort-d'Herelle phenomenon : the phenomenon of transmissible bacterial lysis; bacteriophagia. When to a broth culture of typhoid or dysentery bacilli there is added a drop of filtered broth emulsion of the stool from a convalescent typhoid or dysentery patient, complete lysis of the bacterial culture will occur in a few hours. If a drop of this lysed culture is added to another culture of the bacilli, lysis will take place exactly as in the first. A drop of this culture will then dissolve a third culture, and so on through hundreds of transfers. d'Herelle attributed this phenomenon to the action of an ultramicroscopic parasite of bacteria, which he named the bacteriophage
Web resources : Felix d'Herelle Reference Center for Bacterial Viruses, GREB, Faculte de medecine dentaire, Universite Laval (HER 607).
• plant viruses : viruses that replicate in and may produce diseases of higher plants
• animal viruses : viruses that produce diseases of man and other animals
• insect viruses : viruses capable of causing disease in insects.
• simian viruses : viruses that have been recovered from monkeys; they belong to many different groups, including adenoviruses, enteroviruses, herpesviruses, and reoviruses
• orphan viruses : viruses which when isolated originally in tissue culture showed no specific association with disease, such as the enteric orphan viruses; some have since been found to occur in association with human disease.
• enteric orphan viruses : viruses isolated from the intestinal tract of man and various other animals, called orphan viruses because they are often not specifically associated with illness; they include such viruses isolated from
• cattle (ecboviruses)
• dogs (ecdoviruses)
• human (echoviruses)
• monkeys (ecmoviruses)
• swine (ecsoviruses)

• International Committee on Taxonomy of Viruses (ICTV)
• ICTVdB : the authorized universal virus database at Columbia University
• VIrus Particle ExploreR (VIPER)
• VirGen is a comprehensive viral genome resource that organizes the 'sequence space' of viral genomes in a structured fashion. It has been developed with the objective of serving as an annotated and curated database comprising complete genome sequences of viruses, value-added derived data and data mining tools. The current release (v1.1) contains 559 complete genomes in addition to 287 putative genomes of viruses belonging to eight viral families for which the host range includes animals and plants. Viral genomes in VirGen are annotated using sequence-based Bioinformatics approaches. The genomic data is also curated to identify 'alternate names' of viral proteins, where available. VirGen archives the results of comparisons of genomes, proteomes and individual proteins within and between viral species. It is the first resource to provide phylogenetic trees of viral species computed using whole-genome sequence data. The module of predicted B-cell antigenic determinants in VirGen is an attempt to link the genome to its vaccinome^ref
• The big picture book of viruses
• Tulane University
• All the virology on the WWW
• Virology glossary
• Virology and microbiology course notes
• Virology course
• University of Leicester
• Virus groups
• Information on virus families
• Human virology at University of Stanford
• NCBI
• RefSeqs for viral genomes
• Retrovirus resources
• Arboviruses at University of Toronto
• Plant Viruses Online
• Plant virology at University of Arizona
• Selected Topics in General Virology
• Virology Resources
• Viroceptor at COPE
• Virokine at COPE
• dmoz Open Directory Project (ODP) : Virology
• Journals
• Journal of Virology
• Look here for Homo sapiens diseases caused by viruses

• viroids : a small infectious pathogen of Viridiplantae composed entirely of a 246-375 nt, not encoding, circular ssRNA molecule with high base pairing grade, capable of self-replication in host cell via a rolling circle model. Probably they arose from cellular RNAs (no homology with any viral RNA). They are classified into 2 families :
• Avsunviroidae (type species : avocado sunblotch viroid (ASBVd)) : subcellular locus and replication in chloroplast; no domains; self-cleaving hammer-head ribozyme (RNAse) activity, without central conserved region, symmetric rolling-circle-type replication model in chloroplasts. They need cellular RNA polymerase (used in a RNA-dependent fashion instead of the usual DNA-dependent fashion) and ligase for replication.
