Journal of Molecular Evolution最新文献

{"title":"Genomic Codon Usage is Structurally Consistent with First-Classness Across the Tree of Life.","authors":"Douglas J Huntington Moore","doi":"10.1007/s00239-026-10343-2","DOIUrl":"10.1007/s00239-026-10343-2","url":null,"abstract":"<p><p>Genome-scale codon usage data from 70,950 species spanning the tree of life allow a test of whether the standard genetic code's 21-family degeneracy partition is structurally consistent with the First-Classness (FC) framework, which derives that partition from conformal completion constraints on a four-element dispositional algebra without biological input. We report three findings. First, within-family codon usage uniformity, measured by coefficient of variation, follows a specific ordering across family sizes-2-fold < 4-fold < Ser 6-fold < 3-fold < Leu/Arg 6-fold-that is consistent with the architectural constraints of the FC-derived partition rather than being a simple monotonic function of family size. Second, the three split six-fold families (serine, leucine, arginine) exhibit four-codon sub-block dominance-pooled two-to-four ratios of 0.30--0.56-in archaea, bacteria and eukarya alike, though the strength of the dominance, most markedly for arginine, varies among the domains. Third, a family-balanced global FC ratio, tested against a null model preserving family-size architecture while randomising codon assignment, shows no separable statistical signal ([Formula: see text], [Formula: see text]); the possible interpretations, including limited sensitivity of the statistic at this level of aggregation and non-separability of the partition from the frequencies it governs, are discussed.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"895-906"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermodynamic Constraints on Glycerol-Based Proto-Nucleotides: Phosphate Versus Arsenate in Early Backbone Evolution.","authors":"Lázaro A M Castanedo, Chérif F Matta","doi":"10.1007/s00239-026-10336-1","DOIUrl":"10.1007/s00239-026-10336-1","url":null,"abstract":"<p><p>The emergence of the first nucleic acids required the prebiotic formation of nucleosides and nucleotides under chemically challenging conditions. Because assembly of the canonical ribose-phosphate framework is disfavored in water, simpler ancestral backbones may have preceded RNA and DNA. Semiempirical prescreening and density functional theory (DFT) calculations are used to evaluate the thermodynamics of glycerol-based nucleosides and nucleotides as possible proto-nucleic-acid building blocks. Two assembly routes were examined: a classic pathway, in which glycerol first condenses with a recognition unit and then with an ionized linker, and an alternative pathway, in which glycerol first condenses with the ionized linker and only then with the recognition unit. Although Gibbs free energy is a state function, the two pathways access different regions of the potential energy surface and converge to distinct local minima, leading to pathway-dependent differences in the computed thermodynamic quantities. Glycerol-derived nucleosides are found to form favorably in both vacuum and implicit aqueous solution when combined with either canonical or the studied non-canonical bases. Glycerol-based nucleotides are, likewise, thermodynamically accessible by both pathways, although the classic route is consistently more favorable than the alternative route. Among the most stabilized products are derivatives containing adenine, uracil, and C-glycosylated barbituric acid. Replacement of phosphate by arsenate produces only modest energetic and structural changes, indicating that arsenate-containing analogues cannot be excluded on thermodynamic grounds alone. However, the longer As-OC3 bond relative to P-OC3 suggests a weaker arsenate-based backbone compared to the predominant present-day phosphate-based backbone and therefore a plausible hydrolytic disadvantage for arsenate. These results support the view that glycerol-based backbones could have participated in early proto-nucleic-acid chemistry and suggest that phosphate may have been selected not because arsenate analogues were thermodynamically unstable, but because phosphate-based backbones were more kinetically persistent and more resistant to hydrolysis than arsenate-based ones.