{"title":"Avoiding Catastrophic Mutations Accurately Predicts Amino Acid to Codon Pairing.","authors":"Peter Nonacs, Thomas Nonacs","doi":"10.1007/s00239-025-10294-0","DOIUrl":"10.1007/s00239-025-10294-0","url":null,"abstract":"<p><p>DNA codon mutations involving Stop signals or the amino acid cysteine can be especially damaging. The former can break protein sequences or add extraneous amino acids. The latter can add or subtract disulfide bonds crucial in protein folding. We present a hypothetical scenario where Stop codons were present early in the evolution of the genetic code; and minimizing catastrophic mutations for code networks affected all subsequent amino acid/codon pairings. Predicted features of this \"Catastrophic Mutation Minimization Hypothesis\" (CMMH) are that: (1) Cysteine is mutationally adjacent to Stop, isolating a contiguous codon 'neighborhood' with high potential for catastrophe. (2) The sequence of amino acid additions order determines codon assignments through minimizing network-wide mutation costs. Overall, codon locations for 16 of the 20 amino acids in the genetic code are consistent with the CMMH, as are multiple other predictions. We propose an antecedent genetic code consisted of 16 doublet codons specifying 13-14 amino acids. Two variations of these networks are less susceptible to catastrophic mutations than 88.2-97.5% of randomly generated ones. Unlike some previous hypotheses, CMMH does not require the total replacement or rearrangement of amino acids at codons, with its disruptive potential for protein synthesis. Finally, the composition of this ancestral doublet genetic code has all the modern code's utility: amino acids from four chemical types; start and stop signals; metal-binding ability; disulfide bridging for creating protein shapes; and possible epigenetic gene regulation. Thus, the modern code likely evolutionarily fine-tuned antecedent capabilities, rather than significantly increasing competence for making complex proteins.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"164-176"},"PeriodicalIF":1.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794220","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}
Jack M Craig, Ryan M Tobin, Walter Wolfsberger, Taras K Oleksyk, Sayaka Miura, Glenn S Gerhard, Sudhir Kumar
{"title":"An Evolutionary Metric for Estimating PhyloAges from Bulk Sequencing of Hematopoietic Stem Cells Reveals the Tempo of Blood Aging in Cancer and Longevity.","authors":"Jack M Craig, Ryan M Tobin, Walter Wolfsberger, Taras K Oleksyk, Sayaka Miura, Glenn S Gerhard, Sudhir Kumar","doi":"10.1007/s00239-025-10296-y","DOIUrl":"10.1007/s00239-025-10296-y","url":null,"abstract":"<p><p>The phylogeny of a person's hematopoietic stem cells (HSCs) can be used to quantify physiological aging of blood using a phyloAge model based on diversity decay metrics. However, this procedure currently requires accurate HSC genome sequences, which are expensive and time-consuming to obtain. We show that metrics of diversity decay can be derived from the somatic variant frequency spectrum (VFS) using more affordable, routine bulk sequencing, because HSCs evolve without recombination at a clock-like rate. We found that VFS-based models produce phyloAge estimates similar to those derived from HSC genome phylogenies. Customized for protein-coding variation and sequencing read depth, VFS-based HSC phyloAge estimates were, on average, 168 years more than chronological ages in 157 patients with acute myeloid leukemia, consistent with excess HSC aging observed in cancer patients using single cell genome phylogenies. We also tested the hypothesis that variants in cancer driver genes may confer longevity, as they occur in a significant fraction of long-lived individuals. Indeed, HSC phyloAge estimates were significantly lower, consistent with reduced hematologic cancer risk among extremely old individuals. Thus, the new metrics and models broaden the utility of the phyloAge approach, making it feasible and efficient for clinical and research applications.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"177-189"},"PeriodicalIF":1.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834161","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}
Megan G Behringer, Michael DeGiorgio, Maeva Perez, David A Liberles
{"title":"2025 Zuckerkandl Prize.","authors":"Megan G Behringer, Michael DeGiorgio, Maeva Perez, David A Liberles","doi":"10.1007/s00239-026-10302-x","DOIUrl":"https://doi.org/10.1007/s00239-026-10302-x","url":null,"abstract":"","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989471","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}
Martin Schoenstein, Pauline Mermillod, Arnaud Kress, Odile Lecompte, Yannis Nevers