• Avsunviroid : soluble in 2M LiCl; A+U-rich; quasi-double-stranded, rod-like secondary structure
• Pelamoviroid : insoluble in 2M LiCl; G+C-rich; branched secondary structure
• Pospiviroidae (type species : potato spindle tuber viroid (PSTVd), the first eukaryotic pathogen to be fully sequenced in 1978 !) : soluble in 2M LiCl; G+C-rich; central conserved domain; quasi-double-stranded, rod-like secondary structure; subcellular locus and replication in nucleus; no ribozyme activity (replaced by host factors ?); asymmetric rolling-circle-type replication model in nucleus (expecially in nucleoli). They need nuclear RNA polymerase II (used in a RNA-dependent fashion instead of the usual DNA-dependent fashion) or chloroplast RNA polymerase, ligase and RNAse for replication.
Several groups have investigated the role of individual structural domains in symptom formation. With PSTVd, early work had shown that sequence differences between severe and mild strains were mostly concentratedin the region between the left terminal domain and the central conserved region : this region has therefore become known as the pathogenicity domain. Analysis of chimaeras, constructed by linking domains from different viroids with varying severity of symptoms, on indicator plants has shown that sequences of additional viroid domains, particularly those of the left terminal domain are involved in determining symptom severity. Further work has shown that the correlation between structural elements and severity of symptoms is still more complex and also involves the conserved central region. RNA is the only known biological macromolecule that can function both as genotype and phenotype, therefore allowing  Darwinian evolution to occur at the molecular level in the absence of DNA or proteins. Viroid-resistant plants have been constructed by the introduction of genes into plant genomes, the products of which cleave viroid replication intermediates.
Simplified NCBI taxonomy
• defective ssRNA
• plant satellite ssRNAs : a linear or circular 194-1500 nt ssRNA molecule whose replication depends on a Plantae helper virus.
• virusoid : a satellite viroid-like ssRNA (220-338 nt) with ribozyme activity, not encoding, encapsidated in a virus shell that also contains the helper virus (about 4500 nt) ssRNA genome. Probably they arose from a mixed infection by a virus and a defective viroid in a Plantae cell.
• satellite virus : a satellite (about 1000 nt) ssRNA whose genome encodes for its own protein coat but that depends for its reproduction on an urelated helper virus
• defective interfering (DI) ssRNA : ssRNA molecules resulting from wide deletions in a ssRNA virus genome. They usually shut down the replication of the wild-type virus (e.g.: the von Magnus effect in Influenzavirus infections)
• prions (for proteinaceous infectious protein; Griffith, 1967 => Prusiner, 1984^ref) : a mutated version of a normal cellular protein, capable of switching the secondary structure of the normal protein into that of the mutated version, acting as a negative dominant mutant (just like TP53, Sup35p (=> [PSI+] phenotype) and Ure2p (=> [URE3] phenotype) mutants)^ref. The propagation may be exponential or linear (growth at the ending of a linear aggregate), leading to formation of amyloid plaques termed scrapie-associated fibrils (SAF) : they are stainable by PAS reaction and become birifrangent after staining with Congo red. To reconcile the existence of strains with the 'protein-only' hypothesis of prion transmission, it has been proposed that a single protein can misfold into multiple distinct infectious forms, one for each different strain. Recombinant mouse prion protein (recMoPrP) produced in Escherichia coli was polymerized into amyloid fibrils that represent a subset of b sheet–rich structures by placing the amyloid-forming fragment PrP(89–231) in a shaking device and tracking the process with thioflavin T, a dye that fluoresces in the presence of amyloid. After 40 hours, amyloid was detected. To accelerate the reaction time, the team then took some of these amyloid fibrils and used them as a "seed" for the production of nascent amyloid fibrils in a 2nd shaking tube. This time amyloid fibrils were detected after 10 hours. These were called "seeded" amyloid fibrils. Fibrils consisting of recMoPrP(89–230) were inoculated intracerebrally into transgenic (Tg) mice expressing MoPrP(89–231). The mice developed neurologic dysfunction between 380 and 660 days after inoculation. Brain extracts showed protease-resistant PrP by Western blotting; these extracts transmitted disease to wild-type FVB mice and Tg mice overexpressing PrP, with incubation times of 150 and 90 days, respectively. Neuropathological findings suggest that a novel prion strain was created. In each case, on the primary passage, the scientists detected 4 hallmarks of prion disease -- (1) clinical signs of neurologic dysfunction (ataxia, or loss of motor coordination, and rigidity), (2) neuropathologic changes in the brain (vacuolation, deposits of PrP^Sc and astrocytic gliosis), (3) resistance of PrP^Sc to breakdown by protease and (4) -- most