Patrick Heidbreder, Noora Poikela, Pierre Nouhaud, Tuomas Puukko, Konrad Lohse, Jonna Kulmuni
{"title":"Genomic incompatibilities are persistent barriers when speciation happens with gene flow in Formica ants.","authors":"Patrick Heidbreder, Noora Poikela, Pierre Nouhaud, Tuomas Puukko, Konrad Lohse, Jonna Kulmuni","doi":"10.1093/molbev/msag063","DOIUrl":"10.1093/molbev/msag063","url":null,"abstract":"<p><p>A current goal of speciation research is identifying loci underlying reproductive barriers between species. Locating barrier loci in population genomic data is difficult due to the often-complex demographic history of diverged taxa and heterogeneity in evolutionary forces across the genome. We take advantage of natural hybridization between 2 wood ant species (Formica aquilonia and Formica polyctena) to identify regions of reduced long-term gene flow using demographically explicit scans of nonadmixed genomes. In addition, we identify candidate Bateson-Dobzhansky-Muller incompatibilities (BDMIs) through an imbalanced recombinant haplotype frequency analysis using a large sample of natural F. aquilonia × F. polyctena hybrid genomes. These approaches find barriers and BDMIs scattered across the genome. Furthermore, BDMIs significantly overlap with long-term barriers, indicating that some BDMIs have persisted despite divergence with gene flow. Intriguingly, the number of pairwise interactions a BDMI has correlates with its long-term barrier strength: hub-like BDMIs with many interactions reduce gene flow more effectively. Finally, we find that long-term barriers are depleted for both coding sequences (CDS) and transposable elements (TEs), while candidate BDMIs are associated with snRNAs and LTR transposons, specifically Ty1-copia. In contrast, regions where long-term barriers and BDMIs co-locate are significantly associated with introns but not CDS or TEs, implying a potential role of alternative splicing or gene regulation in long-term incompatibilities. Our results highlight the underappreciated impact of BDMI connectivity on the persistence of reproductive barriers over time.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13143019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147434252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Degeneration and adaptive evolution of digits in ratite birds.","authors":"Wen Kang, Günter Wagner, Qi Zhou","doi":"10.1093/molbev/msag101","DOIUrl":"10.1093/molbev/msag101","url":null,"abstract":"<p><p>The amniote digits have undergone recurrent modifications, with the diversified molecular mechanisms more studied among mammals than reptiles. Here we focus on the emu wings and ostrich feet, both of which experienced species-specific digit changes driven respectively by secondary flight loss and adaptation to running. By comparing their digit transcriptomes to those of chicken and alligator, we identified different gene networks in skeleton/muscle development responsible for the degenerated digits in archosaur ancestors and emu, but those in epidermal development for the load-bearing digit of ostrich. These results provide new clues for developmental programs of different cell types between different digits, on which natural selection can convergently operate.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Balig Panossian, Ailsa H C McLean, Vilas Patel, Taoping Wu, Muhammad Bilal Haider, Kerry M Oliver, Lee M Henry
{"title":"Phage toxin variants are linked to protection specificity in a defensive symbiont.","authors":"Balig Panossian, Ailsa H C McLean, Vilas Patel, Taoping Wu, Muhammad Bilal Haider, Kerry M Oliver, Lee M Henry","doi":"10.1093/molbev/msag079","DOIUrl":"10.1093/molbev/msag079","url":null,"abstract":"<p><p>Insects often depend on symbiotic bacteria for protection; however, the mechanisms by which these microbes target specific natural enemies remain poorly understood. In aphids, different strains of the facultative symbiont Hamiltonella defensa provide highly specific protection against particular species of parasitoid wasps. To uncover the genetic basis of this specificity, we analyzed 26 Hamiltonella genomes and their toxin-encoding APSE bacteriophages with distinct protective phenotypes. Our analyses revealed that Hamiltonella strains share a conserved core genome but differ significantly in accessory gene content, reflecting their distinct evolutionary origins. Strikingly, we show that variation in toxin types is the key distinguishing feature of APSE phages in Hamiltonella strains that protect against different parasitoid species. These toxin repertoires include several novel candidates, such as variants with MAC/perforin domains and leucine-rich repeat (LRR) proteins previously unreported in insect defensive symbionts. We also reveal cases of multiple cointegrated APSE phages carrying different toxins within a single genomic locus. These findings suggest phage-borne toxins are important determinants of enemy-specific defense and point to phage-driven toxin diversification as a major force shaping the functional evolution of this symbiosis. This work highlights how mobile genetic elements influence the ecological roles and diversification of protective symbionts.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yan Hao, Xiang Zhou, Qingshuo Zhao, Huishang She, Yun Fang, Laikun Ma, Zhengting Zou, Weiwei Zhai, Per G P Ericson, Fumin Lei, Fanwei Meng, Shihua Zhang, Yanhua Qu
