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PubMed2026

Hurdles to horizontal gene transfer: species-specific effects of synonymous variation and plasmid copy number determine antibiotic resistance phenotype.

Could codon composition condition the immediate success and the orientation of horizontal gene transfer? Horizontal gene transfer represents a change in the genome of expression of the transferred gene, and experimental evidence has accumulated indicating that the codon composition of a sequence is an important determinant of its compatibility with the translation machinery of the genome in which it is expressed. This suggests that codon composition influences the phenotype and the fitness conferred by a transferred gene and thus the immediate success of the transfer. To directly test this hypothesis, we characterized the resistance conferred by synonymous variants of a gentamicin resistance gene in three bacterial species: Escherichia coli, Acinetobacter baylyi and Pseudomonas aeruginosa. The strongest determinant of the resistance level conferred was the species in which the resistance gene was transferred, very likely because of important differences in the copy number of the plasmid carrying the gene. Significant differences in resistance were also found between synonymous variants within each of the three species, but more importantly, there was a strong interaction between species and variant: variants conferring high resistance in one species confer low resistance in another. However, the similarity in codon usage between the synonymous variants and the host genome only explained part of the phenotypic differences between variants in one species, P. aeruginosa. Further investigation of alternative explanations did not reveal common universal mechanisms across our three bacterial species. We conclude that codon composition can be a determinant of post-horizontal gene transfer success. However, there are multiple paths leading from synonymous sequence to phenotype, and sensitivity to these different paths is species-specific.

Gene Transfer, Horizontal↗
PubMed1992

Context rules of rightward overlapping reading.

We have investigated the mechanism and sequence context rules governing ribosome frameshifting promoted by aminoacyl-tRNA limitation. In the case of one shifty sequence, frameshifting promoted by lysyl-tRNA limitation occurs at the sequence AAG C and is due to rightward movement of the ribosome so as to read the AGC triplet overlapping the hungry codon from the right. The frequency of this event is unaffected by sequence elements more than three bases to the left (upstream) or two bases to the right (downstream) of the hungry codon, and only slightly affected by the identity of the base two bases to the right. It is strongly affected by the base immediately to the right of the hungry codon, which becomes the wobble base of the shifted triplet; and by the third base of the hungry codon, even though the two synonyms (AAG and AAA) call for the same aminoacyl-tRNA; and by the identity of the base immediately to the left of the hungry codon. The latter result suggests that the aminoacyl-tRNA in the P site affects the maintenance of reading frame at the adjacent A site of the ribosome. However, the DNA sequence makes it seem unlikely that the P-site tRNA shifts to the right in concert with the A-site tRNA, a mechanism that can account for leftward frameshifting (in the opposite direction) in retroviral translation. The specificity of sequence determinants of leftwing versus rightwing frameshifting is discussed.

Amino Acid Sequence↗
PubMed2026

No receptor-binding domain adaptation detected in within-host H5N1 surveillance of 4,559 US dairy outbreak sequences.

BACKGROUND: The 2024-2026 US H5N1 clade 2.3.4.4b dairy cattle outbreak has been characterised primarily through consensus-level phylogenetics. Whether mammalian-adaptation variants are emerging at sub-consensus frequencies within infected hosts, particularly at the haemagglutinin receptor-binding domain (RBD), remains unknown because no systematic within-host variant analysis of the public sequencing corpus has been performed. METHODS: We conducted a pre-registered, corpus-wide intrahost single-nucleotide variant (iSNV) analysis of all publicly available H5N1 cattle, feline-spillover, and retail-milk sequences on the NCBI Sequence Read Archive (4559 samples across 7 BioProjects). A dual-caller concordance pipeline (iVar + LoFreq) with empirically determined allele frequency (AF) threshold (3%, set via four-criterion validation including synthetic spike-in controls) was applied to an 11-site Tier 1 mammalian-adaptation panel spanning the polymerase complex, haemagglutinin RBD, and accessory proteins. Within-host nucleotide diversity was compared across host categories. RESULTS: The HA RBD sites Q226L and G228S (H3 numbering) showed zero detections across >4300 adequately sequenced samples at all AF thresholds tested (1-5%), despite the pipeline detecting other non-synonymous variants at these exact codon positions (upper 95% CI for prevalence: 0.08%). Seven of eleven adaptation sites carried statistically significant iSNV signals after Bonferroni correction (corrected α = 0.00417), though all at low prevalence (≤2.95%). Genotype stratification showed that most polymerase-site detections reflected genotype structure rather than within-host emergence: the apparent PB2 631 L→M "reversion" was largely the ancestral avian state of the D1.1 genotype (20 of 23 detections), which never acquired the 631L mammalian adaptation, with only two genuine sub-consensus events in the B3.13 background, while consensus-level PB2 701N was a fixed feature of the D1.1 genotype (10 of 14 detections) rather than independent sub-consensus emergence. Cattle exhibited significantly higher within-host nucleotide diversity than feline-spillover samples (π = 1.59 × 10-4 vs 6.11 × 10-5; Kruskal-Wallis p = 6.6 × 10-15), a finding that persisted after depth-matching (p = 4.6 × 10-5); this may reflect prolonged mammary-gland infection, though sampling differences and host biology cannot be excluded. CONCLUSIONS: We did not detect HA receptor-switching adaptation (the acquisition of human-type α2,6 receptor binding via Q226L/G228S) at any tested allele frequency in the US dairy H5N1 outbreak. Sub-consensus mammalian-adaptation signals exist at polymerase-complex sites but at low prevalence, are genotype-structured rather than independently recurrent, and require functional characterisation before informing risk assessment.