importantly -- serial transmission of prion infectivity to wild-type and other transgenic mice^ref. Preliminary evidence suggests that other b-sheet-rich structures may also harbor prion infectivity. These results provide compelling evidence that prions are infectious proteins (see Koch's postulates), but some say it was still unclear whether the prion was causing the infection or just exposing an underlying infectious process : the prion strain that turned up in the experiment looked like a mouse prion frequently used in Dr. Prusiner's laboratory and that meant that something else might have caused the infection. The data look like contamination, possibly stemming from inadequately washed instruments. Prions are thought to be composed exclusively of the protease-resistant prion protein (PrP^res) that replicates in the body by inducing the misfolding of the cellular prion protein (PrP^C). Although compelling evidence supports this hypothesis, generation of infectious prion particles in vitro has not been convincingly demonstrated. PrP^C --> PrP^res conversion can be mimicked in vitro by protein misfolding cyclic amplification (PMCA), resulting in indefinite amplification of PrP^res of a small number of prions taken from infected hamsters and placed in test tubes containing healthy brain proteins. When the healthy proteins had been largely transformed into prions, the samples were diluted over and over again and the process repeated, until the only remaining prions were those that had been generated in the test tubes The in vitro-generated forms of PrP^res share similar biochemical and structural properties with PrP^res derived from sick brains. Inoculation of wild-type hamsters with in vitro-produced PrP^res led to a scrapie disease identical to the illness produced by brain infectious material : hamsters began showing TSE symptoms within 4 months and, on average, died < 6 months after inoculation. These findings demonstrate that prions can be generated in vitro and provide strong evidence in support of the protein-only hypothesis of prion transmission^ref.
• yeast prions (Saccharomyces cerevisiae)
•  [b] / PrB is a serine protease that is derived from an inactive zymogen activated by cleavage with PrA and PrB itself (acting as a prion !)
• [PSI+] is a conserved, protein-based genetic element that is formed by a change in the conformation and function of the translation termination factor Sup35p, and is transmitted from mother to progeny. [PSI+] is an epigenetic modifier of the fidelity of translation termination that provides the means to uncover hidden genetic variation and produce new heritable phenotypes. Moreover, in each of the 7 genetic backgrounds tested, the constellation of phenotypes produced was unique. The epigenetic and metastable nature of [PSI+] inheritance allows yeast cells to exploit pre-existing genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI+] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits^ref. Conversion of Sup35p to its prion form produces a defective termination phase, generating [PSI +] strains that can be readily screened by cell color and protein analysis. Infection of yeast with different infectious prion amyloids—composed of a fragment of the Sup35p protein (Sup-NM)—generated at different temperatures leads to distinct [PSI +], stably propagating conformations, inferring that Sup-NM conformation determined prion strain variation^ref. Curing cells of [PSI+] alters their survival in different growth conditions and produces a spectrum of phenotypes in different genetic backgrounds. All traits tested involved [PSI+]-mediated read-through of nonsense codons. Notably, the phenotypes analysed were genetically complex, and genetic re-assortment frequently converted [PSI+]-dependent phenotypes to stable traits that persisted in the absence of [PSI+]. Thus, [PSI+] provides a temporary survival advantage under diverse conditions, increasing the likelihood that new traits will become fixed by subsequent genetic change. As an epigenetic mechanism that globally affects the relationship between genotype and phenotype, [PSI+] expands the conceptual framework for phenotypic plasticity, provides a one-step mechanism for the acquisition of complex traits and affords a route to the genetic assimilation of initially transient epigenetic traits^ref. Infectious fibrous aggregates containing a Sup35 prion-determining amino-terminal fragment labelled with GFP were purified from yeast harbouring distinctive prion strains. Using the infectious aggregates as 'seeds', elongated fibres were generated in vitro from the bacterially expressed labelled prion protein. De novo generation of strain-specific [PSI+] infectivity was demonstrated by introducing sheared fibres into uninfected yeast hosts. The cross-sectional morphology of the elongated fibres generated in vitro was indistinguishable from that of the short yeast seeds, as visualized by electron microscopy. Electron diffraction of the long fibres showed the 4.7 Å spacing characteristic of the cross-b structure of amyloids. The fact that the amyloid fibres nucleated in vitro propagate the strain-specific infectivity of the yeast seeds implies that the heritable information of distinct prion strains must be encoded by different, self-propagating cross-beta folding patterns of the same prion protein^ref. Although there are very good parallels between prion behavior in yeast and animal cells, some important differences, for example that yeast prions require Hsp104, may exist. Analysis of 3 distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids^ref
