Journal of Molecular Evolution最新文献

{"title":"Quest for Orthologs in the era of Data Deluge and AI: Challenges and Innovations in Orthology Prediction and Data Integration.","authors":"Sina Majidian, Armin Hadziahmetovic, Felix Langschied, Stefano Pascarelli, Silvia Prieto-Baños, Jorge Rojas-Vargas, Edward L Braun, Christophe Dessimoz, Abdoulaye Baniré Diallo, Dannie Durand, Gang Fang, Toni Gabaldón, Natasha Glover, David A Liberles, Claire McWhite, Erik L L Sonnhammer, Paul D Thomas, Aïda Ouangraoua, Irene Julca","doi":"10.1007/s00239-025-10272-6","DOIUrl":"10.1007/s00239-025-10272-6","url":null,"abstract":"<p><p>The rapid advancement of DNA sequencing technologies and computational algorithms has led to an unprecedented surge in genomic data, driven by several large-scale sequencing projects worldwide. Orthology plays a crucial role in understanding evolutionary patterns of genes and their functions. At the last Quest for Orthologs meeting (Montréal, Canada-2024), we discussed recent advances in orthology inference, with a focus on the impact of artificial intelligence (AI), protein structures, RNA splicing isoforms, and protein domain evolution together with other evolutionary considerations. A long-standing challenge in the field is the functional annotation of paralogs, for which we present novel approaches. The meeting also emphasised strategies for integrating diverse genetic features into the concept of orthology, encouraging frameworks that account for elements like alternative splicing, domain organisation, and regulatory sequences. We discuss various applications of orthology and paralogy to environmental research, agriculture, and comparative genomics. Additionally, we report recent progress in orthology inference methodologies and resources. This work represents a collaborative synthesis of insights and innovations presented at the 8th Quest for Orthologs meeting, highlighting current progress while outlining future directions for orthology research.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"702-719"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286362","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":"Evaluating Pretrained Protein Language Model Embeddings as Proxies for Functional Similarity.","authors":"Robert Shaw, Samuel D Love, Claire D McWhite","doi":"10.1007/s00239-025-10282-4","DOIUrl":"10.1007/s00239-025-10282-4","url":null,"abstract":"<p><p>Protein Language Models (PLMs) have emerged as powerful tools for representing protein sequences. We explore how embeddings (numeric vector representations) from pretrained PLMs can serve as direct numeric proxies for protein structure and function without requiring additional training or fine-tuning. In a proof-of-concept study of 22 cross-species complementation triplets-a gold standard for functional similarity where genes from one species are tested for their ability to rescue gene deletions in another species-we find that ESM-C 600 M embeddings summarized into pooled sliced-Wasserstein embeddings achieved high discrimination of subtle functional differences. This pooling method captures distributional properties of amino acid embeddings by comparing them against reference points using optimal transport theory. While our limited sample size precludes definitive conclusions about whether PLM embeddings systematically outperform sequence-based methods in detecting protein functional similarity, our preliminary results demonstrate the potential of using protein embeddings for functional analysis. Our exploratory analysis of orthology relationships suggests that embedding similarity may correlate with functional conservation, with the least diverged ortholog showing higher embedding similarity in approximately two-thirds of cases. Analyzing the Ortholog Conjecture-that orthologs maintain greater functional similarity than paralogs at equivalent sequence divergence-we do not observe clear differences between one-to-one orthologs and inparalog embedding similarities. Finally, we propose integrating PLMs with phylogenetic methods in a hybrid approach that leverages their complementary strengths: PLM-derived numeric embeddings for rapid homology detection and phylogenetics for evolutionary precision. We introduce embedding-tree versus gene-tree discordance as a potential metric to detect functional divergence between closely related proteins. Integrating protein embeddings with sequence analysis may enable a more nuanced understanding of protein function and evolutionary dynamics.