Dairy cattle↗
PubMed2025

Translation of the downstream ORF from bicistronic mRNAs by human cells: Impact of codon usage and splicing in the upstream ORF.

Biochemistry textbooks describe eukaryotic mRNAs as monocistronic. However, increasing evidence reveals the widespread presence and translation of upstream open reading frames preceding the "main" ORF. DNA and RNA viruses infecting eukaryotes often produce polycistronic mRNAs and viruses have evolved multiple ways of manipulating the host's translation machinery. Here, we introduce an experimental model to study gene expression regulation from virus-like bicistronic mRNAs in human cells. The model consists of a short upstream ORF and a reporter downstream ORF encoding a fluorescent protein. We have engineered synonymous variants of the upstream ORF to explore large parameter space, including codon usage preferences, mRNA folding features, and splicing propensity. We show that human translation machinery can translate the downstream ORF from bicistronic mRNAs, albeit reporter protein levels are thousand times lower than those from the upstream ORF. Furthermore, synonymous recoding of the upstream ORF exclusively during elongation significantly influences its own translation efficiency, reveals cryptic splice signals, and modulates the probability of downstream ORF translation. Our results are consistent with a leaky scanning mechanism facilitating downstream ORF translation from bicistronic mRNAs in human cells, offering new insights into the role of upstream ORFs in translation regulation.

Humans↗
PubMed1992

Molecular analysis of genetic mutation in electrophoretic variant of human lactate dehydrogenase-A(M) subunit.

An electrophoretic variant of lactate dehydrogenase-A (M) subunit was discovered in a patient with multiple myeloma. DNA analysis of the variant allele revealed a nucleotide substitution (transition) of C to T at codon 314 (CGT-TGT), and this mutation resulted in the replacement of an arginine by a cysteine (R314C). This amino acid replacement affects the net charge of the subunit and makes the LDH-A variant have a faster electrophoretic mobility. The responsible missense mutation created a new restriction site, AGGCCT, which can be simply detected by endonuclease AatI digestion. In addition, four synonymous substitutions with no amino-acid replacements were found at codons 51, 119, 163 and 175 in the LDH-A gene from the patient.

Aged↗
PubMed2026

Exploring the Mitochondrial Genomes of Phoebe Species (Lauraceae): Structural Dynamics and Functional Conservation.

Plant mitochondrial genomes (mitogenomes) vary markedly in size and architecture despite generally slow rates of sequence evolution. Phoebe is an ecologically and economically valuable genus of Lauraceae, yet its mitogenome diversity remains poorly characterized. In this study, we newly sequenced, assembled, and annotated the mitogenomes of three nationally protected Class II wild plants (P. bournei, P. chekiangensis, P. zhennan) from China and compared their mitogenomic characteristics. The three assemblies were resolved into representative circular configurations ranging from 808 to 864 kb, with similar GC contents and conserved protein-coding capacity. Each mitogenome contained distinct 41 protein-coding genes, 27-28 transfer RNAs, and three ribosomal RNAs. Synteny analysis revealed extensive changes in homologous-block order and orientation despite substantial sequence homology among the three species. Abundant repeats occurred predominantly in noncoding regions, while plastid-derived fragments documented historical intracellular DNA transfer. The three species exhibited similar codon usage and predicted RNA-editing patterns, whereas low synonymous divergence limited inference from pairwise ratios. Phylogenetic analysis based on mitochondrial protein-coding genes recovered Phoebe as a well-supported monophyletic lineage. These results reveal substantial structural divergence accompanied by conserved nucleotide composition and coding capacity, providing valuable data for further understanding the evolutionary variation of plant mitogenomes of Phoebe and the Lauraceae.

