Molecular Biology And Evolution[JOURNAL]
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200 papers
Novel 20th century rotavirus alphagastroenteritidis strains identified in formalin-fixed and ethanol-preserved museum specimens.
Porter AF, Holleley CE, Donato CM … +5 more , Hahn EE, Smith IL, Haff TM, Wilson CA, Alexander MR
Mol Biol Evol · 2026 May · PMID 42131897 · Full text
Archival specimens held in biorepositories (e.g. natural history collections) offer rare temporal snapshots of global biodiversity. These collections not only preserve species morphology and aspects of ecology, but incre...
Archival specimens held in biorepositories (e.g. natural history collections) offer rare temporal snapshots of global biodiversity. These collections not only preserve species morphology and aspects of ecology, but increasingly provide access to historical molecular data, including insights into wildlife disease. As several pandemics have originated from animal viruses spilling over into the human population (i.e. SARS-CoV-2/COVID-19, 2009 H1N1 influenza, and HIV/AIDS), characterizing the diversity of viruses circulating in wildlife populations is essential for proactive pandemic preparedness. Yet, current surveillance remains biased toward contemporary viruses of economic importance. One solution to bridging spatiotemporal gaps in wildlife virus knowledge is retrospective screening of vouchered wildlife specimens. However, molecular analysis of specimens has been hindered by formalin fixation, which degrades and cross-links nucleic acids. Here, we demonstrate that formalin-fixed vouchered wildlife specimens retain both host and viral RNA fragments after being stored for up to 60 years. We recovered fragments of divergent strains of Rotavirus alphagastroenteritidis from two Australian species of order Chiroptera; Nyctophilus geoffroyi (lesser long-eared bat) and Rhinolophus megaphyllus (smaller horseshoe bat), representing the first characterization of R. alphagastroenteritidis (RVA) in Australian bats, and the oldest identification of the virus to date worldwide. Concurrently, we sequenced endogenous host RNA, providing a proof-of-concept for dual host-virus transcript recovery from vouchered specimens. This study highlights the role biorepositories can play in reconstructing unbiased historical viral landscapes from specimens, irrespective of the host disease status, and enabling spatiotemporal host-virus insight to advance both biodiversity science and global pandemic preparedness.
Beyond genomes: functional signatures reveal evolutionary patterns across the tree of life.
Muñoz-Mérida A, Muñoz-Pajares AJ
Mol Biol Evol · 2026 Jun · PMID 42126263 · Full text
Protein function evolution provides a powerful lens to uncover biological complexity. Here, we introduce the concept of the pan-functionome-the full set of protein functions encoded by the proteome of individuals belongi...
Protein function evolution provides a powerful lens to uncover biological complexity. Here, we introduce the concept of the pan-functionome-the full set of protein functions encoded by the proteome of individuals belonging to a taxonomic group-and explore its evolutionary implications. By analyzing over 1,000 annotated proteomes across major branches of life, we identify systematic differences in functional composition that reflect deep evolutionary patterns. The number of biological processes per protein increases nonlinearly over time, with functional diversification rather than protein expansion driving organismal complexity. Distinct taxonomic divisions invest differently in biological processes, highlighting signatures of multicellularity, metabolism, and stress response. Phylogenetic analyses suggest that the evolution of protein functions follows a non-neutral model. Furthermore, functional profiles allow robust taxonomic classification and reveal unique adaptations in individual organisms. Our findings suggest that the functionome provides a complementary perspective on evolution, with potential applications in taxonomy, evolutionary biology, and comparative genomics.
Pseudogene revival drives repeated adaptation in fission yeast.
Wu Z, Liu X, Xu H … +1 more , Han GZ
Mol Biol Evol · 2026 May · PMID 42102264 · Full text
Repeated (parallel or convergent) evolution is often taken as evidence of adaptation and is relevant to the predictability of evolution. However, much remains unknown about the genetic basis of repeated evolution. Here,...
