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PubMed1994

Development of transforming function during transduction of proto-ras into Harvey sarcoma virus.

Oncogenic retroviruses are generated by transduction of the coding region of a protooncogene and acquire genetic changes during subsequent replication. Critical genetic events which occurred during and after transduction of rat proto-ras-1Ha into Harvey sarcoma virus were identified by evaluating the transforming activity of plausible synthetic progenitor proviruses encompassing the complete proto-ras genomic region with or without various 5' deletions. All progenitor proviruses induced phenotypic transformation of mouse NIH 3T3 cells, although with a 5- to 10-fold lower frequency than Harvey sarcoma provirus. Although no tumor formation was observed in vivo after inoculation in the absence of helper murine retrovirus, both wild-type and progenitor viruses inoculated in the presence of helper virus induced tumors in newborn BALB/c mice. No critical alterations of the p21ras coding region and no deletion of 5' genomic elements were detected in a progenitor virus encompassing the complete proto-ras genomic region that had been isolated from tumors. However, one progenitor virus that included all proto-ras exons induced tumors with a decreased latency. This virus contained a mutation in codon 12 (glycine to valine), which had apparently been selected during tumorigenesis in vivo. During the genesis of Harvey sarcoma virus, critical steps conferring transforming function are therefore transduction of coding proto-ras exons and enhancement of their transforming function by specific amino acid changes in p21ras.

3T3 Cells↗

PubMed1993

Relationship between G + C in silent sites of codons and amino acid composition of human proteins.

We have investigated the relationship between the G + C content of silent (synonymous) sites in codons and the amino acid composition of encoded proteins for approximately 1,600 human genes. There are positive correlations between silent site G + C and the proportions of codons for Arg, Pro, Ala, Trp, His, Gln, and Leu and negative ones for Tyr, Phe, Asn, Ile, Lys, Asp, Thr, and Glu. The median proteins coded by groups of genes that differ in silent-site G + C content also differ in amino acid composition, as do some proteins coded by homologous genes. The pattern of compositional change can be largely explained by directional mutation pressure, the genetic code, and differences in the frequencies of accepted amino acid substitutions; the shifts in protein composition are likely to be selectively neutral.

Amino Acids↗

PubMed2001

Molecular evolution: Please release me, genetic code.

The genetic code is no longer universal, even in non-mitochondrial genomes. Recent studies have implicated the eukaryotic release factor eRF1 in mediating coding changes that are not as inconceivable as once thought. Specific residues in eRF1 proteins can be correlated with specific code changes in a wide variety of taxa.

Animals↗

PubMed2005

Molecular genetics of adult-type hypolactasia.

Adult-type hypolactasia (lactase non-persistence; primary lactose malabsorption) is characterized by the down-regulation of the lactase enzyme activity in the intestinal wall after weaning. The down-regulation is genetically determined and a mutation has occurred that has made part of mankind tolerate milk (lactase persistence). A DNA-variant, single nucleotide polymorphism C/T-13910 located 13 910 base pairs (bp) upstream of the lactase gene (LCT) at chromosome 2q21-22 has been shown to associate with the lactase persistence/non-persistence trait both in family and case-control studies. The C/T-13910 variant is located in a non-coding region in the genome in intron 13 of the minichromosome maintenance type 6 gene (MCM6). Significant correlation between the C/T-13910-variant and lactase activity in the intestinal biopsy specimens has been demonstrated. Molecular epidemiological studies on the prevalence of the C/C-13910 genotype associated with low lactase activity are in agreement with the prevalence figures for adult type hypolactasia in>70 diverse ethnic groups studied. Recent functional studies have suggested that this variant has an enhancer effect over the lactase gene. Based on the biochemical, functional, genetic and molecular epidemiological studies of the C/T-13910 variant, genetic testing for adult type hypolactasia has been introduced into clinical practice in Finland. Identification of the genetic change has highlighted the role of non-coding variants in the regulation of common genes and created new tools to study the mechanism of lactase enzyme activation.

Adult↗

PubMed1992

Evolution of multilocus genetic structure in an experimental barley population.