Phoebe↗
PubMed1992

Rates of synonymous substitution and base composition of nuclear genes in Drosophila.

We compared the rates of synonymous (silent) substitution among various genes in a number of species of Drosophila. First, we found that even for a particular gene, the rate of synonymous substitution varied considerably with Drosophila lineages. Second, we showed a large variation in synonymous substitution rates among nuclear genes in Drosophila. These rates of synonymous substitution were correlated negatively with C content and positively with A content at the third codon positions. Nucleotide sequences were also compared between pseudogenes and their functional homologs. The C content of the pseudogenes was lower than that of the functional genes and the A content of the former was higher than that of the latter. Because the synonymous substitution for functional genes and the nucleotide substitution for pseudogenes are exempted from any selective constraint at the protein level, these observations could be explained by a biased pattern of mutation in the Drosophila nuclear genome. Such a bias in the mutation pattern may affect the molecular clock (local clock) of each nuclear gene of each species. Finally, we obtained the average rates of synonymous substitution for three gene groups in Drosophila; 11.0 x 10(-9), 17.5 x 10(-9) and 27.1 x 10(-9)/site/year.

Animals↗
PubMed1992

A muscle-specific actin gene from the Mediterranean fruit fly, Ceratitis capitata.

A characterization of an actin gene isolated from the genome of the Mediterranean fruit fly, Ceratitis capitata, including the complete sequencing of the coding, 3' and 5' flanking regions of this gene and a partial cDNA was carried out. The partial cDNA was derived from the 3' untranslated region of the actin gene described here, and has been used to identify this gene uniquely. The DNA sequence data presented here, together with the pattern of expression exhibited by this gene during development, strongly support the interpretation that this is a muscle-specific actin gene. Peaks of expression are seen in tissues and during temporal phases of development where muscle differentiation is occurring. The derived protein sequence of the Medfly acting gene shows the highest degrees of similarity, 98.4 and 96.6% respectively, with the two muscle-specific actin genes 79B and 88F from D. melanogaster. The Medfly actin gene also has a single intervening sequence, and an intron is found at the same position in the 79B and 88F actin genes. In the coding region at the DNA level, 17.2 and 16.4% nucleotide differences, respectively, are observed between the Medfly actin gene and these same two D. melanogaster actin genes. The disparity between the amino acid and nucleotide comparisons can be explained, in part, by a high level of synonymous changes in the DNA sequence. In addition, despite the many similarities, codon usage appears to be very different between the actin genes of these species.

Actins↗
PubMed1992

Molecular population genetics of Escherichia coli: DNA sequence diversity at the celC, crr, and gutB loci of natural isolates.

The DNA sequences of three genes--celC, crr, and gutB--have been determined for each of 11 or 12 natural isolates of Escherichia coli from the ECOR collection. These genes encode the phosphoenolpyruvate-dependent phosphotransferase-system enzyme III proteins specific for beta-glucoside sugars (celC), glucose (crr), and glucitol (gutB), respectively. There is little evidence of recombination at or among these loci; among these strains, relationships inferred from each gene are largely consistent with each other and with the relationship inferred from multilocus enzyme electrophoresis. DNA sequence diversity is similar for all three genes, particularly when silent (synonymous) sites only are considered. This is surprising because there is much stronger codon usage bias at crr than at celC or gutB. The extent of divergence in the protein sequences encoded by these three genes varies considerably. The constitutively expressed glucose-specific enzyme is completely conserved. It is surprising that the inducible glucitol-specific enzyme, which is functional, is more variable than the cellobiose-specific enzyme, which is cryptic; the latter might be expected to be under less (if any) purifying selection.

Amino Acid Sequence↗
PubMed2026

Selection profiles in RNA viruses reflect the characteristics of viruses more than individual proteins.