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"765-776"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145581999","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":"Understanding Functional Evolution in Orthologs and Paralogs.","authors":"Maeva Perez, Katherine Hurm, David A Liberles","doi":"10.1007/s00239-025-10274-4","DOIUrl":"10.1007/s00239-025-10274-4","url":null,"abstract":"<p><p>The Quest for Orthologs has focused on identifying orthologs from the perspective that they are more likely to have retained function over a given evolutionary distance than paralogs (or xenologs) have, enabling the transfer of functional annotation. It has become clear that function is defined by biochemistry that is under selective pressure. Quantitative descriptions of function are available within this framework and may offer understanding that is not provided by more qualitative descriptions of function. Changes in selected biochemistry, mutational processes, and selective strength can all lead to quantitative changes in function. This is discussed for proteins that have been subjected to gene duplication and for proteins that have evolved simply through the speciation process.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"730-739"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286319","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":"Perspectives on Orthology During the Quest for Orthologs.","authors":"Natasha Glover, David A Liberles","doi":"10.1007/s00239-025-10290-4","DOIUrl":"10.1007/s00239-025-10290-4","url":null,"abstract":"<p><p>This special issue from the Quest for Orthologs community highlights ongoing challenges in detecting and characterizing orthologous genes in the annotation of protein functions. Eleven articles are presented describing ongoing research in this area.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"699-701"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564278","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":"Evolution of the Metazoan Protein Domain Repertoire Revealed by a Birth-Death-Gain Model.","authors":"Yuting Xiao, Maureen Stolzer, Larry Wasserman, Dannie Durand","doi":"10.1007/s00239-025-10286-0","DOIUrl":"10.1007/s00239-025-10286-0","url":null,"abstract":"<p><p>Reconstruction of the ancestral protein repertoire offers valuable insights into the tempo and mode of protein content evolution, but can be highly sensitive to model choice. We used a phylogenetic Birth-Death-Gain model to investigate the evolution of the metazoan protein domain repertoire. Domains, protein modules with a distinct structure and function, represent the basic components of protein repertoire.  Given a species tree and a census of protein domain families in present-day species, we estimated the most likely rates of domain family origination, duplication, and loss. Rates were allowed to vary across species lineages and domain families, decoupling these factors. Statistical hierarchical clustering of family-specific rates reveals groups of domains evolving in concert. Moreover, we observe a strong and significant association between family rate and family function.  Interestingly, families with functions associated with metazoan innovations tend to have the fastest rates. We further inferred the expected ancestral domain content and the history of domain family gains, losses, expansions, and contractions in each species lineage. Our analysis reveals an ongoing process of domain family replacement and resizing, consistent with extensive remodeling of the protein domain repertoire. This stands in contrast to recent reports of widespread loss during metazoan evolution, which were obtained with more constrained models. The use of a powerful, probabilistic Birth-Death-Gain model reveals an unexpected level of genomic plasticity.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"777-799"},"PeriodicalIF":1.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12756402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850384","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":"Efficiency of Ancestral Inference and Characterization of Genetic Structure of Chinese Kazakh Group with a Novel InDel Panel.","authors":"Qinglin Liu, Lisiteng Luo, Qinglin Liang, Xiaolian Wu, Ming Zhao, Xi Yuan, Yifeng Lin, Chunmei Shen, Bofeng Zhu","doi":"10.1007/s00239-025-10275-3","DOIUrl":"10.1007/s00239-025-10275-3","url":null,"abstract":"<p><p>Inferring the biogeographic origin of unknown individual is crucial in forensic practice. To enhance the efficacy of biogeographic origin inference, we previously developed a novel panel containing 56 ancestry-informative insertion/deletions (AI-InDels), three Y-InDels, and the Amelogenin gene, all with amplicons less than 200 bp, facilitating DNA analysis of degraded samples. In this research, we investigated the forensic performance of the InDel panel in the Kazakh group in China, elucidated the genetic structure of Kazakh group, and verified the panel's efficacy in assigning unknown individuals to the appropriate intercontinental regions. The findings demonstrated that the novel panel showed relatively high genetic polymorphisms of autosomal InDels and could serve as an efficient tool for forensic individual identification in Kazakh group. Furthermore, the multiple results of population genetic analyses indicated that the Kazakh group has a mixture of ancestral components from East Asian and European populations, with East Asian ancestry predominating. Using different machine learning models, we found that the novel panel assigned unknown individuals to their intercontinental regions with at least 99% accuracy at the three-continental level and at least 90% accuracy at the five-continental level. In conclusion, we demonstrated that the novel panel can effectively reveal the genetic structure of the group with mixed genetic background and infer the biogeographic origins of unknown individuals with high accuracy.