{"title":"Avian lung single-cell atlas elucidates evolutionary divergence in endothermic respiration.","authors":"Yan Hao, Xiang Zhou, Qingshuo Zhao, Huishang She, Yun Fang, Laikun Ma, Zhengting Zou, Weiwei Zhai, Per G P Ericson, Fumin Lei, Fanwei Meng, Shihua Zhang, Yanhua Qu","doi":"10.1093/molbev/msag072","DOIUrl":"10.1093/molbev/msag072","url":null,"abstract":"<p><p>The evolution of distinct lung architectures in birds (tubular air capillaries) and mammals (alveoli) represents a classic example of convergent evolution, yet their cellular differences remain poorly characterized. We present the comparative single-cell atlas of avian and mammalian lungs, revealing four key findings. First, we discover a persistent hybrid cell population (AT1/AT2) in neonatal and adult birds that disappears postnatally in mice, uncovering distinct strategies for lung maintenance. Second, cross-species comparisons highlight striking divergence in alveolar cell types, reflecting specialized adaptations to different respiratory demands. Third, avian lungs show unique molecular signatures in proliferation and saccular development pathways, potentially explaining their superior respiratory efficiency. Fourth, our viral receptor analysis uncovered differential ACE2 (SARS-CoV-2 receptor) expression but conserved EGFR (influenza A receptor), suggesting species-specific disease vulnerabilities. This work provides unprecedented insights into the evolutionary and developmental mechanisms shaping lung diversity in endotherms, with implications for respiratory biology, regenerative medicine, and zoonotic disease research.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":"43 5","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"evo3D R package: a spatial haplotype framework for structure-informed analysis of molecular evolution.","authors":"Bradley K Broyles, Qixin He","doi":"10.1093/molbev/msag111","DOIUrl":"https://doi.org/10.1093/molbev/msag111","url":null,"abstract":"<p><p>At the molecular level, selection pressures often act on protein structural features, yet most evolutionary analyses remain confined to linear sequences. Early structure-informed approaches improved interpretability by mapping single-site metrics onto protein structures, and later methods introduced 3D sliding windows to capture spatially clustered signals missed by linear window approaches. These frameworks, however, are restricted to predefined statistics and narrowly defined 3D window types, limiting the scope of questions that can be addressed. We developed an R package, evo3D, as a new framework for structure-informed evolutionary analysis that supports a wide range of downstream statistics and scales from simple to complex structures. evo3D extracts structure-informed multiple sequence alignment subsets (spatial haplotypes), making the structure-informed unit of analysis directly available to users. The framework supports fixed-count and fixed-distance spatial windows, introduces residue and codon analysis modes, and extends to multimers, interfaces, and multiple structural models through a single wrapper, run_evo3d(). We demonstrate evo3D's utility by performing an epitope-level diversity scan of Hepatitis C virus E1/E2 complex, identifying conserved spatial neighbourhoods missed by linear sliding windows, and by evaluating evo3D's scalability on the octameric Chikungunya virus E1/E2 assembly. Importantly, evo3D formalises the core components of structure-informed analysis of molecular evolution and removes technical barriers. As a result, the framework streamlines the evaluation of evolutionary patterns directly within 3D structural contexts, and we anticipate its wide application in molecular evolution studies. The package is available at github.com/bbroyle/evo3D.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mridula Nandakumar, Max Lundberg, Mehrnaz Nouri, Christine Valfridsson, Fredric Carlsson, Lars Råberg