Repeated (parallel or convergent) evolution is often taken as evidence of adaptation and is relevant to the predictability of evolution. However, much remains unknown about the genetic basis of repeated evolution. Here, we use genome editing to progressively knock out all the complete transposable elements, a rich source of mutations, in the fission yeast Schizosaccharomyces pombe. While progressive knockout has no apparent effect on the biology or fitness of S. pombe under normal conditions, certain transposable element knockout strains exhibit growth arrest under acid challenge. We next perform parallel replay experiments by evolving S. pombe strains with a single transposable element and without transposable element under acid stress. Adaptation occurs rapidly and repeatedly. We do not detect any new transposable element insertions at appreciable frequencies, indicating that the observed repeated adaptation is not driven by transposable element insertions. Instead, revival mutations in SPBC409.08, a pseudogene that encodes a putative transporter of the major facilitator superfamily, repeatedly undergo hard or soft selective sweeps and drive adaptation in all the replicates. Although the revival mutations exhibit a trend of diminishing returns, they also repeatedly become fixed in all evolved wild-type populations. This work unveils the significance of pseudogene revival on repeated evolution and thus evolutionary predictability.
Orthologs of an essential orphan gene vary in their capacities for function and subcellular localization in Drosophila melanogaster.
Patel PH, Eicholt LA, Lange A … +3 more , McDermott KL, Bornberg-Bauer E, Findlay GD
Mol Biol Evol · 2026 May · PMID 42098939 · Full text
Orphan genes evolve rapidly, raising questions about whether their functions remain conserved or diverge across species. To address this, we investigated goddard (gdrd), an orphan gene essential for spermatogenesis in Dr...
Orphan genes evolve rapidly, raising questions about whether their functions remain conserved or diverge across species. To address this, we investigated goddard (gdrd), an orphan gene essential for spermatogenesis in Drosophila melanogaster. Within the Drosophila genus, Gdrd proteins retain a conserved core structure but display substantial variation in length and primary sequence. Here we perform cross-species gene swap assays in D. melanogaster testes to examine how these lineage-specific changes affect Gdrd function. Strikingly, the highly divergent D. mojavensis ortholog fully rescues fertility in gdrd null flies, suggesting that ancestral Gdrd acted within a conserved spermatogenesis pathway. By contrast, several orthologs, including one from a more closely related species, cannot substitute for the melanogaster gene. Cytological analysis shows that all divergent Gdrd orthologs retain some ability to interact with axonemes and ring centrioles, consistent with the protein's structural conservation, but many noncomplementing orthologs display weaker axonemal binding. Furthermore, all tested orthologs exhibit divergent localizations to organellar structures. Using computational analyses and molecular dynamics simulations, we identified intrinsic protein qualities that may account for several observations made in the gene swap assays. Rescuing orthologs bear motifs with shared physicochemical properties in their intrinsically disordered regions, while nonrescuing variants exhibit structural instabilities. Taken together, these findings show that while Gdrd's ancestral structure and interactions are conserved, several orthologs have undergone lineage-specific evolutionary changes.
Experimental evolution toward extinction in a molecular host-parasite system.
Yukawa K, Yoshiyama T, Mizuuchi R … +1 more , Ichihashi N
Mol Biol Evol · 2026 May · PMID 42098915 · Full text
Theoretical studies have proposed that coevolution with parasitic replicators plays a critical role in the evolution of primitive life; however, experimental verification of the potential outcomes of such coevolutionary...