• PrP^Sc


Misshapen prion proteins were obtained from hamsters, broke them up using a detergent, and sorted them according to size. They then injected strings of known length into other hamsters. One group of 4 hamsters received protein chains that were 21 prions long, and these animals all succumbed to the disease after about 90 days. Hamsters receiving a solution with protein chains more than 300 prions long died after 90 days only if the solution of prions was 70 times more concentrated, making these longer chains some 70 times less dangerous. Hamsters given 6-unit chains stayed healthy for an additional month, and the concentration needed to cause illness indicated that such short clusters are some 600 times less infectious than the 21-prion chains. Very few of the animals receiving chains of 5 or fewer prions seemed to get sick at all, living a normal hamster lifespan of 2 years. With respect to PrP content, infectivity and converting activity peaked markedly in 17-27-nm (300-600 kDa) particles, whereas these activities were substantially lower in large fibrils and virtually absent in oligomers of <= 5 PrP molecules. These results suggest that non-fibrillar particles, with masses equivalent to 14-28 PrP molecules, are the most efficient initiators of TSE disease^ref. In a variety of systems, proteins have been linked to processes historically limited to nucleic acids, such as infectivity and inheritance. Prions lack sequence homology but are collectively defined by their capacity to adopt multiple physical and therefore functional statesin vivo. Newly synthesized prion protein generally adopts the form already present in the cell, and this in vivo folding bias directs the near faithful transmission of the corresponding phenotypic state. Switches between the prion and non-prion phenotypes can occur in vivo; however, the fate of existing protein during these transitions and its effects on the emergence of new traits remain major unanswered questions. The changes in protein-state that induce phenotypic switching for the yeast prion Sup35/[PSI+] : the prion form does not need to be specified by an alternate misfolding pathway initiated during Sup35 synthesis but instead can be accessed by mature protein. This remodelling of protein from one stable form to another is accompanied by the loss of Sup35 activity, evoking a rapid change in cellular phenotype within a single cell cycle^ref. Amyloid or amyloid-like fibrils are elongated, insoluble protein aggregates, formed in vivo in association with neurodegenerative diseases or in vitro from soluble native proteins, respectively. The underlying structure of the fibrillar or 'cross-' state has presented long-standing, fundamental puzzles of protein structure. These include whether fibril-forming proteins have 2 structurally distinct stable states, native and fibrillar, and whether all or only part of the native protein refolds as it converts to the fibrillar state. A designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity. In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model in which a cross-b spine is decorated with 3D domain-swapped functional units, retaining native-like structure^ref.
Neurons and neuroblastoma cells infected with prions have reduced proteasomal activity against model substrates. The 20S proteasome contains within its central chamber six proteolytic sites: two prefer to cleave proteins immediately after hydrophobic amino acids; 2, after basic residues; and 2, after acidic ones^{ref1, ref2}. Using peptide substrates specific for each site, Kristiansen et al. showed that all 3 activities were reduced in prion-infected neurons. Furthermore, they showed in infected neurons in culture that some PrP^Sc was present in the cytosol and that these cells had a decreased capacity to degrade a transfected fluorescent protein that is a substrate of the ubiquitin–proteasome pathway. Moreover, "curing" these cells of prions restored normal rates of degradation. By infecting transgenic mice expressing this reporter protein with prions, Kristiansen et al. showed that PrP^Sc induced similar defects in the brain's capacity to degrade this fluorescent protein. In infected neurons of these mice, ubiquitinated deposits accumulated in the cytosol, reminiscent of those found in various adult-onset neurodegenerative diseases, and in cells treated with pharmacologic inhibitors of the proteasome.3 Although the decreased degradative capacity is consistent with a loss of proteasomal activity, it could also be due to defects in ubiquitination or other steps in the pathway. However, the authors obtained further supporting data using purified 26S