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"682-697"},"PeriodicalIF":1.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145377631","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":"Cystathionine Gamma-Lyase: A Potential Longevity Gene Under Selection?","authors":"Gary J Ren, Frances E Hauser, Elissa Khodikian, Nathan R Lovejoy, Cosima S Porteus","doi":"10.1007/s00239-025-10273-5","DOIUrl":"10.1007/s00239-025-10273-5","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) plays a crucial role in various physiological processes and has been implicated in modulating aging through its impacts on oxidative stress and cellular health. This study investigates the evolutionary dynamics of the cystathionine-β-synthase (CBS), the cystathionine-ƴ-lyase (CSE), and the 3-mercaptopyruvate sulfurtransferase (3-MST) genes, involved in endogenous H₂S production. We investigated CBS, CSE, and 3-MST in long-lived mammals, focusing on the naked mole-rat (Heterocephalus glaber). We hypothesized that these genes would exhibit signs of positive selection linked to extended lifespan. Codon-based evolutionary models were used to compare these genes across 114 mammalian species. Our results revealed a relaxation of purifying selection instead of positive selection in CSE, but not CBS and 3-MST, in long-lived mammals, suggesting an accumulation of mutations that enhance physiological functions related to longevity. In the naked mole-rat, CSE exhibited clear signs of positive selection, particularly in residues G116A and T118V, associated with increased protein stability and enhanced binding affinity to the cofactor pyridoxal-5'-phosphate (PLP). These mutations possibly improve CSE catalytic efficiency and potentially H₂S production, supporting the naked mole-rat's unique adaptations to its subterranean habitat and contributing to its remarkable lifespan. Our findings indicate a potential correlation between longevity and selection on the CSE gene, but not the CBS and 3-MST genes, highlighting the complex role of H₂S in aging and cellular health. The study provides new insights into the molecular mechanisms underlying lifespan extension in long-lived mammals and underscores the potential adaptive significance of H₂S biogenesis in the naked mole-rat.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"665-681"},"PeriodicalIF":1.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191747","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":"Screening for Viruses in Pallas's Long-Tongued Bats (Glossophaga soricina) in Brazil.","authors":"Alexandre Sita, Gabriela E Birlem, Deivid S da Silva, Larissa Mallmann, Meriane Demoliner, Mariana S da Silva, Juliana S Gularte, Vyctoria M A G Pereira, Paula R de Almeida, Alana W Hansen, André A Witt, Juliane D Fleck, Fernando R Spilki, Daniela T da Rocha, Matheus N Weber","doi":"10.1007/s00239-025-10264-6","DOIUrl":"10.1007/s00239-025-10264-6","url":null,"abstract":"<p><p>Bats are considered a unique group of mammals and are recognized as natural hosts for a variety of emerging viral agents of One Health importance. In Brazil, nine bat families are described, of which the family Phyllostomidae contains the highest number of cataloged species. Within them, the Pallas's long-tongued bat (Glossophaga soricina) is one of the most widely distributed species in South America. G. soricina are specialized in the use of nectar and pollen as food and therefore are extremely important in the dynamics of ecosystems. In this way, the present study aimed to evaluate the presence of viruses from the families Coronaviridae, Paramyxoviridae, Orthomyxoviridae, Reoviridae, and Rhabdoviridae in G. soricina bats. Samples of oral and rectal swabs from 40 bats in four bat colonies were collected in Southern Brazil. Four samples tested positive for coronavirus by PCR. Following DNA sequencing and phylogenetic analyses, they were classified into the Amalacovirus subgenus, within the alphacoronavirus (α-CoV) genus. In addition, it was possible to observe two distinct strains within the same bat colony. The results obtained reinforce that phyllostomids are the main reservoirs of amalacoviruses. Eco-vigilance in bats with close access to urban environments is essential for monitoring possible future spillover events.