Molecular biology and evolution最新文献

Mutation accumulation in a hybrid parthenogenetic vertebrate. 杂交孤雌脊椎动物的突变积累。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-03 DOI: 10.1093/molbev/msag214

Zoë Müller, Joshua Orlando Rivera, Kathleen Currie, Hairo Isaac Rios, Sean Rovito, Corey Roelke, Matthew Fujita

{"title":"Mutation accumulation in a hybrid parthenogenetic vertebrate.","authors":"Zoë Müller, Joshua Orlando Rivera, Kathleen Currie, Hairo Isaac Rios, Sean Rovito, Corey Roelke, Matthew Fujita","doi":"10.1093/molbev/msag214","DOIUrl":"https://doi.org/10.1093/molbev/msag214","url":null,"abstract":"Asexual lineages are thought to experience elevated extinction rates compared with sexual species, yet direct evidence for the underlying genetic causes remains scarce. Muller's ratchet predicts that the absence of recombination in asexual organisms facilitates the accumulation of deleterious mutations, thereby reducing long-term fitness. Here, we test this hypothesis in the hybrid-origin, parthenogenetic whiptail lizard Aspidoscelis tesselatus by integrating short-read RNAseq and long-read IsoSeq data from both the asexual lineage and its parental sexual species. We reconstructed phased transcripts for A. tesselatus to quantify mutation accumulation relative to the parental sexual species. Comparative analyses revealed elevated ω ratios in both parental genomic complements (subgenomes) of the parthenogenetic lineage, consistent with accelerated accumulation of nonsynonymous mutations. Structural variant analyses identified multiple indels in expressed transcripts predicted to disrupt protein domains. Functional annotation indicated that genes affected by both single-nucleotide variants and indels were enriched for roles in chromatin organization, apoptosis regulation, and transcriptional control. While both parental subgenomes showed similar evolutionary patterns, the maternal complement exhibited more structural and missense mutations than the paternal complement. Together, these results provide evidence that mutations accumulate in asexual A. tesselatus in genes involved in core cellular functions, supporting theoretical predictions that Muller's ratchet contributes to mutation accumulation in asexual lineages.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887273","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}

引用次数: 0

From neuropeptides to toxins: illuminating the origins of venom complexity in cone snails. 从神经肽到毒素：阐明锥螺毒液复杂性的起源。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag206

Thomas Lund Koch, Giada Ferrari, Sunita B Sumanam, Paula Flórez Salcedo, Maren Watkins, Kevin Chase, Ave Tooming-Klunderud, Arturo O Lluisma, Angel Yanagihara, Neil D Young, Baldomero M Olivera, Eivind A B Undheim, Helena Safavi-Hemami

{"title":"From neuropeptides to toxins: illuminating the origins of venom complexity in cone snails.","authors":"Thomas Lund Koch, Giada Ferrari, Sunita B Sumanam, Paula Flórez Salcedo, Maren Watkins, Kevin Chase, Ave Tooming-Klunderud, Arturo O Lluisma, Angel Yanagihara, Neil D Young, Baldomero M Olivera, Eivind A B Undheim, Helena Safavi-Hemami","doi":"10.1093/molbev/msag206","DOIUrl":"10.1093/molbev/msag206","url":null,"abstract":"New genes and gene functions are key drivers of evolutionary innovation. Venomous animals, such as cone snails, provide striking examples of gene innovation, yet the mechanisms by which toxins arise remain poorly understood. Using the Conus textile genome, we uncover how neuropeptide genes were recruited into the venom and neofunctionalized as doppelgänger toxins. We identify over 20 independent recruitment events that evolved dynamically across the Conus lineage. Rather than arising from ohnologs of a whole-genome duplication event ∼200 mya, these toxins evolved through diverse mechanisms, including exon shuffling, alternative splicing, and ectopic recombination, often facilitated by lineage-specific transposable elements. Our findings reveal a dynamic interplay between genome architecture and molecular innovation, offering broad insight into the evolution of complex gene repertoires in venoms and beyond.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766246","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}

引用次数: 0

Questioning the evidence for host-symbiont codiversification in mycorrhizal symbioses. 菌根共生中宿主-共生体共多样化证据的质疑。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag207