{"title":"Profylo: A Python Package for Phylogenetic Profile Comparison and Analysis.","authors":"Martin Schoenstein, Pauline Mermillod, Arnaud Kress, Odile Lecompte, Yannis Nevers","doi":"10.1007/s00239-025-10280-6","DOIUrl":"10.1007/s00239-025-10280-6","url":null,"abstract":"<p><p>Phylogenetic profiling, involving the analysis of presence-absence of orthologs in a set of species, is a way to infer functional association between genes through co-evolutionary patterns. Since its inception, numerous methods have been described to construct phylogenetic profiles, evaluate their similarity, or identify clusters of co-evolving genes. However, few of these methods are available as downloadable software. We present Profylo, a phylogenetic profiling toolkit made available as an open-source Python 3.0 package. Profylo implements seven methods for comparing phylogenetic profiling, four algorithms for identification of co-evolving clusters, as well as tools to help with their analysis, including visualization features. We take advantage of the variety of methods implemented in Profylo to benchmark their ability to predict functional relationships between human genes, using different datasets. Finally, we demonstrate the utility of the package with an example case study of the presence-absence of all protein-coding genes in the human genome. Profylo is available on GitHub at https://github.com/MartinSchoenstein/Profylo .</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"806-819"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401055","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}
Dong-Ha Oh, Alexander Astashyn, Barbara Robbertse, Nuala A O'leary, W Ray Anderson, Laurie Breen, Eric Cox, Olga Ermolaeva, Robert Falk, Vichet Hem, J Bradley Holmes, Patrick Masterson, Kelly M McGarvey, Eyal Mozes, John P Torcivia, Mirian T N Tsuchiya, Craig Wallin, Françoise Thibaud-Nissen, Terence D Murphy, Vamsi K Kodali
{"title":"NCBI Orthologs: Public Resource and Scalable Method for Computing High-Precision Orthologs Across Eukaryotic Genomes.","authors":"Dong-Ha Oh, Alexander Astashyn, Barbara Robbertse, Nuala A O'leary, W Ray Anderson, Laurie Breen, Eric Cox, Olga Ermolaeva, Robert Falk, Vichet Hem, J Bradley Holmes, Patrick Masterson, Kelly M McGarvey, Eyal Mozes, John P Torcivia, Mirian T N Tsuchiya, Craig Wallin, Françoise Thibaud-Nissen, Terence D Murphy, Vamsi K Kodali","doi":"10.1007/s00239-025-10268-2","DOIUrl":"10.1007/s00239-025-10268-2","url":null,"abstract":"<p><p>Orthologs are fundamental for enabling comparative genomics analyses that further our understanding of eukaryotic biology. The unprecedented increase in the availability of high-quality eukaryotic genomes necessitates scalable and accurate methods for orthology inference. The National Center for Biotechnology Information (NCBI) developed \"NCBI Orthologs\", a resource and a computational pipeline designed to meet this challenge within the NCBI RefSeq framework. This system integrates protein similarity, nucleotide alignment, and microsynteny to achieve high-precision ortholog assignments across diverse eukaryotes. The pipeline leverages high-quality RefSeq annotations and processes genomes individually, ensuring scalability. Resulting ortholog data, organized into gene-level anchored sets, enables propagation of functional annotation information and facilitates comparative genomics. Critically, these data are integrated into the NCBI Gene resource, providing users with access from various entry points. The NCBI Datasets resource provides an intuitive interface to explore orthologous relationships on the web and allows bulk data download via the web, command-line tools, and an API. We detail the methodology, including anchor species selection and the decision tree used to arrive at high-confidence one-to-one orthology relationships. NCBI Orthologs is a valuable resource for facilitating functional annotation efforts and enhancing our understanding of eukaryotic gene evolution.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"843-859"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137838","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}
Felix Langschied, Ruben Iruegas, Mateusz Sikora, Roberto Covino, Ingo Ebersberger
{"title":"A Multi-level Perspective on the Evolution of Orthologs and Their Functions.","authors":"Felix Langschied, Ruben Iruegas, Mateusz Sikora, Roberto Covino, Ingo Ebersberger","doi":"10.1007/s00239-025-10276-2","DOIUrl":"10.1007/s00239-025-10276-2","url":null,"abstract":"<p><p>Orthologs, evolutionarily related genes that diverged through speciation, are mutually the closest related sequences in different species. Consequently, they are ideal candidates for identifying functionally equivalent genes across taxa, a prerequisite for transferring gene function information from model to non-model organisms in silico. However, orthologs are not immune to functional divergence. Failing to recognize such divergent instances results in spurious functional annotation transfer. Here, we propose to treat the functional equivalence of orthologs as a null hypothesis that must be critically tested rather than assumed. This requires integrating several lines of evidence to evaluate both changes in an ortholog's network of molecular interactions and alterations in its biochemical activity. We outline how such activity shifts can be assessed using increasingly fine-grained analyses, including comparisons of protein feature architectures and predicted 3D structures. While some orthology resources incorporate aspects of this evidence, such assessments are often manual and not scalable. We argue for a systematic, multi-level perspective to detect functional divergence prior to annotation transfer. To support the broader adoption of this approach, we offer methodological recommendations and practical examples that demonstrate the value of this framework in large-scale comparative genomics.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"720-729"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280385","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}