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"600-609"},"PeriodicalIF":1.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957415","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":"Unveiling the Evolutionary History and Functional Significance of the Protein Z-Dependent Protease Inhibitor (ZPI) Across Vertebrates.","authors":"Chennakesavan Suganthi, Parthiban Akshayaa, Tanusree Sengupta, Narayanan Manoj","doi":"10.1007/s00239-025-10267-3","DOIUrl":"10.1007/s00239-025-10267-3","url":null,"abstract":"<p><p>Serpins, characterized by a conserved structural fold, serve diverse biological roles. Protein Z-dependent protease inhibitor (ZPI), a serpin superfamily member, acts as an endogenous anticoagulant by inhibiting clotting factors Xa (fXa) and XIa (fXIa). Beyond anticoagulation, ZPI has roles in inflammation, cancer, and immune regulation. However, its exact pathophysiological role is yet to be fully characterized. To elucidate ZPI's evolutionary trajectory and non-haemostatic roles, we conducted a comprehensive phylogenetic analysis integrating sequence, gene structure, and synteny data. We identified a lamprey-specific serpin, ZPIL_AGTL_PMA, containing both an inhibitory reactive center loop (RCL) and an angiotensin II (Ang II) motif. This finding suggests that ZPIL_AGTL_PMA represents an ancestral bifunctional serpin from which ZPI and angiotensinogen (AGT), a non-inhibitory serpin involved in blood pressure regulation, evolved by sub-functionalization in jawed vertebrates. This bifunctionality within a single gene in lamprey likely reflects an ancestral vertebrate trait. Gene cluster analyses showed serpinA10 (ZPI) as possibly the earliest member, with other Clade A serpins arising via subsequent duplication. The chromosomal location of this gene cluster is conserved in most vertebrates, except Carnivores and Suidea. Sequence analysis indicated potential non-inhibitory ZPI variants in certain species with atypical non-serine residues at the P1' position within its RCL, a critical determinant of inhibitory serpin activity. The close evolutionary relationship between ZPI and AGT further suggests mechanistic interplay between coagulation and blood pressure regulation, highlighting shared regulatory pathways involving these serpins. Together, these findings expand the functional landscape of ZPI and underscore the dynamic evolution of serpin-mediated physiological processes.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"636-649"},"PeriodicalIF":1.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064954","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":"Chlorophyllide a Oxygenase (CAO) Gene Duplication Across the Viridiplantae.","authors":"Mackenzie C Poirier, Roberta Wright, Marina Cvetkovska","doi":"10.1007/s00239-025-10266-4","DOIUrl":"10.1007/s00239-025-10266-4","url":null,"abstract":"<p><p>Viridiplantae, a diverse group of green plants and algae that have evolved from a common ancestor, are unified in their ability to produce and use two types of chlorophyll (chlorophyll a and chlorophyll b) to capture light energy. In addition to playing a role in light harvesting, chlorophyll b is required at the appropriate level for the accumulation, assembly, and stability of light-harvesting complexes within the photosynthetic apparatus. Chlorophyll b is synthesized from chlorophyll a by the enzyme chlorophyllide a oxygenase (CAO), a Rieske-type mononuclear non-heme iron oxygenase. A regulatory degron sequence, described in detail only in land plants, regulates the stability of CAO proteins based on the availability of chlorophyll b. Recent identification of CAO gene duplication in bryophyte and green algal species, combined with expanded availability of sequenced genomes within the Viridiplantae, prompted further investigation into the role of gene duplication in the evolution of chlorophyll b biosynthesis. Examination of genomes from 246 plant and algae species revealed independently occurring CAO duplications throughout the Viridiplantae, with a higher prevalence of duplication in land plants compared to their algal relatives. Additionally, we demonstrate that the degron sequence is poorly conserved in chlorophytes, but first appears as a conserved sequence in charophytes, and is very highly conserved among the embryophytes. The evolutionary history and functional role of CAO throughout the Viridiplantae lineage is discussed based on these key observations, adding to our understanding of chlorophyll b biosynthesis and the role of CAO in photosynthetic species.</p>","PeriodicalId":16366,"journal":{"name":"Journal of Molecular Evolution","volume":" ","pages":"620-635"},"PeriodicalIF":1.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069770","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}