Data from 311 selfed families isolated from four generations (F8, F13, F23, F45) of an experimental barley population were analyzed to determine patterns of change in character expression for seven quantitative traits, and in single-locus allelic frequencies, and multilocus genetic structure, for 16 Mendelian loci that code for discretely recognizable variants. The analyses showed that large changes in single-locus allelic frequencies and major reorganizations in multilocus genetic structure occurred in each of the generation-to-generation transitions examined. Although associations among a few traits persisted over generations, dynamic dissociations and reassociations occurred among several traits in each generation-transition period. Overall, the restructuring that occurred was characterized by gradual decreases in the number of clusters of associated traits and increases in the number of traits within each cluster. The observed changes in single-locus frequencies and in multilocus genetic structure were attributed to interplay among various evolutionary factors among which natural selection acting in a temporally heterogeneous environment was the guiding force.

Alleles↗

PubMed1997

Genome organization, natural genetic engineering and adaptive mutation.

Bacterial evolution is considered in the light of molecular discoveries about genome organization, biochemical mechanisms of genetic change, and cellular control networks. Prokaryotic genetic determinants are organized as modular composites of coding sequences and protein-factor binding sites joined together during evolution. Studies of genetic change have revealed the existence of biochemical functions capable of restructuring the bacterial genome at various levels and joining together different sequence elements. These natural genetic engineering systems can be subject to regulation by signal transduction networks conveying information about the extracellular and intracellular environments. Mu-mediated araB-lacZ coding sequence fusions provide one example of adaptive mutation (increased formation of useful mutations under selection) and illustrate how physiological regulation can modulate the activity of a natural genetic engineering system under specific conditions.

Bacteria↗

PubMed2002

Evolution of amino acid frequencies in proteins over deep time: inferred order of introduction of amino acids into the genetic code.

To understand more fully how amino acid composition of proteins has changed over the course of evolution, a method has been developed for estimating the composition of proteins in an ancestral genome. Estimates are based upon the composition of conserved residues in descendant sequences and empirical knowledge of the relative probability of conservation of various amino acids. Simulations are used to model and correct for errors in the estimates. The method was used to infer the amino acid composition of a large protein set in the Last Universal Ancestor (LUA) of all extant species. Relative to the modern protein set, LUA proteins were found to be generally richer in those amino acids that are believed to have been most abundant in the prebiotic environment and poorer in those amino acids that are believed to have been unavailable or scarce. It is proposed that the inferred amino acid composition of proteins in the LUA probably reflects historical events in the establishment of the genetic code.

Amino Acid Sequence↗

PubMed2006

A simplified explanation for the frameshift mutation that created a novel C-terminal motif in the APETALA3 gene lineage.

BACKGROUND: The evolution of type II MADS box genes has been extensively studied in angiosperms. One of the best-understood subfamilies is that of the Arabidopsis gene APETALA3 (AP3). Previous work has demonstrated that the ancestral paleoAP3 lineage was duplicated at some point within the basal eudicots to give rise to the paralogous TM6 and euAP3 lineages. This event was followed in euAP3 orthologs by the replacement of the C-terminal paleoAP3 motif with the derived euAP3 motif. It has been suggested that the new motif was created by an eight-nucleotide insertion that produced a translational frameshift. RESULTS: The addition of 25 eudicot AP3 homologs to the existing dataset has allowed us to clarify the process by which the euAP3 motif evolved. Phylogenetic analysis indicates that the euAP3/TM6 duplication maps very close to the base of the core eudicots, associated with the families Trochodendraceae and Buxaceae. We demonstrate that although the transformation of paleoAP3 into euAP3 was due to a frameshift mutation, this was the result of a single nucleotide deletion. The use of ancestral character state reconstructions has allowed us to demonstrate that the frameshift was accompanied by few other nucleotide changes. We further confirm that the sequence is evolving as coding region. CONCLUSION: This study demonstrates that the simplest of genetic changes can result in the remodeling of protein sequence to produce a kind of molecular 'hopeful monster.' Moreover, such a novel protein motif can become conserved almost immediately on the basis of what appears to be a rapidly generated new function. Given that the existing data on the function of such C-terminal motifs are somewhat disparate and contradictory, we have sought to synthesize previous findings within the context of the current analysis and thereby highlight specific hypotheses that require further investigation before the significance of the euAP3 frameshift event can be fully understood.

Amino Acid Sequence↗

PubMedDate not supplied

Lost in translation: implications of HIV-1 codon usage for immune escape and drug resistance.

