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PubMed2026

Synonymous mutations in essential genes infrequently produce fitness effects in human cell lines.

The assumption that synonymous mutations are fitness-neutral is central to many foundational results in the fields of genetics, genomics, evolutionary biology, and medicine. However, recent results suggest synonymous mutations have pervasive and strong fitness effects. These vigorously debated studies in non-human model systems have even suggested that the proportion of synonymous mutations and their fitness effect sizes are similar to non-synonymous mutations. To probe the fitness effect of synonymous mutations, we utilized recent advances in base editing to test 8558 potential synonymous mutations in 128 highly essential genes in human cell lines. Importantly, our library design excluded splice-proximal sites, ensuring a direct test of codon-level synonymous effects independent of splicing disruption. We find that synonymous mutations rarely have fitness effects on growth, occurring around 37.9-fold (95% CI: 22.16-81.48-fold) less frequently than missense mutations. In this experimental context, these findings demonstrate that synonymous mutations impact cellular fitness far less frequently than missense mutations. These results deviate from earlier reports of widespread synonymous fitness effects in yeast, yet they align with recent prime editing data observed in other human cell lines.

Humans↗
PubMed2026

Reading another hidden message in the genetic code.

The genetic code determines not only the amino acid sequences of proteins but also mRNA stability. How is this hidden message read? Hia and colleagues have now identified human DHX29 as a reader of the mRNA stability code carried by codons, providing new mechanistic insights into translation-coupled gene regulation.

Genetic Code↗
PubMed1979

Nucleotide sequences of trpA of Salmonella typhimurium and Escherichia coli: an evolutionary comparison.

The complete nucleotide sequences of trpA of Salmonella typhimurium and Escherichia coli were determined. The nucleotide sequences are 24.8% divergent, compared with amino acid sequence divergence of 14.9%. Over half of the codons of each gene contain synonymous nucleotide changes. The pattern of synonymous nucleotide changes is consistent with the interpretation that such changes result from random mutational events. We do not find any evidence indicating that codon selection or RNA structure is of major selective value. We conclude that polypeptide function is the primary basis of selection in trpA and that most synonymous codon changes are selectively neutral.

Base Sequence↗
PubMed1992

Interchromosomal gene conversion as a possible mechanism for explaining divergence patterns of ZFY-related genes.

The divergence pattern of mammalian ZFY-related genes from human (ZFY and ZFX) and mouse (Zfy-1 and Zfx) was reexamined on the basis of nucleotide substitutions at the synonymous codon-alternating positions. It is possible to explain the unusual divergence pattern of the mammalian Y-linked ZF genes by interchromosomal gene conversion by X-linked ZF genes. Furthermore, the rates of evolution of mammalian X- and Y-linked ZF genes were shown to agree well with those expected from our model.

Animals↗
PubMed1992

Compliance of genetic code with base-composition deflecting pressure.

Gene DNAs of different organisms show a wide variation in their G+C content as much as 20% to 80%. This variation has been regarded as the result of the compliance of the genetic code with the base-composition-deflecting mutational pressure. To make possible a quantitative discussion of this genetic code's elasticity, we made a statistical study of the G+C frequency at the 1st, 2nd, and 3rd positions of codons: 4.5 x 10(6) codons in 11,981 protein coding regions in the DNA data base were analyzed. The data were examined quantitatively by using a species-independent universal equation which describes the base frequencies at the three codon sites in terms of the constraint parameters characteristic of the sites and an intersite interaction. By a best fitting procedure between theoretical curves and data points, the constraint parameters and the characteristic G+C contents to which the 1st and the 2nd site base compositions are bound were determined. The base substituting mutation of the coding sequence under the base-composition-deflecting pressure is divided into following three stages of the different compliance from the elastic one to the rigid: 1) the 3rd position of codons change by synonymous substitution; 2) the 1st and then 2nd positions change accompanying amino acid replacement; and 3) in the organisms exposed under an extremely high base composition deflecting pressure, the codon table is forced to be altered. The compliance parameters were derived quantitatively for the first two stages. In conclusion, a simultaneous analysis of data from organisms as divers as virus and man discovered that there is a set of constraints common to species, which governs the frequency of codon bases, and it can be described by a universal equation.

Animals↗
PubMed1978

Neutral changes during divergent evolution of hemoglobins.

A comparison of the mRNAs for rabbit and human beta-hemoglobins shows that synonymous changes in codons have accumulated three times as rapidly as nucleotide replacements that produced changes in amino acids. This agrees with predictions based on the so-called 'neutral theory'. In addition, seven codon changes that appear to be single-base changes (according to 'maximum parsimony') are actually two-base changes. This indicates that the construction of "primordial sequences" is of limited signficance when based on inferences that assume minimum base changes for amino acid replacements.

Amino Acids↗
PubMed2025

A novel regulation on the developmental checkpoint protein Sda that controls sporulation and biofilm formation in Bacillus subtilis.

UNLABELLED: Biofilm formation by Bacillus subtilis is triggered by an unusually simple environmental sensing mechanism. Certain serine codons, the four TCN codons (N for A, T, C, or G), in the gene for the biofilm repressor SinR caused lowered SinR translation and subsequent biofilm induction during transition from exponential to stationary growth. Global ribosome profiling showed that ribosomes pause when translating the four UCN (U for T on the mRNA) serine codons on mRNA, but not the two AGC/AGU serine codons. We proposed a serine codon hierarchy (AGC/AGT vs TCN) in that genes enriched in the TCN serine codons may experience reduced translation efficiency when serine is limited. In this study, we designed an algorithm to score all protein-coding genes in B. subtilis NCIB3610 based on the serine codon hierarchy. We generated a short list of 50 genes that could be subject to regulation by this novel mechanism. We further investigated one such gene from the list, sda, which encodes a developmental checkpoint protein regulating both sporulation and biofilm formation. We showed that synonymously switching the TCN serine codons to AGC in sda led to delayed biofilm formation and sporulation. This engineered strain also outgrew strains with other synonymously substituted sda alleles (TCN) in competition assays for biofilm formation and sporulation. Finally, we showed that the AGC serine codon substitutions in sda elevated the Sda protein levels. This serine codon hierarchy-based novel signaling mechanism could be exploited by bacteria in adapting to stationary phase and regulating important biological processes. IMPORTANCE: Genome-wide ribosome profiling in Bacillus subtilis shows that under serine limitation, ribosomes pause on the four TCN (N for A, C, G, and T), but not AGC/AGT serine codons, during translation at a global scale. This serine codon hierarchy (AGC/T vs TCN) differentially influences the translation efficiency of genes enriched in certain serine codons. In this study, we designed an algorithm to score all 4,000+ genes in the B. subtilis genome and generated a list of 50 genes that could be subject to this novel serine codon hierarchy-mediated regulation. We further investigated one such gene, sda, encoding a developmental checkpoint protein. We show that sda and cell developments controlled by Sda are also regulated by this novel mechanism.

Bacillus subtilis↗
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↗