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"785-795"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hierarchical Organization of Evolutionary Constraint in Duplicated EF-Hand Motifs.","authors":"Abdul Basit","doi":"10.1007/s00239-026-10353-0","DOIUrl":"https://doi.org/10.1007/s00239-026-10353-0","url":null,"abstract":"<p><p>Calmodulin is a conserved [Formula: see text]-binding protein composed of four EF-hand motifs that retain structural symmetry despite functional differences. How evolutionary constraint is organized across these repeated EF-hands remains unclear. Here, we analyzed calmodulin using a protein language model (PLM) to determine whether divergence is distributed uniformly across the motifs or concentrated at residues in the [Formula: see text]-binding loops. In native embedding space, EF-hands showed greater similarity between duplicated pairs than between same-lobe pairs. Position-specific differences were strongest at loop positions, including both canonical coordinating and non-coordinating positions. These results support a hierarchical organization in which the duplicated structure remains conserved while divergence emerges through localized specialization. Our findings show that the PLM captures sequence-context information that is not fully explained by alignment-based conservation.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and Evolutionary Analysis of Non-specific Lipid Transfer Proteins (nsLTPs) in Cereus (Cactaceae).","authors":"M I O Cardoso, J A Teodoro, T A Costa-Silva, D T Amaral","doi":"10.1007/s00239-026-10351-2","DOIUrl":"10.1007/s00239-026-10351-2","url":null,"abstract":"<p><p>The genus Cereus (Cactaceae), widely distributed across arid and semi-arid environments of South America, exhibits adaptive capacity that is partly associated with proteins involved in lipid metabolism and stress responses, such as non-specific lipid transfer proteins (nsLTPs). Although well-characterized in model plants, the structural diversity and functional roles of these proteins in cacti remain largely unexplored. In this study, we characterized the nsLTP repertoire of Cereus by integrating transcriptomic data, phylogenetic analyses, structural modeling, and ligand-binding site mapping. Structural comparisons revealed conservation of the typical nsLTP fold, with variations mainly localized to loop regions surrounding the binding cavity, suggesting functional plasticity without compromising scaffold stability. Phylogenetic analyses revealed frequent duplication and loss events, as well as species-specific paralogs. Several lineage-specific copies exhibited distinctive loop architectures and pocket geometries relative to their closest orthologs, suggesting rapid structural diversification following duplication. This pattern is consistent with functional fine-tuning after gene duplication. Positive selection analyses identified nine codons with significant evidence of episodic diversifying selection (p < 0.05), some of which mapped near predicted functional regions, supporting the hypothesis that selective pressures have shaped key interaction interfaces. Together, these results provide the first integrated characterization of nsLTPs in Cereus, supporting a gate-modulation hypothesis in which structural variation concentrated at tunnel entrances may contribute to functional diversification while preserving the conserved nsLTP fold (four-helix scaffold). Rather than asserting adaptation directly, our findings provide a structural basis and testable predictions for how nsLTP diversification may influence lipid trafficking processes relevant to cuticle/membrane function under abiotic stress.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"1002-1018"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolutionary Signatures of Thermotolerance Shaped by Adaptive Admixtures in the Ghurrah Pig of India.","authors":"Rangasai Chandra Goli, Kiyevi G Chishi, Oguru Sai Sruthi, Tanuj Gunturu, Nidhi Sukhija, Muralidhar Metta, K K Kanaka, Madhusudan R Nandineni","doi":"10.1007/s00239-026-10337-0","DOIUrl":"10.1007/s00239-026-10337-0","url":null,"abstract":"<p><p>India's indigenous pig genetic resources are central to sustainable meat production and rural livelihoods, yet their genomic potential remains underexplored. The Ghurrah pig, a native breed from northern India, is among the most genetically distinct and adaptively resilient populations, shaped by ancestral admixture from Asian, European, and Indian wild boar lineages. This study elucidates the genetic uniqueness, population structure, and adaptive introgression of the Ghurrah