Synonymous nucleotide substitutions in protein-coding sequences are often regarded as evolutionarily neutral and not subject to selective pressure. However, synonymous codons can sometimes lead to different patterns of amino acid substitution by single nucleotide changes. Based on the deconstruction of the standard genetic code, we propose the term 'quasi-synonymous' to describe codons that specify the same amino acid, but lie on different mutational pathways, and we show that in at least one rapidly evolving organism, HIV-1, quasi-synonymy plays a role in its evolution. We present concrete examples that demonstrate the relevance of codon usage in the development of antiretroviral-drug resistance. In the case of the host immune response, the data indicates that viral evasion is achieved through use of codons that lie on the direct path to escape mutants, and equally, permit rapid reversion to wild-type in the absence of these selective pressures. Quasi-synonymy conditions HIV-1 and, potentially, other rapidly evolving organisms in their exploration of the mutational space.

Anti-HIV Agents↗

PubMed2005

Genetic recombination at different points in the Npro-coding region of bovine viral diarrhea viruses and the potentials to change their antigenicities and pathogenicities.

Cytopathogenic (cp) bovine viral diarrhea virus (BVDV) strain KS86-1 cp was isolated from a cow persistently infected with non-cytopathogenic (ncp) BVDV strain KS86-ncp after development of mucosal disease by superinfection with cp BVDV strain Nose. cp BVDV strains 799cp and 839cp were also isolated from independent cattle that developed mucosal disease by superinfection with cp BVDV KS86-1cp. In the present study, genetic analysis revealed that the genes of cp BVDV strains 799cp and 839cp were chimeras between the genes of the persisting ncp BVDVs and that of superinfecting KS86-1cp. The genetic recombination that generates 799cp occurred between the identical points in the N(pro) gene region, whereas genetic recombination that generates 839cp occurred between different points in the N(pro) gene region. Both 799cp and 839cp were inherited Jiv gene of KS86-1cp strain and envelope protein genes of the persisting viruses. In addition, neutralization test disclosed that antigenicities of 799cp, 839cp, and KS86-1cp were also similar to each persisting virus. These findings indicate that exogenous cp BVDV containing insertion of Jiv gene in the 5 terminal region can induce genetic recombination with the original ncp BVDV at different points in the N(pro) gene region, and those viruses have high potential to change those antigenicities and pathogenicities by RNA recombination.

Animals↗

PubMed2005

Inhibited cell growth and protein functional changes from an editing-defective tRNA synthetase.

The genetic code is established in aminoacylation reactions catalyzed by aminoacyl-tRNA synthetases. Many aminoacyl-tRNA synthetases require an additional domain for editing, to correct errors made by the catalytic domain. A nonfunctional editing domain results in an ambiguous genetic code, where a single codon is not translated as a specific amino acid but rather as a statistical distribution of amino acids. Here, wide-ranging consequences of genetic code ambiguity in Escherichia coli were investigated with an editing-defective isoleucyl-tRNA synthetase. Ambiguity retarded cell growth at most temperatures in rich and minimal media. These growth rate differences were seen regardless of the carbon source. Inclusion of an amino acid analogue that is misactivated (and not cleared) diminished growth rate by up to 100-fold relative to an isogenic strain with normal editing function. Experiments with target-specific antibiotics for ribosomes, DNA replication, and cell wall biosynthesis, in conjunction with measurements of mutation frequencies, were consistent with global changes in protein function caused by errors of translation and not editing-induced mutational errors. Thus, a single defective editing domain caused translationally generated global effects on protein functions that, in turn, provide powerful selective pressures for maintenance of editing by aminoacyl-tRNA synthetases.

Amino Acyl-tRNA Synthetases↗

PubMed1994

Compositional frequencies of amino acids in the proteins and the genetic code.

It was found that amino acid compositional frequencies in proteins demonstrate a pseudosymmetry pattern in respect of the genetic code arrangement as we discussed in earlier papers (Siemion and Stefanowicz, 1992a, BioSystems, 27, 77-84; Siemion and Stefanowicz, 1992b, Bull. Pol. Acad. Sci., Chem. 40, 11-20; Siemion, 1994, BioSystems, 32, 25-35). The type of pseudosymmetry observed is very similar to that found in the changes of Chou-Fasman P alpha conformational parameters within the genetic code arrangement. It is also shown that the compositional frequencies of amino acids belonging to the 'G' and 'C' families of codons (excluding UCN Ser codons) change linearly with the sequence of the one-step mutations expected by our arrangement of proper codons.