Theoretical studies have proposed that coevolution with parasitic replicators plays a critical role in the evolution of primitive life; however, experimental verification of the potential outcomes of such coevolutionary dynamics remains limited. We previously conducted a coevolutionary experiment using an RNA-protein replication system that resulted in the spontaneous diversification of host and parasitic RNAs into five distinct lineages with robust coreplication. Here, we report contrasting evolutionary outcomes from a second long-term coevolutionary experiment. Using a droplet flow reactor (FR) system with increased dilution frequency over 5,000 h (1,600 generations), we observed reduced diversity and frequent extinctions in later experimental stages. Coreplication assays of RNA clones revealed that the primary cause of this diversity loss was the shortened reaction time resulting from frequent dilution. Further analysis of RNA clones that emerged during evolution suggested that the frequent extinctions resulted from the appearance of highly competitive parasite species and the dominance of host species that exhibited reduced replication ability. These findings demonstrate that coevolution between host and parasitic replicators can result in diversity loss and frequent extinctions depending on dilution conditions, highlighting the critical role of environmental parameters, such as dilution ratio and frequency, in enabling primitive replicators to evolve sustainably toward the emergence of life.
Avian lung single-cell atlas elucidates evolutionary divergence in endothermic respiration.
Hao Y, Zhou X, Zhao Q … +10 more , She H, Fang Y, Ma L, Zou Z, Zhai W, Ericson PGP, Lei F, Meng F, Zhang S, Qu Y
Mol Biol Evol · 2026 May · PMID 42098914 · Full text
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 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.
Using drift coefficients as a basis for inferring times, effective population sizes, and genetic adaptations.
Nakamichi R, Thorne JL, Kishino H
Mol Biol Evol · 2026 May · PMID 42097573 · Full text
Genetic drift and gene flow can give rise to a complex population genetic structure. The inverse problem of estimating the genetic drift and gene flow in the past, based on the present-day genomic population structure, c...
Genetic drift and gene flow can give rise to a complex population genetic structure. The inverse problem of estimating the genetic drift and gene flow in the past, based on the present-day genomic population structure, can be solved using an admixture graph. This describes differentiated local populations in terms of population splits and migrations between populations. The history and associated levels of genetic drift and admixture can be estimated based on the genome-wide single nucleotide polymorphism allele frequency data. Here, we present a set of statistical methods based on the admixture graph. Applying a prior on the stochastic variation of the effective population size decomposes the genetic drift values that are associated with the non-migration edges into the timings of the population splits and the effective population sizes at those times. This decomposition facilitates downstream analyses such as reconstruction of ancestral allele frequencies via a Brownian motion model with admixture. To trace changes in allele frequencies on a world map, we estimated the geographic locations of the ancestral populations using Brownian motion, the rate of which depends on the genetic drift values. Mapping the history of putative adaptations onto a world map can illuminate factors responsible for regional population heterogeneity. We investigated the effectiveness of detecting adaptations with a numerical simulation that mimics human population history, and by analyzing the expression quantitative trait loci of the melanocortin 1 receptor gene, which is involved in regulation of skin and hair pigmentation.
Sequential origin of an alternative colony founding strategy driven by two supergenes in Temnothorax ants.
Darras H, Yu C, Kever M … +3 more , Stoldt M, Feldmeyer B, Foitzik S
Mol Biol Evol · 2026 May · PMID 42095269 · Full text
Recent discoveries reveal that many complex intraspecific polymorphisms are shaped by a single supergene that maintains coadapted genetic variants through suppressed recombination. Here, we show that in the ant Temnothor...
Recent discoveries reveal that many complex intraspecific polymorphisms are shaped by a single supergene that maintains coadapted genetic variants through suppressed recombination. Here, we show that in the ant Temnothorax rugatulus, an extreme reproductive polymorphism is instead governed by two independent genomic rearrangements that arose sequentially on different chromosomes. Colonies of this species contain either a single large dispersing queen or multiple queens, including extremely miniaturized microgynes that cannot establish new colonies on their own and reproduce only by joining established multiple-queen colonies. Using chromosome-scale assemblies and population genomic data, we identify two genomic rearrangements, 9.3 and 7.0 Mb in size, that jointly determine these strategies. Divergence dating shows that the supergene underlying colony social structure arose first, creating the conditions for the subsequent emergence of a miniaturization supergene. These findings demonstrate that complex adaptive strategies can be assembled stepwise through the sequential origin of multiple supergenes.
The genomic basis of independent marine transitions in turtles: convergent episodic adaptation and demographic shifts.