pig by jointly analysing 35,777 high-quality SNPs across 270 global pig genotypes. Higher observed heterozygosity (Ho = 0.287) and lower inbreeding coefficient (F_IS = 0.206) in Ghurrah indicated substantial genetic variability and minimal inbreeding, while its effective population size (Ne = 26 at 13 generations ago) revealed demographic constraint. Linkage disequilibrium (r² = 0.325) and haplotype block structure (average block size = 415.56 kb) reflected reduced recombination and hybrid ancestry. Admixture analysis at K = 5 positioned Ghurrah intermediate between Asian and European clusters, with 39.07% Asian ancestry and significant European introgression. Local ancestry inference identified adaptive admixtures from Asian ancestry on Sus scrofa chromosome (SSC) 10, SSC12, and SSC15 associated with thermotolerance, immune regulation, and stress resilience, while European ancestry on SSC11 enriched pathways for muscle growth and carcass traits. Functionally, genes such as PTPRC, CTSL, and HSPA14 contributed to environmental adaptability, whereas ATP11A influenced lean meat yield. A 1000 SNP ancestry informative marker (AIM) panel revealed 97.25% unique ancestry for Ghurrah, underscoring its genetic distinctiveness. These findings establish Ghurrah as a genomic bridge between Asian and European domestication centres, embodying hybrid vigour and adaptive potential. The study emphasizes the need for genomic-assisted conservation breeding to safeguard Ghurrah's genetic integrity and promote its sustainable use in tropical production systems.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"796-813"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory Evolution and the Genetic Basis of Human Brain Expansion.","authors":"Nilmini Hettiarachchi","doi":"10.1007/s00239-026-10344-1","DOIUrl":"10.1007/s00239-026-10344-1","url":null,"abstract":"<p><p>The evolution of the human brain is characterized by profound changes in structure and function, despite relatively limited divergence in protein-coding genes compared to other primates. This paradox has led to increasing recognition of gene regulatory elements (GREs) as primary drivers of evolutionary innovation. In this review, we synthesize current knowledge on the role of conserved noncoding elements (CNEs), human accelerated regions (HARs), and transposable element (TE)-derived sequences in shaping gene regulatory networks (GRNs) underlying brain development. Comparative analyses across humans and closely related primates, including the chimpanzee, gorilla, and orangutan, reveal that while core regulatory architectures are highly conserved, subtle changes in regulatory elements drive species-specific gene expression patterns. We highlight how CNEs provide a stable regulatory framework, whereas HARs and TE-derived elements introduce lineage-specific modifications that fine-tune neurodevelopmental processes. Advances in functional genomics, including CRISPR-based perturbations, massively parallel reporter assays, and single-cell multi-omics, have enabled direct interrogation of regulatory function, linking sequence variation to cellular phenotypes. Furthermore, we discuss how regulatory evolution contributes to both cognitive innovation and susceptibility to neurological disorders. Despite significant progress, challenges remain in establishing causal relationships between regulatory variation and phenotypic outcomes. Future integration of multi-omics data and comparative models will be essential for resolving these complexities. Together, this review provides a comprehensive framework for understanding the molecular basis of primate brain evolution through the lens of gene regulation.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"761-784"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitogenomic Insights into the Tinfoil Barb Barbonymus schwanefeldii from Sumatra, Indonesia: Structural Features, Selective Pressure, Genetic Diversity, and Phylogenetic Placement.","authors":"Angkasa Putra, Sarifah Aini, Muhammad Misi Muslimin, Hye-Eun Kang, Ah Ran Kim, Soo Rin Lee, Gde Raka Angga Kartika, Sang Van Vu, Hyun-Woo Kim, Shantanu Kundu","doi":"10.1007/s00239-026-10350-3","DOIUrl":"10.1007/s00239-026-10350-3","url":null,"abstract":"<p><p>Prior to this study, the mitogenomic characterization, genetic diversity, and phylogenetic placement of the Tinfoil Barb Barbonymus schwanefeldii remained largely unexplored, despite its notable ecological and economic