Ali Yazdizadeh Kharrazi, Adrian M Altenhoff, Nikolai Romashchenko, Christophe Dessimoz, Sina Majidian
{"title":"OrthoXML-Tools: A Toolkit for Manipulating OrthoXML Files for Orthology Data.","authors":"Ali Yazdizadeh Kharrazi, Adrian M Altenhoff, Nikolai Romashchenko, Christophe Dessimoz, Sina Majidian","doi":"10.1007/s00239-025-10271-7","DOIUrl":"10.1007/s00239-025-10271-7","url":null,"abstract":"<p><p>The OrthoXML file is a standard file format for orthology data. It provides a standardized structure for describing orthologous and paralogous relationships while allowing the user to store custom and database-specific data in the same format. Although many orthology databases use it as a way to export data, there is no comprehensive toolkit for working with this format. Here, we introduce the OrthoXML-tools ( https://github.com/DessimozLab/orthoxml-tools ), a comprehensive toolkit for loading, manipulating, and exporting the OrthoXML files to other formats. We show its capabilities and performance on our benchmarks.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"800-805"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149411","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":"OrthoGrafter: Rapid Identification of Orthologs from Precomputed Placement in Phylogenetic Trees.","authors":"Christopher M Williams, Paul D Thomas","doi":"10.1007/s00239-025-10279-z","DOIUrl":"10.1007/s00239-025-10279-z","url":null,"abstract":"<p><p>The identification of orthologs plays an important role in comparative genomics and function inference. Here, we present OrthoGrafter, a bioinformatics tool for taking one or more query sequences and inferring a set of orthologs drawn from the collection of 143 well annotated species in the PANTHER database of reconciled gene trees. OrthoGrafter takes sets of graft points output by the highly used TreeGrafter software (either the standalone package or InterProScan), and for each one, outputs a list of predicted orthologous genes from the grafted PANTHER tree (with the ability to additionally output paralog and xenolog sets). If the taxonomic identifier for the query is also provided, OrthoGrafter incorporates the novel step of adjusting the graft point to facilitate consistent taxonomic assignment for the graft within the reconciled gene family, which we demonstrate shows an improvement in the ortholog inference via correlation with orthologs provided by the OMA database. Lightweight and utilizing precomputed results to enable rapid determination of ortholog predictions for large sample groups, OrthoGrafter is available at https://github.com/pantherdb/OrthoGrafter. .</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"820-829"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582097","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}
Garance Sarton-Lohéac, Nikolai Romashchenko, Clément Marie Train, Sina Majidian, Natasha Glover
{"title":"Reconstructing Evolutionary Histories with Hierarchical Orthologous Groups.","authors":"Garance Sarton-Lohéac, Nikolai Romashchenko, Clément Marie Train, Sina Majidian, Natasha Glover","doi":"10.1007/s00239-025-10277-1","DOIUrl":"10.1007/s00239-025-10277-1","url":null,"abstract":"<p><p>With the rapid advancement of large-scale sequencing initiatives, the need for efficient and accurate methods for inferring orthologous and paralogous relationships has never been more critical. Hierarchical orthologous groups (HOGs) provide a powerful solution to this challenge, offering a precise, scalable framework to study gene families and their evolutionary histories across diverse species. In this review, we introduce the concept of HOGs and explore their advantages over traditional methods. Next, we highlight key applications of HOGs, including their use in representing gene families, inferring ancestral genomes, tracking gene gain and loss events, functional annotation, and phylogenetic profiling. We overview the process of constructing HOGs and discuss the challenges and limitations of HOG inference. The HOG framework provides a clear and structured approach to organizing homologous genes, making it possible to gain deeper insights into gene family and species evolution.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"740-764"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564275","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}