Ramos E, Hilgers L, Carrasco-Valenzuela T … +11 more , De Panis D, Picorelli A, Sullivan J, Uliano-Silva M, Bentley BP, Scott PA, Hiller M, Nery MF, Shaffer HB, Komoroske L, Mazzoni CJ
Mol Biol Evol · 2026 May · PMID 42093114 · Full text
The transition from terrestrial to marine environments represents one of the most fundamental evolutionary shifts in vertebrate history, requiring radical physiological and genomic remodeling. We investigated the genomic...
The transition from terrestrial to marine environments represents one of the most fundamental evolutionary shifts in vertebrate history, requiring radical physiological and genomic remodeling. We investigated the genomic signatures of saltwater adaptation in the green sea turtle (Chelonia mydas), the leatherback turtle (Dermochelys coriacea), and the independently evolved estuarine diamondback terrapin (Malaclemys terrapin). Our analyses reveal that the marine transition is characterized by rapid evolution and expansion in gene families linked to iron metabolism, organ morphogenesis, and sensory perception-patterns that mirror those seen in other secondarily marine tetrapods. Notably, while we identified shared targets of positive selection across these independent lineages, we found no evidence of repeated evolution at the nucleotide level, reinforcing that functional convergence often arises through distinct molecular trajectories. Furthermore, demographic reconstructions reveal that saltwater-adapted turtles share a history of deep-time population declines; however, the delayed recovery of M. terrapin underscores the specific susceptibility of estuarine specialists to Pleistocene sea-level volatility. By bridging comparative genomics and historical demography, this study provides new insights into the genomic basis of marine adaptations in turtles and a comprehensive framework for understanding the molecular and ecological mechanisms that facilitate major vertebrate transitions into the marine realm.
IQ-TREE 3: phylogenomic inference software using complex evolutionary models.
Wong TKF, Ly-Trong N, Ren H … +13 more , Demotte P, Baños H, Roger AJ, Susko E, Bielow C, De Maio N, Goldman N, Hahn MW, Dos Reis M, Vinh LS, Huttley G, Lanfear R, Minh BQ
Mol Biol Evol · 2026 May · PMID 42085559 · Full text
IQ-TREE (https://iqtree.github.io/) is a widely used open-source software tool for efficiently inferring phylogenetic trees under maximum likelihood. Here, we present IQ-TREE version 3, the third major release of the sof...
IQ-TREE (https://iqtree.github.io/) is a widely used open-source software tool for efficiently inferring phylogenetic trees under maximum likelihood. Here, we present IQ-TREE version 3, the third major release of the software. IQ-TREE 3 significantly extends version 2 with new features, including mixture models as an alternative to partitioned models, gene and site concordance factors to quantify discordance between genomic regions, integration with phylogenomic divergence time estimation, and a fully featured sequence simulator. The IQ-TREE 3 source code is available at https://github.com/iqtree/iqtree3.
evo3D R package: a spatial haplotype framework for structure-informed analysis of molecular evolution.
Broyles BK, He Q
Mol Biol Evol · 2026 May · PMID 42060840 · Full text
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 m...
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 three-dimensional (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 neighborhoods missed by linear sliding windows, and by evaluating evo3D's scalability on the octameric Chikungunya virus E1/E2 assembly. Importantly, evo3D formalizes 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.
Divergent cis-regulatory haplotypes at Tlr2 are associated with immune responsiveness.
Nandakumar M, Lundberg M, Nouri M … +3 more , Valfridsson C, Carlsson F, Råberg L
Mol Biol Evol · 2026 May · PMID 42052896 · Full text
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/balanc...
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 CDS, 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.
Sex chromosome identification and genome curation from a single individual with SCINKD.
Pinto BJ, Gable SM, Keating SE … +4 more , Smith CH, Gamble T, Nielsen SV, Wilson MA
Mol Biol Evol · 2026 Apr · PMID 42050848 · Full text
In most animal species, the sex-determining pathway is typically initiated by the presence/absence of a primary genetic cue at a critical point during development. This primary genetic cue is often located on a single lo...