proteasomes and PrP^Sc isolated from infected mouse brain, recombinant mouse PrP folded into an a-helical structure resembling the native PrPC, or a predominantly beta-sheet species that mimics the properties of PrP^Scc. A clear reduction in the activity of the purified proteasomes (as well as those in neurons) occurred only with the aggregated forms of PrPSc. This inhibition was shown to result from a stoichiometric association of the oligomeric species with the proteasomes. Although it is now clear that cytosolic PrP^Sc can interfere with the proteasome's peptidase activities and that infected neurons are defective in protein degradation, there is no proof that this is the only toxic mechanism, or even the critical one leading to neuronal loss in prion diseases. Loss of proteasomal function affects many critical cellular processes and can induce apoptosis. In addition to serving as a quality-control system, this pathway is critical in regulating cell signaling networks and metabolic pathways and achieves exquisite selectivity because of the presence in humans of hundreds of different ubiquitin ligases that function in the removal of different proteins. Not surprisingly, in cellular models of all neurodegenerative diseases, treatment with inhibitors of the proteasome promotes pathogenesis and neuronal death. The proteolytic sites of the 20S proteasome are the target of the anticancer drug bortezomib (Velcade), which is widely used in the treatment of multiple myeloma — a cancer that seems to be particularly dependent on proteasomes for survival and for the degradation of misfolded immunoglobulins. An important feature of this drug's selectivity is that it does not enter the central nervous system, where it would probably accelerate the onset of neurodegenerative disease. It also remains unclear exactly how small aggregates of the PrP^Sc inhibit the cleavage of peptides by the proteasome. The "decision" of which proteins are translocated into the particle and degraded depends on the ring of ATPases in the 19S regulatory component, which is probably the site where PrPSc oligomers bind. Normally, cell proteins that are destined for degradation bind to and are unfolded by these ATPases before being translocated into the 20S particle. However, the exceptional stability of PrP^Sc makes it unlikely that these structures can be disassembled similarly, and the microaggregates of PrP^Sc are probably too large to traverse the ATPase ring and the narrower, gated pore into the 20S particle. Thus, they may behave like a sticky cork that interferes with the entry of other substrates into the 20S particle. Such a simple mechanism is now amenable to testing^ref.

• ... capability of transfer
• conjugative plasmids : a plasmid that is transferred from one bacterial cell to another during conjugation; they contain sex factor, i.e. :
rep genes for replication protein
inc genes for incompatibility (repressor)
tra operon (13 genes for transfer : pilin, ...) : their expression  may be prevented, expecially in R plasmids, by...
fin genes
The plasmid containg cell is indicated as F⁺ (male) while the plasmid-less cell as F^- (female).
Once every 10⁵ times, the plasmid may become integrated in the chromosome as an episome (high frequency (10^-4) of recombination cell (Hfr)) : when the episome become excised  (F' cell) it may transduce chromosome genes (see F-duction).
• unconjugative plasmids
• ... function
• fertility (F) plasmid, factor or element / sex factor : a conjugative plasmid found in F⁺ (male) bacterial cells that leads with high frequency to its transfer and much less often to transfer of the bacterial chromosome. A cell possessing the F plasmid (F⁺, male) can form a conjugation bridge (F pilus) to a cell lacking the F plasmid (F^-, female), through which genetic material may pass from one cell to another. It codes for pilin
• F' plasmid : a hybrid F plasmid that contains also a segment of the host chromosome
• resistance (R) plasmids or factor : a conjugative factor in bacterial cells that promotes resistance to agents such as antibiotics, metal ions, ultraviolet radiation, and bacteriophage. R plasmids are large with 2 functionally distinct parts:
• conjugative plasmids made up of ...
• resistance transfer factor (RTF) : the portion of an R plasmid in a bacterial cell that contains the genes for conjugation (pilin) and replication
• R determinant containing the genes for resistance (R genes), coding for drug resistance proteins. Their control may be stringent (e.g. in E.coli) or relaxing (e.g. in Proteus). Some of them contain fin genes that inhibit the transfer of F plasmid (fi⁺) (those which don't contain fin are indicated as fi^-).
• R1 (streptomycin, sulfonamides, chloramphenicol, kanamycin and ampicillin resistance)
• R6 (streptomycin, sulfonamides, chloramphenicol, kanamycin and tetracyclines resistance)
• R100 (streptomycin, sulfonamides, chloramphenicol and tetracyclinesresistance)
• oligomeric plasmid : a plasmid that contains repeating segments of a determinant, formed by recombination between strands during replication and resulting in gene amplification.