importance. Hence, this study aimed to provide the first in-depth insight into the mitogenomic features of this species from its native range in Sumatra, Indonesia. The generated mitogenome is 16,578 bp in length and contains 37 genes along with a control region (CR). The genome also exhibited a 57.03% A + T bias and all protein-coding genes (PCGs) initiated with the ATG codon, except COI (GTG). The codon usage was dominated by arginine, leucine, and serine, whereas methionine and tryptophan were rare. The pairwise nonsynonymous-to-synonymous substitution ratios demonstrated strong purifying selection across all Barbonymus species. This pattern was further supported by complementary codon-based approaches, which showed that the 13 PCGs were predominantly subject to strong evolutionary constraints, with evidence of positive selection confined to a small number of sites in a limited subset of genes. Most transfer RNA genes of B. schwanefeldii maintained the canonical cloverleaf secondary structure, except tRNA-Ser1, which lacked the dihydrouridine stem. The comparative profiling of conserved sequence blocks within the CR among Barbonymus taxa highlighted variation in length and nucleotide composition, with tandem repeats exclusively detected in B. gonionotus. A mitogenome-wide assessment of B. schwanefeldii revealed considerable intra-specific genetic divergence (0%-3.932%) and notable haplotypic diversity across Southeast Asian islands and mainland populations. This population genetic structure likely reflects historical connectivity during the Pleistocene via ancient drainage systems of the Malacca Strait or North Sunda, followed by subsequent isolation after post-glacial eustatic sea-level rise. The phylogenetic inference robustly corroborated a sister-species relationship between B. schwanefeldii and Barbonymus altus within the clade 'Poropuntiinae'. Collectively, these findings elucidate the phylogeographic patterns and evolutionary history of this Southeast Asian endemic cyprinid fish within the Sundaland biodiversity hotspot.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"978-1001"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Characterization of Banana Lectins from Musa acuminata and M. balbisiana Reveals BanLec-Glycan Interactions Relevant to Hypermannosylation in Breast Cancer.","authors":"Fenny M Dwivany, Hansley Kurniawan, Munsif Ali Shad, Adena Salsabila, Sofia Safitri Hessel, Krisdiantoro, Ima M Zainuddin, Fenryco Pratama, Heni Rachmawati, Marselina Irasonia Tan, Rizkita Rachmi Esyanti, Tri Rini Nuringtyas, Riezki Amalia, Annisa, Andri Fadillah Martin, Yashanti Berlinda Paradisa, Trina Ekawati Tallei","doi":"10.1007/s00239-026-10352-1","DOIUrl":"10.1007/s00239-026-10352-1","url":null,"abstract":"<p><p>Banana Lectin (BanLec) is a mannose-binding jacalin-related lectin that has attracted considerable scientific interest due to its affinity toward high-mannose-type N-glycans and its immunomodulatory and antiviral properties. It also has the potential to suppress cancer cell proliferation and stimulate macrophage activity. In this study, evolutionary relationships among BanLec sequences across the Musa genus were also examined, while the primary focus was the identification and characterization of BanLec-encoding genes from Musa acuminata subsp. malaccensis (Malaysian Dwarf Banana) and Musa balbisiana (Banana Klutuk Wulung), with emphasis on their molecular properties and potential interactions with a hypermannosylated N-glycan structure (Man8GlcNAc2) reported to be abundant in breast cancer. Seven and four high-confidence BanLec protein sequences were identified from M. acuminata subsp. malaccensis and M. balbisiana genomes, respectively, which all share conserved structural domains characteristic of BanLec with variable exon-intron organizations. Gene locations, duplications, and synteny analyses revealed lineage-specific diversification of lectin genes within each species and between the two Musa genomes. The identified BanLec proteins were modelled and then evaluated by molecular docking and molecular dynamics simulations using a hypermannosylated N-glycan structure. The computational binding analyses demonstrate that BanLec variants from different Musa genomes exhibit distinct energetic and structural preferences toward the hypermannosylated N-glycan structure. Among the tested complexes, Ma09_t10450 (M. acuminata subsp. malaccensis) showed the most stable interaction, followed by Mba09_g09930 (M. balbisiana), each demonstrating strongly favourable binding free energies (ΔG ≤ -22.43 ± 3.01 kcal mol⁻¹ and ΔG ≤ -17.87 ± 10.81 kcal mol⁻¹ respectively) and therefore considered suitable candidates for lectin binding assays conducted at neutral pH, 300 K, and physiological ionic strength. These findings strengthen BanLec's potential as a promising candidate for lectin-based biomarker development and glycan-targeted therapeutic applications.