Proteins that are exposed on the surface of a virus are frequently subject to strong selection to escape from neutralizing antibodies. To investigate whether surface-exposed (SE) and non-exposed (NE) proteins encoded by RNA viruses exhibit different patterns of evolution under selection, we analyzed 244 protein-coding genes from 28 species of RNA viruses representing 15 taxonomic families. First, we show that gene-wide rates of non-synonymous (dN) and synonymous (dS) substitutions do not differentiate between SE and NE proteins. To incorporate variation in substitution rates among codon sites, we inferred the posterior distribution over a fixed grid of dN and dS rates for each alignment. This 'evolutionary fingerprint' provides a common framework for comparing the selection profiles of non-homologous genes. Next, we computed the Wasserstein distance for every pair of fingerprints, which is analogous to amount of work required to reshape one distribution to another. After compensating for differences in genetic variation among alignments, we found a small but significant difference between the fingerprints of SE and NE proteins (PERMANOVA, P&#x2009;=&#x2009;0.03). However, we observed larger and more significant effects of whether the virus is enveloped (P&#x2009;<&#x2009;10-5) and the interaction between these factors (P=6.9&#xd7;10-4). The latter effects were driven by high levels of purifying selection in capsid proteins of Picornaviruses. Furthermore, greater amounts of variation in fingerprints were explained by significant differences among virus families and modes of transmission (P&#x2009;<&#x2009;10-5). These results imply the pattern of selection on a virus protein is shaped more by characteristics of the virus than the protein itself.

RNA Viruses↗
PubMed1992

High expression vectors for the production of recombinant single-chain urinary plasminogen activator from Escherichia coli.

An expression cassette containing a synonymous gene for human single-chain urokinase-type plasminogen activator (Rscu-PA) 5'-flanked by a trp promoter and the Shine-Dalgarno sequence of the xyl A operon of Bacillus subtilis and terminated by the terminators trp A and Tn10 was constructed and inserted into a pBR322 derivative to yield pBF160. When compared to pUK54 trp 207-1 containing the natural scu-PA gene without the Shine-Dalgarno sequence and terminator, the expression efficiency of pBF160 in Escherichia coli strains was improved by one order of magnitude. Replacement of the trp by the tac promoter (pBF171) did not affect expression. Inserting the Shine-Dalgarno sequence and Tn10 terminator into pUK54 trp 207-1 (pWH1320) slightly increased the expression level, whereas elimination of the Shine-Dalgarno sequence and the terminators from pBF160 with almost complete conservation of the synonymous structural gene (pBF191) significantly reduced the expression. Variation of the distance between the Shine-Dalgarno sequence and the start codon between 8 and 10 bp (pBF163) proved irrelevant. In conclusion, poor expression of mammalian genes in E. coli may result from both improperly designed regulatory elements and structural features of the coding region and therefore de-novo synthesis of the gene may be required to obtain satisfactory expression.

Amino Acid Sequence↗
PubMed2026

CRISPR/Cas9-Mediated Site-Directed Mutagenesis of Genes in Klebsiella pneumoniae.

Constructing target-gene mutants with a common genetic background is crucial for elucidating gene function in antimicrobial resistance (AMR) research. Taking advantage of the single-guide RNA (sgRNA) and protospacer adjacent motif (PAM) sequence (3'-NGG) specificity of the Cas9 protein in the CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system and codon degeneracy, the authors design a repair template that incorporates the desired point mutation while excluding the PAM sequence disrupted by a synonymous substitution, thereby preventing re-cleavage by CRISPR/Cas9. This method employs two available plasmids, pCasKP-apr and pSGKP-spe, offering straightforward operation and high screening specificity. As a result, the approach enables efficient generation of genetically defined mutant strains of Klebsiella pneumoniae (K. pneumoniae) and is readily adaptable to routine laboratory settings. Furthermore, the protocol minimizes off-target editing, shortens experimental timelines, reduces screening workload, and provides a reliable platform for investigating resistance mechanisms, validating candidate genes, and supporting functional genomics studies in clinically relevant bacterial pathogens.

Klebsiella pneumoniae↗
PubMed1992

Variable rates of evolution among Drosophila opsin genes.

DNA sequences and chromosomal locations of four Drosophila pseudoobscura opsin genes were compared with those from Drosophila melanogaster, to determine factors that influence the evolution of multigene families. Although the opsin proteins perform the same primary functions, the comparisons reveal a wide range of evolutionary rates. Amino acid identities for the opsins range from 90% for Rh2 to more than 95% for Rh1 and Rh4. Variation in the rate of synonymous site substitution is especially striking: the major opsin, encoded by the Rh1 locus, differs at only 26.1% of synonymous sites between D. pseudoobscura and D. melanogaster, while the other opsin loci differ by as much as 39.2% at synonymous sites. Rh3 and Rh4 have similar levels of synonymous nucleotide substitution but significantly different amounts of amino acid replacement. This decoupling of nucleotide substitution and amino acid replacement suggests that different selective pressures are acting on these similar genes. There is significant heterogeneity in base composition and codon usage bias among the opsin genes in both species, but there are no consistent relationships between these factors and the rate of evolution of the opsins. In addition to exhibiting variation in evolutionary rates, the opsin loci in these species reveal rearrangements of chromosome elements.

Amino Acid Sequence↗