• bacteriocin plasmids : they may be conjugative (e.g. : B, I and V in E.coli) or unconjugative (e.g. : E1, E2, E3 and K in E.coli)
• virulence plasmids
• CFA (colony and adhesion factor in E.coli)
• TS (thermostable toxin in E.coli)
• TL (thermolabile toxin in E.coli)
• HA (haemolysin in E.coli)
• coagulase, haemolysin, fibrinolysin and enterotoxin in Staphylococcus aureus
• metabolic plasmids (in Staphylococcus aureus)
• tumor-inducing plasmids : Ti plasmid in Agrobacterium tumefaciens
• cryptic plasmids
• artificial plasmids
• cosmids
• phasmids

mobile genetic elements (MGE) : a sequence of DNA that moves within their host's genome from one position to another integrating itself by transpositional recombination.

• with no RNA intermediate (in both Prokarya and Eukarya but rare !) : the mobile elements codes for the integrase translocase / transposase.
• non replicative or simple transposons (2 DSBs in the donor site + 1 DSB in the recipient site)
• insertion sequence (IS) element (usually 700-1,800 bp, but IS101 is just 200 bp while others reach 5,700 bp; containing direct STR). E.g. IS1, IS2, IS10R in E.coli.
• class I elements / compound transposons / transposable element(TE) (containing at least another gene flanked by direct or inverted LTRs = ISs => the ends of the transposon are capable of transpose separately). E.g. Tn5, Tn9, Tn10, Tn903, Tn1681, Tn2571, P, Ac-DS. The maternal transcriptome in mouse eggs and very early cleavage embryos contains an unusually high level of TEs that act as promoters and first exons for numerous RNA molecules, revealing a role as stage-specific alternative promoters for a number of host genes, governing the transition from oocyte to embryo
• replicative transposons (coding for resolvase).
• class II elements / complex transposons (coding for another protein; flanked by IR => must always trasponse as a unit) : e.g. Tn1, Tn3, Tn4, Tn7, Tn501 and Tn551 in E.coli.
• class III elements (miscellanea : bacteriophages, coding for a B gene). E.g. Mu in E.coli.
• with RNA intermediate (particular retronuons))
• retroelements (coding for RT: viral family)
• endogenous retroviruses and retrovirus-like elements (RTE / RTLV). Some inverted LTRs are contained in the direct LTRs (one of which acts as a promoter). 5000-9000 bp long.
• with polyA in 3'. E.g. 412 in Drosophila, IAP in Mus.
• without polyA in 3'. E.g. Ty in yeasts, copia in Drosophila.
• there are 98,000 human endogenous retroviral (HERV) sequences in the human genome, most inactivated by mutation, most likely the result of germline reinfection rather than retrotransposition or complementation^ref. In the past 30 million years there have been very many of these elements, not fixed but just present in a small number of individuals : these would have been infecting and moving about, possibly between individuals, but certainly within individuals, from somatic cells back into germline cells. Periodically, one would pick up a mutation that would stop it from moving about  : once dead, there would be no selection against it from the host. They're just a bit of junk, and they could then drift to fixation by chance. The idea which some people had held was that a lot of these elements, although they come originally from viruses, had actually spread around the genome by mechanisms other than virological ones. Data mining techniques used to reconstruct the ratio of nonsynonymous to synonymous changes (dN/dS), and the acquisition of stop codons, during the evolution of human endogenous retrovirus K (HERV-K) (HML2) family (related to the mouse mammary tumor virus (MMTV) and present also in the genomes of apes and cercopithecoids (Old World monkeys)) showed that all genes have been under continuous purifying selection and dead viruses that have drifted to fixation by chance and represent fallout from a 30-million year-old persistent infection by retroviral elements^ref
• retrotransposons / retroposons (with polyA in 3' but with neither env gene nor LTR => external promoter). E.g. : LINEs (5000-8000 bp) in Homo and Mus.