Fantine Bodin, Hélène Morlon, Benoît Perez-Lamarque

{"title":"Questioning the evidence for host-symbiont codiversification in mycorrhizal symbioses.","authors":"Fantine Bodin, Hélène Morlon, Benoît Perez-Lamarque","doi":"10.1093/molbev/msag207","DOIUrl":"10.1093/molbev/msag207","url":null,"abstract":"The vast majority of plants form mycorrhizal symbioses. The ecological importance of these mutualistic interactions has sparked interest in their long evolutionary history. By examining interaction networks and phylogenetic trees, several studies have suggested that plants codiversify with their associated mycorrhizal fungi. However, recent research has demonstrated that phylogenetic congruence (interpreted as codiversification when divergence times match) is often conflated with another pattern called cophylogenetic signal (ie closely related plants interacting with closely related fungi and vice versa), which may arise from different biological processes. We performed cophylogenetic analyses on 29 diverse mycorrhizal networks to reevaluate the evidence for codiversification in mycorrhizal symbioses. We found a significant cophylogenetic signal but no phylogenetic congruence: Closely related plants often interact with closely related fungi, but their phylogenies do not match. Instead of codiversification, this finding is consistent with trait matching between plants and mycorrhizal fungi, where compatible, evolutionarily conserved plant and fungal traits govern their interactions. Our work highlights the importance of appropriately interpreting the cophylogenetic methods used to study the macroevolution of plants and their mycorrhizal fungi. It suggests that previous evidence of codiversification in mycorrhizal symbioses actually detected cophylogenetic signal, since, across the multiple and diverse networks analyzed here, there is no evidence that codiversification occurred during the evolution of mycorrhizal symbioses.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759794","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}

引用次数: 0

Gene-level complexity explains genome-wide variation in the distribution of fitness effects. 基因水平的复杂性解释了适应度效应分布的全基因组变异。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag216

Burçin Yıldırım, Jennifer E James

{"title":"Gene-level complexity explains genome-wide variation in the distribution of fitness effects.","authors":"Burçin Yıldırım, Jennifer E James","doi":"10.1093/molbev/msag216","DOIUrl":"10.1093/molbev/msag216","url":null,"abstract":"The distribution of fitness effects (DFE)-describing how harmful, neutral, or beneficial new mutations are-is central to understanding how populations evolve. Although the DFE varies across genomes and species, it remains unclear which aspects of genomic organization drive this variation. Here, we inferred gene-level selective constraints across the genomes of Mus musculus castaneus, Drosophila melanogaster and Saccharomyces cerevisiae using a combination of population genetics and machine learning trained on diverse gene features. Many gene features were predictive of selective constraint, with conservation, gene structure, and expression being the most informative. These selective constraints delineated gene classes with distinct DFEs. Genes with higher connectivity and expression-features reflecting how many traits a gene influences-experienced stronger and less dispersed deleterious effects with increasing selective constraint. Between species, the rate of adaptation decreased with increasing organismal complexity, whereas across the genome it did not decrease monotonically with selective constraint, but tended to be higher at intermediate levels. While between-species comparisons of DFE parameters were less consistent with predictions of Fisher's geometric model (FGM) based on organismal complexity, variation in DFE parameters across the genome aligned more closely with FGM when complexity was considered at the gene level. Our results suggest that gene-level complexity, captured by genomic feature proxies, provides a more informative definition of complexity for DFE variation than organism-level labels, and highlight the value of using gene features collectively to link genomic architecture, fitness landscapes, and patterns of molecular evolution.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851327","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}

引用次数: 0

Redesign of energetically frustrated regions rescues function in defective T4 clamp loaders. 重新设计能量受挫区域挽救功能有缺陷的T4钳装载机。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag204

Siddharth Nimkar, Thu Nguyen, Deepti Karandur, Subu Subramanian, Michael E O'Donnell, John Kuriyan