Amino Acid Sequence↗

PubMed2000

Bovine viral diarrhea virus induced apoptosis correlates with increased intracellular viral RNA accumulation.

Non-cytopathic (NCP) and cytopathic (CP) parent-daughter pairs are often isolated from cattle with bovine viral diarrhea virus (BVDV) induced mucosal disease. Alignment of these pair genomes revealed that genetic changes in CP BVDV involve the NS2-3 coding region and correlate with expression of NS3. However, additional mutations are present elsewhere in the genomes of these natural pairs, precluding unambiguous mapping of this function to the NS2-3 region. To evaluate this phenomenon in identical genetic backgrounds, we have constructed an NCP isogenic pair of the NADL by deletion of the cIns from NS2 region. The levels of viral protein synthesis in infected cells revealed no marked difference between the CP and the isogenic NCP BVDV mutant. In contrast, RNA accumulation in cells infected with CP virus was up to 25 times higher than that in cells infected with NCP BVDV. No significant difference in growth kinetics and viral yields were observed between the CP BVDV and the isogenic NCP pair. Analyses of additional NCP/CP parent-daughter field BVDV isolates revealed a similar pattern of macromolecular synthesis, suggesting the generality of this phenomenon. These results implicate increased levels of RNA accumulation in CP BVDV infected cells, along with the production of NS3 as potential contributors to viral cytopathogenicity.

Animals↗

PubMed2005

Nucleotide and amino acid changes in West Nile virus strains exhibiting renal tropism in hamsters.

Recent studies have shown that West Nile virus (WNV) can induce an asymptomatic persistent infection in the kidneys of experimentally infected hamsters. The chronically infected rodents shed virus in their urine for up to 8 months, despite the disappearance of viremia and the development of high levels of neutralizing antibodies. WNV, like most members of the Japanese encephalitis virus complex (Flavivirus; Flaviviridae), is assumed to be mainly neurotropic; little is known about the genetic basis for its renal tropism. In this study, complete sequence analyses were done to compare four WNV isolates from the urines of persistently infected hamsters with the wild-type parent virus (NY 385-99). Nucleotide changes, ranging from 0.05% to 0.09%, were identified in all of the WNV isolates from urine; most of the changes were in coding regions, causing amino acid substitutions in the E, NS1, NS2B, and NS5 proteins. The genetic changes associated with renal tropism were also accompanied by a loss of virulence for hamsters and a change in plaque morphology.

Amino Acid Sequence↗

PubMed2026

Codon bias variation in Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus causes a multiplicity of human diseases acquired in community and healthcare settings alike around the globe. While most studies focus on coding changes to assess genome evolution and study genetic adaptation, interrogation of silent mutations in the form of synonymous codon usage bias is less well-studied. As such, understanding of patterns in codon bias at the gene and genome levels, and how codon bias impacts protein expression in S. aureus remains incomplete. METHODS: The codon bias of 2,565 protein encoding genes from NCTC 8325 was queried against all publicly available closed S. aureus genomes. Using public BioSample data, genomes were sorted by disease state, submitting institution, and collection site. Codon bias was assessed at the level of gene and genome using the codon adaptation index (CAI), calculated using 30S and 50S ribosomal genes. Gene set enrichment analysis was applied to determine associations between physiological functions, CAI gene scores, and interquartile ranges. CAI scores were also compared to an in vitro S. aureus proteomics database to correlate codon bias and protein expression. RESULTS: CAI scores varied within and between isolates at the gene and genome levels. Genes with ribosome-associated functions were most enriched among high CAI genes, and had low CAI interquartile ranges (IQR), suggesting selective pressure to maintain high expression of these genes across all S. aureus isolates. Genome sequences submitted by Aga Khan University Hospital, Nairobi, Kenya were most different from others. For the LAC USA 300 strain, CAI and protein expression were moderately positively correlated (cor = 0.534, p < 2.2e-16). CONCLUSIONS: Codon bias in S. aureus was shown to vary between gene, and to be a source of genetic variation between isolates; CAI and in vitro protein expression were positively correlated.

Staphylococcus aureus↗

PubMed1998

Mitochondrial gene defect in patients with chronic progressive external ophthalmoplegia.