In most animal species, the sex-determining pathway is typically initiated by the presence/absence of a primary genetic cue at a critical point during development. This primary genetic cue is often located on a single locus-referred to as sex chromosomes-and can be limited to females (in a ZZ/ZW system) or males (in an XX/XY system). One trademark of sex chromosomes is a restriction or cessation of recombination surrounding the sex-limited region (to prevent its inheritance in the homogametic sex). This may lead to-through a variety of mechanisms-higher amounts of genetic divergence within this region, ie between the X/Z and Y/W chromosomes, especially when compared with their autosomal counterparts. Recent advances in genome sequencing and computation have brought with them the ability to resolve haplotypes within a diploid individual, permitting assembly of previously challenging genomic regions like sex chromosomes. Leveraging these advances, we identified replicable diagnostic characteristics between typical autosomes and sex chromosomes (within a single genome assembly). Under this framework, we can use this information to identify putative sex chromosome linkage groups across divergent vertebrate taxa and simultaneously curate misassembled regions on autosomes. Here, we present this conceptual framework and associated tool for identifying candidate sex chromosome linkage groups from a single, diploid individual dubbed Sex Chromosome Identification by Negating Kmer Densities.
Characterization of de novo germline mutations suggests a strong male mutation bias in coppery titi monkeys (Plecturocebus cupreus).
Versoza CJ, Bales KL, Jensen JD … +1 more , Pfeifer SP
Mol Biol Evol · 2026 May · PMID 42047107 · Full text
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...
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.
GAPIT version 4: integration of GWAS into genomic prediction.
Wang J, Zhang Z
Mol Biol Evol · 2026 May · PMID 42047095 · Full text
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 statist...
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, such as 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.
Evolutionary conservation and divergence of phagocytic and coagulation programs across bilaterian circulating immune cells.
Li Y, Liu X, Chen H … +26 more , Yang Q, Liu Q, Wang HY, Li S, Zhang X, Huang Y, Chen JY, Doretto LB, Rosa IF, Han S, Li C, Seim I, Lu Y, Liu K, Xu J, Zhang Y, Hao S, Liao S, Pan S, Shi J, Chen Y, Li C, Wang Q, Liu S, Fan G, Shao C
Mol Biol Evol · 2026 May · PMID 42041094 · Full text
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...
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 MiT/TFE 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.
Uncovering viral protein acquisition events and human-specific folds with pairwise comparisons of predicted protein structures.
Malnak JC, Montermoso S, Bushman FD … +1 more , Auslander N
Mol Biol Evol · 2026 May · PMID 42041085 · Full text
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 ra...
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 toward 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.
A milestone in C4 carbon concentration mechanism evolution: structural remodeling of NADP-malic enzyme in Poaceae.
Böhm JM, Willms S, Ferrao O … +11 more , Buitrago-Arango M, Hüdig M, Poschmann G, Fazelnia N, Nagel-Steger L, Klinke S, Drakonaki A, Gatsogiannis C, Tronconi MA, Alvarez CE, Maurino VG
Mol Biol Evol · 2026 Apr · PMID 42017302 · Full text
The evolution of C4 photosynthesis required extensive modification of ancestral enzymes enabling the development of an efficient carbon concentrating mechanism. A key example is NADP-malic enzyme (NADP-ME), which, in mai...