{"title":"Redesign of energetically frustrated regions rescues function in defective T4 clamp loaders.","authors":"Siddharth Nimkar, Thu Nguyen, Deepti Karandur, Subu Subramanian, Michael E O'Donnell, John Kuriyan","doi":"10.1093/molbev/msag204","DOIUrl":"10.1093/molbev/msag204","url":null,"abstract":"DNA polymerase clamp loaders are AAA + ATPases that load sliding clamps on DNA for high-speed replication. Using a platform for high-throughput mutagenesis of replication proteins in T4 bacteriophage, we carried out saturation mutagenesis of the AAA + ATPase module of the T4 clamp loader bearing a mutation, Gln 118→Asn (Q118N), that reduces fitness. We identified residues for which different mutations improve the fitness of the Q118N variant but are neutral in the wild-type background. These conditionally neutral \"rescue hotspots\" overlap with those identified earlier in another defective variant (D110C). These rescue hotspots localize to regions where the sequence is not optimal for the structure, as determined by energetic frustration analysis. We designed new sequences for three of these regions, using the protein-design algorithm ProteinMPNN. In two helical regions, several designed sequences increased the fitness of both wild-type and mutant proteins, likely due to enhanced stability. An inter-domain hinge in the AAA + module changes conformation during activation, and designs for the hinge lead to loss of fitness in the wild-type background. However, when using the active conformation as the template, designs for the hinge increase the fitness of defective variants. In contrast, designs templated on the inactive conformation lead to loss of fitness, suggesting that a proper conformational balance is crucial. Thus, adaptive capacity in the clamp loader resides in a network of conditionally neutral sites that enable functional tuning through shifts in stability and conformational equilibria.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761565","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}

引用次数: 0

Evolutionary persistence of a highly prevalent multicopy mitochondrial-derived nuclear insertion (Mega-NUMT) in Neotropical Drosophila flies. 在新热带果蝇中高度流行的多拷贝线粒体衍生核插入（Mega-NUMT）的进化持久性。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag227

Merce Montoliu-Nerin, Anton Strunov, Eleanor Heyworth, Daniela I Schneider, Julia Thoma, Aurélie Hua-Van, Cécile Courret, Lisa Klasson, Wolfgang J Miller

{"title":"Evolutionary persistence of a highly prevalent multicopy mitochondrial-derived nuclear insertion (Mega-NUMT) in Neotropical Drosophila flies.","authors":"Merce Montoliu-Nerin, Anton Strunov, Eleanor Heyworth, Daniela I Schneider, Julia Thoma, Aurélie Hua-Van, Cécile Courret, Lisa Klasson, Wolfgang J Miller","doi":"10.1093/molbev/msag227","DOIUrl":"https://doi.org/10.1093/molbev/msag227","url":null,"abstract":"Although strict maternal transmission of mitochondria is a general feature of animals for ensuring homogeneity in mitochondrial DNA (mtDNA) across generations, exceptions were reported in the recent past. For example, some extremely rare but spectacular cases of heteroplasmy and paternal transmission in humans have questioned the universal evolutionary principle. Hence, as an alternative, the Mega-NUMT concept was coined to explain this discovery and was thereafter partly proven to exist. This concept expands on the quite common transfer of mtDNA fragments to the nucleus (NUMTs) by considering the existence of multicopy mitochondrial nuclear insertions. Mega-NUMT reports are currently restricted to a few cases in animals, including humans. However, their detailed genomic organization, natural prevalence, and potential biological functions remain unclear. Here, we discovered that up to 60 full-sized mitochondrial genomes are integrated into the nuclear genome of the neotropical Drosophila paulistorum using long-read sequencing and in situ hybridization. The copies are organized in one cluster on chromosome 3, which we designated the \"Dpau Mega-NUMT\". Contrary to the rarity in humans, this Mega-NUMT is found at high prevalence (40%) in both laboratory lines and natural D. paulistorum populations of different semispecies. Additionally, the Mega-NUMT copies are phylogenetically separated from the current mitotypes of D. paulistorum. Together, these observations suggest long-term maintenance of the Mega-NUMT in nature. Hence, we propose that the Dpau Mega-NUMT may have been transferred to the nuclear genome before the D. paulistorum semispecies radiation and speculate based on these findings that it possibly is maintained at relatively high prevalence in nature by balancing selection or due to a yet undetermined function.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874747","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}