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"1019-1037"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Equivalence and Conserved Sexual Dimorphism in the Gut Microbiome: A Cross-Species Meta-analysis.","authors":"Jorge Luis Gutiérrez-Ávila, Gabriel Alfonso Gutiérrez-Rebolledo, Rodolfo Gamaliel Avila-Bonilla, María Elena Sánchez Pardo","doi":"10.1007/s00239-026-10338-z","DOIUrl":"10.1007/s00239-026-10338-z","url":null,"abstract":"<p><p>The murine model is a standard system in translational microbiome research, yet its functional equivalence to the human microbiome remains debated. To evaluate its translational validity, we conducted a comparative whole-genome shotgun (WGS) metagenomic meta-analysis, integrating an initial retrieval of 520 datasets from 5 independent cohorts (BioProjects) across Homo sapiens (n = 202), Mus musculus (n = 75), and Drosophila melanogaster (n = 243) samples. Taxonomic and functional profiles were evaluated using strict bioinformatic quality control and batch-effect mitigation. Taxonomic profiling revealed pronounced divergence driven by host-specific ecological constraints and filtering. However, metabolic reconstruction demonstrated substantial functional equivalence, supporting the functional redundancy hypothesis for core mammalian metabolic circuits. We also noted a methodological vulnerability in our dataset: a low-depth murine sample clustered with invertebrate profiles, suggesting that technical noise or insufficient depth might artificially compress mammalian functional diversity. Comparative analysis identified sex-biased metabolic pathways conserved across mammalian hosts. Specifically, we observed a consistent enrichment of steroid metabolism in females and mineralocorticoid regulation in males. These findings indicate that functional conservation between humans and mice is modular rather than global. Consequently, the translational value of the murine model lies in domain-specific functional equivalence rather than taxonomic imitation. Moreover, the conservation of sex-specific metabolic signatures suggests that biological sex is a fundamental organising principle of microbiome function. This study highlights the necessity of mapping conserved metabolic modules and rigorously controlling inter-study variance to effectively deploy murine models in biomedical research.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"814-834"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ineffectual Genomic Error Correction Under Environmental Perturbation Dynamically Regulates Mutational Supply and Robustness.","authors":"Sashikanta Barik, Parthasarathi Sahu, Koushik Ghosh, Hemachander Subramanian","doi":"10.1007/s00239-026-10341-4","DOIUrl":"10.1007/s00239-026-10341-4","url":null,"abstract":"<p><p>Adaptation requires an adequate supply of heritable variation, yet too much mutation can limit organismal viability by disrupting essential molecular functions. Our study shows that this trade-off arises inherently from the kinetic proofreading mechanism that dictates the replication fidelity. In our model, environmental shifts alter the optimal driving rate constant of proofreading enzymes, transiently elevating replication error rates and triggering rapid evolutionary change until a new fidelity optimum is reached. This produces alternating periods of stasis and rapid adaptation, the central signature of punctuated equilibrium. We further show that coding-region length and population size jointly determine whether adaptation succeeds or mutational collapse occurs, reflecting the balance between mutation supply and error tolerance. The resulting limit on mutation rates is qualitatively consistent with predictions of the drift-barrier hypothesis. Therefore, evolution is shown to select a mutation rate that supports evolutionary adaptation while avoiding genomic meltdown.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"879-894"},"PeriodicalIF":2.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}