{"title":"Divergent cis-regulatory haplotypes at Tlr2 are associated with immune responsiveness.","authors":"Mridula Nandakumar, Max Lundberg, Mehrnaz Nouri, Christine Valfridsson, Fredric Carlsson, Lars Råberg","doi":"10.1093/molbev/msag113","DOIUrl":"https://doi.org/10.1093/molbev/msag113","url":null,"abstract":"<p><p>Positive and balancing selection on pattern recognition receptors (PRRs) is widely thought to target ligand-binding domains and affect the specificity of recognition of different pathogens. Alternatively, positive/balancing selection on PRRs could affect general responsiveness by targeting for example signaling domains or cis-regulatory variation. Studies of a wild rodent (the bank vole, Clethrionomys glareolus) have shown that Tlr2-a lipoprotein-binding PRR-is highly polymorphic with divergent haplotypes and signatures of balancing selection, and that Tlr2 genotype is associated with susceptibility to Borrelia afzelii infection in the wild. To investigate what aspect of Tlr2 function has been under selection, we here perform integrated population genetic and functional analyses. Ex vivo infection experiments show that the protective Tlr2 haplotype produces a stronger proinflammatory response to B. afzelii compared to the haplotype associated with susceptibility. Tlr2 genotype has a similar, albeit not statistically significant, effect on responsiveness to the phylogenetically distant pathogen Streptococcus pyogenes. We find that the strongest signature of balancing selection is 4.6 kb upstream of the Tlr2 coding sequence, near a putative enhancer, and that Tlr2 exhibits allele-specific expression such that the protective haplotype is more expressed. Collectively these results indicate that balancing selection has primarily acted on cis-regulatory variation affecting the general responsiveness via Tlr2-signaling rather than on polymorphisms affecting Tlr2 ligand-binding specificity.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GAPIT Version 4: Integration of GWAS into Genomic Prediction.","authors":"Jiabo Wang, Zhiwu Zhang","doi":"10.1093/molbev/msag107","DOIUrl":"https://doi.org/10.1093/molbev/msag107","url":null,"abstract":"<p><p>Genomic prediction leverages all available markers, irrespective of their statistical significance in genome-wide association studies (GWAS). Recent advancements in marker density, sample sizes, and sophisticated statistical GWAS methods have demonstrated that integrating GWAS results can potentially boost the accuracy of genomic predictions. The Genomic Association and Prediction Tool (GAPIT) has recently begun incorporating GWAS findings into its prediction framework, streamlining this approach, referred to as GWAS-Assisted Genomic Best Linear Unbiased Prediction (GAGBLUP). A sufficient simulation study revealed that the benefits of GAGBLUP depend on the GWAS model used. Multiple-locus models, such as Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK), outperformed single-locus models, like the mixed linear model. Specifically, when BLINK GWAS results in a real trait were incorporated into genomic Best Linear Unbiased Prediction (GBLUP), prediction accuracy improved by over 20% compared to GBLUP alone. This approach integrates the trait-specific insights from GWAS with the polygenic modeling capacity of GBLUP, resulting in more stable prediction across varying genetic backgrounds. This broader applicability enhances the utility of genomic selection in breeding programs, enabling its deployment across a wider range of crops and trait architectures.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyril J Versoza, Karen L Bales, Jeffrey D Jensen, Susanne P Pfeifer
{"title":"Characterization of de novo germline mutations suggests a strong male mutation bias in coppery titi monkeys (Plecturocebus cupreus).","authors":"Cyril J Versoza, Karen L Bales, Jeffrey D Jensen, Susanne P Pfeifer","doi":"10.1093/molbev/msag112","DOIUrl":"10.1093/molbev/msag112","url":null,"abstract":"<p><p>Although recent advances in genomics have enabled the high-resolution study of whole genomes, our understanding of one of the key evolutionary processes, mutation, still remains limited. In primates specifically, studies have largely focused on humans and their closest evolutionary relatives, the great apes, as well as a handful of species of biomedical or conservation interest. Yet, as mutation rates vary across genomic regions, individuals, and species, a greater understanding of the underlying evolutionary dynamics at play will ultimately be illuminated by not only additional sampling across the Order, but also by a greater depth of sampling within-species. To address these needs, we here present the first population-scale genomic resources for the coppery titi monkey (Plecturocebus cupreus)-a platyrrhine of considerable biomedical interest for both social behavior and neurobiology. Deep whole-genome sequencing of 15 parent-offspring trios, together with a computational de novo mutation detection pipeline based on pan-genome graphs, has provided a detailed picture of the sex-averaged mutation rate-0.63 × 10-8 (95% CI: 0.43 × 10-8-0.90 × 10-8) per site per generation-as well as the effects of both sex and parental age on underlying rates, demonstrating a significant paternal age effect. Coppery titi monkey males exhibit long reproductive lifespans, afforded by long-term pair bonding in the species' monogamous mating system, and our results have demonstrated that individuals reproducing later in life exhibit one of the strongest male mutation biases observed in any non-human primate studied to date. Taken together, this study thus provides an important piece of the puzzle for better comprehending the mutational landscape across primates.