The evolution of C4 photosynthesis required extensive modification of ancestral enzymes enabling the development of an efficient carbon concentrating mechanism. A key example is NADP-malic enzyme (NADP-ME), which, in maize and sorghum-members of the same C4 lineage-underwent gene duplication and neofunctionalization, resulting in 2 plastidic isoforms with distinct oligomeric states: a tetrameric C4-specific isoform and a dimeric housekeeping (nonC4) isoform. In this study, we resolve the structural basis of this oligomeric divergence using X-ray crystallography, cryo-electron microscopy, and molecular modeling combined with targeted biochemical analysis. Our findings demonstrate that the N-terminal region of nonC4-NADP-ME is involved in its oligomeric organization, whereas a suite of adaptive substitutions at the dimer interface drives the transition to the stable tetramer characteristic of the C4 isoform. Moreover, the C-terminal region stabilizes the oligomeric states of C4- and nonC4-NADP-ME through specific interactions with adaptive residues. We propose that tetramerization mitigates aggregation at the high expression levels demanded by the C4 cycle and likely creates a scaffold for the emergence of regulatory properties. Collectively, the data show that remodeling of terminal domains and inter-subunit interfaces rewires the quaternary architecture of the enzymes, illustrating how subtle structural changes can drive the evolution of complex innovations such as C4 photosynthesis.
From structural pangenomes to functional panomics in plants.
Cochetel N, Cantu D
Mol Biol Evol · 2026 Apr · PMID 42015654 · Full text
Understanding how genome structure and gene content evolve within and among plant species requires analytical frameworks that capture the full spectrum of allelic and structural variation. Plant pangenomes have progresse...
Understanding how genome structure and gene content evolve within and among plant species requires analytical frameworks that capture the full spectrum of allelic and structural variation. Plant pangenomes have progressed from gene-focused and linear representations to chromosome-scale, haplotype-resolved graphs that preserve allelic and structural diversity across populations. Attention is increasingly focused on the evolutionary processes that generate and maintain pangenome architecture, alongside the adoption of graph-based coordinate systems that reduce reference bias and enable multi-omics integration. Here, we review plant pangenome paradigms, from early homology-based gene sets to haplotype-resolved graph models, and summarize tradeoffs in construction, mapping, and variant analysis. We synthesize patterns of core and variable gene compartments across studies and examine how transposable elements, gene duplication, and selection shape their contrasting evolutionary dynamics. Using panNLRomes and crop domestication as case studies, we illustrate how graph-based frameworks clarify evolutionary and functional signals obscured by single references, including birth-death dynamics at resistance loci and structural variants associated with domestication. Finally, we discuss emerging applications in pantranscriptomics and panepigenomics and outline key methodological and infrastructural challenges.
Environmental and mutational modulation of collateral fitness effects informs their mechanisms.
Goff C, Tsou EY, Mehlhoff JD … +1 more , Ostermeier M
Mol Biol Evol · 2026 May · PMID 42012237 · Full text
Fitness effects of mutations that do not arise from changes in a protein's ability to perform its physiological functions (called collateral fitness effects or CFEs) are an understudied aspect of fitness landscapes. We h...
Fitness effects of mutations that do not arise from changes in a protein's ability to perform its physiological functions (called collateral fitness effects or CFEs) are an understudied aspect of fitness landscapes. We have previously systematically measured the CFEs of all possible single amino acid substitutions in four proteins and found the frequency of deleterious mutations to vary by two orders of magnitude. Of these proteins, TEM-1 β-lactamase had the highest frequency, and deleterious mutations caused TEM-1 aggregation. Here, we systematically measured TEM-1 collateral fitness landscapes in environments and situations expected to alter protein aggregation or protein stability. We found a moderate correlation between deleterious CFEs and predicted thermodynamic stability effects in TEM-1's α-domain. Empirically, we found that the frequency and magnitude of deleterious CFEs can be reduced by altering the growth environment to disfavor aggregation (i.e. reducing the growth temperature or shifting to minimal media) or by stabilizing TEM-1 (via the M182T mutation or the addition of the β-lactamase inhibitor avibactam to the growth medium). However, although raising the growth temperature to favor aggregation exacerbated deleterious CFEs of many mutations, many mutations' effects were reduced. Furthermore, although reductions in CFEs occurred with reductions in TEM-1 aggregation for some mutants, for many mutants, they did not. We propose that mutational destabilization exposes protein motifs that can cause deleterious CFEs, but that these motifs and those that cause aggregation are not necessarily the same motifs.
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