OBJECTIVE: To detect the gene defect of mitochondrial DNA (mtDNA) from skeletal muscles in 2 patients with chronic progressive external ophthalmoplegia (CPEO). METHODS: After extraction of mtDNA, Southern hybridization was performed after restrictive digestion by Pvu II, EcoRI, Hind III, and Sacl. Then, we carried out polymerase chain reaction (PCR) and the enzyme digestion of the PCR products. Finally, mtDNA sequencing was done by automatic DNA sequence analyzer. RESULTS: In case 1, a 5 kb deletion was found by Southern blot analysis and PCR. And dosage analysis showed a heteroplasmic change with 44% mtDNAs deleted. In case 2, PCR plus restriction endonuclease Pvu II digestion demonstrated a mutation which was confirmed by DNA sequencing to be a single base substitution (T-->C) inducing a novel Pvu II site around 10,909 on mtDNA sequence. The laser image analyzer measurement revealed the mutation was almost homologous (99.4% mutant). CONCLUSIONS: In case 1, a 5 kb deletion found in mtDNA is called "common deletion" according to the literature. In case 2, a novel Pvu II site was found. It seems to be a de novo point mutation affecting ND4 in published CPEO research and is first reported in Chinese population. This point mutation does not induce an amino acid(Phe) change according to the published human mitochondrial genetic code as well as the mtDNA sequence. Whether it affects the translation efficiency or transportation of signals between mitochondrial and nuclear genome needs further studies.

Adult↗

PubMedDate not supplied

[Evolution of the genetic code and earliest proteins. Reconstruction from the current sequences].

One would expect that present-day protein sequences have changed many times during their evolution, at every point, so that there is no chance to recognize in the sequences any traces of their ancient organization. It turns out to be not true. Massive analysis of complete genomes of bacteria allows one to derive, according to very specific predictions, distinct features of very early sequences and to outline the history of evolution protein. Modern proteins appear to have evolved from short peptides of mixed sequences of two alphabet types. They were then closed to sequences of optimal size from which modern folds/domains and multidomain proteins were formed. The reconstruction of amino acid and codon chronology is described. A specific idea on the nature and evolutionary significance of gene splicing is suggested. The gene splicing, while obeying the rules of basic structural organization of proteins, offers accessibility to regions of sequence space that could not be reached by mutational changes typical for prokaryotes.

Amino Acid Sequence↗

PubMed2004

Enhanced cytoplasmic sequestration of the nuclear export receptor CRM1 by NS2 mutations developed in the host regulates parvovirus fitness.

To investigate whether a DNA virus can evade passive immunotherapy with a polyclonal antiserum, we analyzed the protection of a neutralizing capsid antiserum against a lethal infection of the immunosuppressive strain of the parvovirus minute virus of mice (MVMi) in 42 immunodeficient mice over a period of 200 days. A few mice were effectively protected, but most developed a delayed lethal leukopenic syndrome during the treatment or weeks afterwards. Unexpectedly, viruses isolated from treated but also from control leukopenic mice showed no amino acid changes throughout the entire capsid coding region, although the viral populations were genetically heterogeneous, mainly in the second exon of the coding sequence of the NS2 nonstructural protein. The NS2 point amino acid changes (T88A, K96E, L103P, and L153 M) that were consistently selected in several mice clustered within the nuclear exportin CRM1 binding domain, in a reading frame that did not alter the overlapping NS1 coding region. These mutations endowed emerging viruses with an increased fitness that was demonstrable by their relative resistance to the neutralizing capsid antiserum in a postentry plaque-forming assay, the rapid overgrowth of a competing wild-type (wt) population in culture, and a larger yield of infectious particles. Mutant NS2 proteins interacted with a higher affinity and sequestered CRM1 in the perinuclear region of the cytoplasm more efficiently than the wt. Correspondingly this phenomenon, as well as the following timely ordered release of the NS1 nonstructural protein and the empty capsid from the nucleus to the cytoplasm, occurred markedly earlier in the infection cycle of the mutant viruses. We hypothesize that the enhanced cytoplasmic sequestration of CRM1 by the NS2 mutations selected in mice may trigger pleiotropic effects leading to an accelerated MVMi life cycle and thus to increased fitness. These results strengthen our earlier report on the rapid evolutionary capacity of this mammalian-specific DNA virus in vivo and indicate that the NS2-CRM1 interaction is an important determinant of parvovirus virulence that can be modulated in nature, hampering the effectiveness of passive antibody therapies in the long term.

Amino Acid Substitution↗