Identification of the Novel Allele HLA-DPB1*1782:01 in a Deceased Donor by Third-Generation Sequencing.
HLA-DPB1*1782:01 differs from HLA-DPB1*04:02:01:01 by a non-synonymous nucleotide substitution at codon 87.
Humans↗
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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↗
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↗
The Novel HLA-DPB1*1799:01 Allele Identified by Next-Generation Sequencing in Two Members of an Indian Family.
HLA-DPB1*1799:01 differs from HLA-DPB1*05:01:01:01 by a single non-synonymous change in exon 3, changing codon 148 from AAT → AAA.
South Asian People↗
Identification of the Novel Allele, HLA-DQB1*05:368.
HLA-DQB1*05:368 differs from DQB1*05:01:01:02 by one non-synonymous nucleotide substitution in exon 2 at codon 29 (Arginine to Lysine).
Humans↗
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↗
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↗
The Novel Allele, HLA-DQA1*03:80, With a Non-Synonymous Mutation in Exon 3.
The HLA-DQA1*03:80 allele contains a single nucleotide substitution in codon 134 (GGT to CGT).
Humans↗
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 = 0.03). However, we observed larger and more significant effects of whether the virus is enveloped (P < 10-5) and the interaction between these factors (P=6.9×10-4). 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 < 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↗
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↗
Discovery of the Novel HLA-DQB1*05:386 Allele in a Brazilian Volunteer Donor.
HLA-DQB1*05:386 differs from HLA-DQB1*05:01:01:01 by a non-synonymous substitution in exon 4.
Humans↗
Resurgence and molecular epidemiology of dengue virus serotype 4 amid the COVID-19 pandemic in Thailand.
INTRODUCTION: Dengue virus serotype 4 (DENV4) co-circulates with other serotypes in Thailand, a hyperendemic setting characterized by cyclical shifts in serotype predominance. During the COVID-19 pandemic, related public health interventions may have influenced dengue detection, transmission and epidemiological dynamics. MATERIALS AND METHODS: A total of 413 dengue NS1/PCR-positive samples collected from 2018 to 2024 at a tertiary hospital in Bangkok were serotyped using a real-time PCR DENV1-4 subtyping assay. Forty-seven DENV4-positive samples (Ct < 32) underwent whole-genome sequencing using the ATOPlex DENV1-4 panel on the DNBSEQ-G99RS platform. Sequencing reads were processed using CLC Genomics Workbench, followed by phylogenetic, mutation, codon-based selection-pressure, and epitope-mapping analyses. RESULTS: DENV4 was identified in 18.2% (75/413) of samples, with 48% of cases requiring hospitalization. Detection increased markedly from 11.8% (22/186) during 2018-2021-23.3% (53/227) during 2022-2024 (proportion ratio, 1.97; p = 0.0025). Among the 47 whole-genome-sequenced samples, most strains clustered within genotype I lineage 4I_A.3 and showed lineage-associated non-synonymous substitutions. NS1-A90T, NS2A-L113F, and NS3-F523Y appeared exclusively during 2022-2024 (p < 0.001), whereas NS2A-L113F, NS5-G223S, and NS5-Q631R showed concordant positive-selection signals by FEL and MEME. CONCLUSIONS: This hospital-based study highlights an increase in DENV4 detection in Bangkok during 2022-2024 compared with 2018-2021, accompanied by predominance of lineage 4I_A.3 distinct from Malaysian and Indonesian strains reported during a similar period. These findings support integrated clinical and genomic surveillance to monitor DENV serotype and genotype dynamics and inform public health and vaccine strategies.
COVID-19 pandemic↗
The Novel HLA-DQB1*06:03:60 Allele Identified by Next-Generation Sequencing and Confirmed by Nanopore Sequencing.
HLA-DQB1*06:03:60 differs from HLA-DQB1*06:03:01:01 by a single synonymous nucleotide substitution at position 174 in Exon 2.
Humans↗
Sequence optimization targeting mRNA stability enhances monoclonal antibody titers in CHO cells.
This study presents a DNA sequence optimization approach that integrates mRNA stability as a tunable design parameter to enhance monoclonal antibody expression in Chinese hamster ovary (CHO) cells. A comprehensive combinatorial library of synonymous coding-sequence variants of an IgG1 light chain was integrated as single copies at a defined genomic locus in CHO cells with identical regulatory elements. Steady-state mRNA abundance, quantified by deep sequencing of gDNA and mRNA, served as a proxy for mRNA stability. These data were used to train a machine learning model that predicts mRNA abundance from coding sequence using embeddings from a pre-trained nucleotide transformer. This abundance predictor, together with established translational metrics, was incorporated into a genetic algorithm for multi-objective codon optimization. As proof-of-concept, we optimized sequences encoding Trastuzumab to either maximize or minimize the abundance criterion and obtained benchmark sequences from two commercial providers. Using targeted integration, we generated CHO cell lines and measured protein titer and cell-specific productivity. Sequences optimized for high abundance significantly increased intracellular mRNA levels (+41%), protein titer (+59%), and cell-specific productivity (+85%) relative to low-abundance designs, while viable cell densities remained comparable. Compared to commercial benchmarks, high-abundance sequences achieved significantly higher titer (+70%) and cell-specific productivity (+98%). These findings establish mRNA stability as a practical and complementary design parameter for codon optimization in monoclonal antibody production, with potential applicability to other proteins and expression systems.
CHO↗
Mitogenome assembly and phylogenetic relationships of Phalaris arundinacea.
INTRODUCTION: As a perennial herb of Poaceae, Phalaris arundinacea plays key roles in grazing, production, and soil and water conservation because of its well-developed rhizomes and seed dispersal. We assembled and annotated the first mitogenome of P. arundinacea to support evolutionary and taxonomic research. METHODS: We assembled and annotated the first complete mitochondrial genome of P. arundinacea by integrating Illumina short reads with Nanopore long reads via a hybrid assembly strategy. The genome architecture was comprehensively characterized, encompassing codon usage bias, repetitive sequence organization, and inter-organellar genetic exchange with the chloroplast genome. RESULTS AND DISCUSSION: Assembly of the P. arundinacea mitogenome revealed two circular structures with a combined length of 526,717 bp. The genome comprised a set of 37 protein-coding genes (PCGs), 27 tRNAs, and 8 rRNAs, with the rRNA genes exhibiting full assembly (100% coverage). The mitochondrial genome contained 154 forward and 164 palindromic repeats, along with 25 tandem repeats and 124 simple sequence repeats (SSRs). Notably, 102 SSRs were distributed on contig1, predominantly in tetrameric form. Furthermore, 376 RNA editing sites were predicted. A total of 104 fragments were integrated into the mitochondrial genome from the chloroplast, amounting to 55,866 bp of transferred sequence. Finally, phylogenetic analysis of 28 plant mitogenomes placed P. arundinacea closest to species within the genus Poa (P. chaixii and P. pratensis). Comparative analysis of non-synonymous-to-synonymous substitution rate (Ka/Ks) ratios across divergent species revealed that the mitochondrial genome of P. arundinacea underwent stabilizing evolutionary dynamics, characterized by predominant purifying selection with several lineage-specific variations in selective pressure. Our findings support the close phylogenetic relationship between P. arundinacea and species of the genus Poa and provide a reference mitochondrial genome resource for future comparative studies within Phalaris that incorporate broader taxon sampling. These results support deeper phylogenetic investigations of P. arundinacea and facilitate future work on its germplasm characterization and applied use.
Phalaris arundinacea↗