• LINE-1 (L1) are very ancient, dating back about 100 million years, and distinctive families containing many thousands of members are found in plants, fungi, invertebrates, and vertebrates. Because of their ability to amplify themselves, they constitute about 30% of genomic DNA in mammals, and their mobility within the genome coupled with their disruptive effects have affected the evolution, structure, and function of mammalian genomes. L1 expression is elevated in certain cancers, reflecting a lack of control over both expression regulation and genetic damage. Use of multiple canonical and noncanonical polyadenylation (polyA) sites in the A-rich region of L1 sequences in a cell- and tissue-specific fashion limits the spread and consequent genetic damage of retrotransposons, revealing both a transposon survival mechanism and a previously unrecognized method of mRNA regulation by means of conventional 3' end formation in mammalian cells. Revealing the mechanisms for neuronal somatic diversification remains a central challenge for understanding individual differences in brain organization and function. An engineered human L1 element can retrotranspose in neuronal precursor cells (NPCs) derived from rat hippocampus neural stem cells. The resulting retrotransposition events can alter the expression of neuronal genes, which, in turn, can influence neuronal cell fate in vitro : if an L1 lands in the middle of an NPC gene associated with neural function, it could affect which type of neuron the NPC eventually becomes^ref. Retrotransposition of a human L1 in transgenic mice results in neuronal somatic mosaicism. The molecular mechanism of action is probably mediated through Sox2, because a decrease in Sox2 expression during the early stages of neuronal differentiation is correlated with increases in both L1 transcription and retrotransposition. Neuronal genomes might not be static, but some might be mosaic because of de novo L1 retrotransposition events.
• a disproportionate number of genes involved in sex determination and function have abandoned the X chromosome, ignored the Y, and relocated to autosomes to function in a male sex–biased fashion in fruit flies^ref, mice (105) and humans (94). The X chromosome generates an almost 300% excess of retrogenes compared with autosomes in humans, and 305% in the mouse. Rapidly evolving genes tend to show male sex bias in their expression. There is more evidence indicating that genes involved with rapid evolution of the genome are very often associated with male-specific dimorphic traits. The reason for the abandonment lies in
• the X chromosome being present for 2/3 of the time in female cells compared with only half the time for autosomes, resulting in “feminization” of the X-linked genes. Inactivation of one of the X chromosomes during male germ cell meiosis results in X-linked male-specific gene inhibition. Genes, therefore, migrate from the X into autosomes to enable them to function to the benefit of the male.
• if a mutation affects a gene controlling some aspect of male reproduction such as fertility or behavior, that gene will be retained because it is under strong selection pressure, and multiple copies will be favored. Stronger selection on male sexual traits also applies to the differential movement of genes from the X to autosomes, as these are mostly sex-related genes and they are more likely to be retained by natural selection than genes moving in the opposite direction
• conversely, genes having a non–sex determining role relocated to the X chromosome : only 14% of these show female expression, compared with 71% in autosomes. This non–sex biased expression may be a result of repression of expression of genes that would have a deleterious effect on females.
• retrosequences (non coding for RT: non viral family, RT-dependent)
• retropseudogenes / processed pseudogenes (polyA in 3')
• low copy number (transcripted by RNA polymerase II)
• high copy number (transcripted by RNA polymerase III). E.g. : the promoter of RNA 7SL and SINEs in Homo (< 500 bp : Alu), B1 in Mus.

• American Society for Virology
• Subcellular life forms by John Baez
• Subviral RNA database by Martin Pelchat
• Virus Oligonucleotide (VirOligo) Compilation Lab
• Viral Bioinformatics Resource Center : Virus Orthologous Clusters (VOCs) at University of Victoria, Canada

• Knipe, David M.; Howley, Peter M. : Fields, Virology. 4^th ed..
• Flint; Enqvist; Krug; Racaniello; Skalka : Virology: Molecular Biology, Pathogenesis and Control. ASM Press, Washington
• Specter; Hodinka; Young : Clinical Virology Manual. ASM Press, Washington
• Retroviruses by Coffin, John M.; Hughes, Stephen H.; Varmus, Harold E., Plainview (NY): Cold Spring Harbor Laboratory Press; © 1997

Copyright © 2001-2005 Daniele Focosi. All rights reserved  |  Terms of use  | Legal notices
About this site  |  Site map  |  Acknowledgements | Open forum  |  Tell a friend about this site  |  Current link partners
 Abbreviations and acronyms  |  Medical terminology  |  Add a link  |  Translate this site into your favourite language  |  Softwares

---