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolutionary conservation and divergence of phagocytic and coagulation programs across bilaterian circulating immune cells.","authors":"Yanan Li, Xiang Liu, Hongxi Chen, Qi Yang, Qun Liu, Hong-Yan Wang, Shuo Li, Xianghui Zhang, Yingyi Huang, Jian-Yang Chen, Lucas B Doretto, Ivana F Rosa, Shenglei Han, Chen Li, Inge Seim, Yifang Lu, Kaiqiang Liu, Junqiang Xu, Yingying Zhang, Shijie Hao, Sha Liao, Shanshan Pan, Junjie Shi, Yadong Chen, Chenghua Li, Qian Wang, Shanshan Liu, Guangyi Fan, Changwei Shao","doi":"10.1093/molbev/msag109","DOIUrl":"https://doi.org/10.1093/molbev/msag109","url":null,"abstract":"<p><p>Innate immunity represents a foundational defense strategy across bilaterians, with phagocytosis and coagulation serving as its central effector mechanisms. However, it remains uncertain whether these mechanisms evolved from conservative ancestral regulatory modules or emerged through lineage-specific adaptations. This ambiguity currently impedes a deeper understanding of immune system evolution. We constructed a cross-phylum single-cell atlas of circulating immune cells from nine bilaterian species. Our comparative analysis revealed a pattern of evolutionary tinkering, wherein core functional modules followed largely independent evolutionary trajectories. The specific phagocytic-like cells (PLCs) identified in invertebrates share a core gene regulatory network orchestrated by the TFE/MiT transcription factor family with vertebrate myeloid cells, indicating deep homology. Notably, we identify and characterize coagulation effector cells in invertebrates for the first time. These clot-associated hemocytes demonstrate transcriptome-level convergence in the absence of a conserved regulatory framework, achieving similar functional states through lineage-specific genetic pathways. Our findings highlight the distinct evolutionary trajectories of innate immune cells, distinguishing the ancient, hardwired regulatory program of phagocytosis from the convergent, adaptive nature of coagulation. This study offers a unified single-cell perspective on the assembly and diversification of the bilaterian immune system.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia C Malnak, Saira Montermoso, Frederic D Bushman, Noam Auslander
{"title":"Uncovering viral protein acquisition events and human-specific folds with pairwise comparisons of predicted protein structures.","authors":"Julia C Malnak, Saira Montermoso, Frederic D Bushman, Noam Auslander","doi":"10.1093/molbev/msag110","DOIUrl":"https://doi.org/10.1093/molbev/msag110","url":null,"abstract":"<p><p>Pairwise sequence comparisons are at the center of molecular evolutionary analyses. However, viral pairwise comparisons are challenging because extreme mutation rates and evolutionary pressure cause genomes to diverge rapidly, limiting detectable sequence similarity to fewer than 3% of virus pairs. To overcome these limitations, we compared viruses based on structural similarity, using predicted protein structures from ColabFold and Foldseek to define protein fold clusters. We represented each virus genome by its protein structural content. Pairwise similarities between viruses were then quantified using the Jaccard index based on the presence or absence of protein fold clusters. Using a recently established viral protein fold database, we compared all pairs of eukaryotic viruses in RefSeq. This approach increased the proportion of comparable viral genome pairs from 2.4% to 16.5%. Using this protein-fold representation of viruses, we were able to accurately predict viral families with an average sensitivity of 85.9%. Investigation of viral families showing limited sensitivity with this approach uncovered a laterally transferred structural cluster (Rep/NS1) broadly shared across diverse viral families and found in the avian lineage of adenoviruses. Sequence homology suggests that this Rep was acquired from Parvoviridae, but the protein is mutant in the ATPase active site, indicating possible exaptation towards a purely DNA binding function. In Gammapapillomaviruses, several E4 clusters were associated with human tropism. In summary, by representing viruses with structural protein clusters, we can classify highly divergent viruses, trace lateral gene transfer, and uncover features associated with viral host range.</p>","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}