引用次数: 0

Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids. 无义介导的mRNA衰变的特征，但没有证据表明转录适应与野生酵母二倍体中蛋白质截断变异相关。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag219

Marzena Marszałek, Wiesław Babik, Ryszard Korona, Katarzyna Tomala

{"title":"Signatures of nonsense-mediated mRNA decay but no evidence for transcriptional adaptation associated with protein-truncating variants in wild yeast diploids.","authors":"Marzena Marszałek, Wiesław Babik, Ryszard Korona, Katarzyna Tomala","doi":"10.1093/molbev/msag219","DOIUrl":"10.1093/molbev/msag219","url":null,"abstract":"Transcriptional adaptation (TA) is a regulatory process in which loss or disruption of gene function caused by protein-truncating variants (PTVs) triggers compensatory changes in expression of the healthy allele or in expression of related genes. Nonsense-mediated mRNA decay (NMD), a conserved RNA surveillance pathway that degrades transcripts containing premature termination codons, is required to initiate this process. In natural yeast populations, PTV mutations occur relatively frequently, raising the question of whether and how their effects are mitigated. In this study, we investigated TA and NMD among PTVs occurring in natural yeast populations. We observed a strong reduction in the abundance of PTV-containing transcripts, suggesting efficient recognition and degradation of transcripts containing premature stop codons. However, despite evidence of this mRNA surveillance activity, we did not detect a clear signature of transcriptional adaptation. While compensation may still occur in specific contexts, particularly for dosage-sensitive genes, it does not appear to represent a general response to PTVs in yeast. The transcriptional deregulation caused by PTVs in natural isolates may be causing too little harm to favor the evolution or maintenance of complex mechanisms required for adequate compensation. The ability to resist specific transcriptomic ruptures would thus rely mostly on the general robustness of genetic networks. Overall, our findings suggest that TA is not a universal response to loss-of-function mutations in yeast.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795444","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}

引用次数: 0

Identification and masking of artifactual and misleading within-host variants in deep-sequencing SARS-CoV-2 data. SARS-CoV-2数据深度测序中人为和误导性宿主内变异的识别和掩盖

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag209

Klara Marie Anker, Rosario Evans Pena, Steven A Kemp, Joseph Clarke, Lele Zhao, David Bonsall, Nicholas Grayson, Matthew Bashton, Ann Sarah Walker, Tanya Golubchik, Matthew Hall, Katrina Lythgoe

{"title":"Identification and masking of artifactual and misleading within-host variants in deep-sequencing SARS-CoV-2 data.","authors":"Klara Marie Anker, Rosario Evans Pena, Steven A Kemp, Joseph Clarke, Lele Zhao, David Bonsall, Nicholas Grayson, Matthew Bashton, Ann Sarah Walker, Tanya Golubchik, Matthew Hall, Katrina Lythgoe","doi":"10.1093/molbev/msag209","DOIUrl":"10.1093/molbev/msag209","url":null,"abstract":"Deep-sequencing data are increasingly used to study within-host viral diversity and to inform evolutionary inference. For SARS-CoV-2, analyses based on intra-host single-nucleotide variants (iSNVs) have been widely applied to quantify within-host diversity and infer transmission dynamics. However, these applications critically depend on the reliable identification of low-frequency variants, which remain vulnerable to systematic and technical artifacts. In this study, we show that recurrent artifactual iSNVs are common in large-scale SARS-CoV-2 sequencing data and can persist even under conservative minor allele frequency thresholds. Using data from the UK's Office for National Statistics COVID-19 Infection Survey, we demonstrate that such artifacts are predominantly sequencing center-specific rather than primer-specific. Each center exhibits a modest, distinct set of recurrent artifactual variants showing little overlap with sites routinely masked at the consensus level. To address this, we developed a systematic, dataset-aware framework that uses recurrence within sequencing datasets to identify small, noise-adapted sets of artifactual iSNVs to mask. Applying this framework reduces spurious sharing of low-frequency variants between samples and qualitatively alters downstream inferences, including estimates of within-host diversity and transmission bottleneck sizes. Although this study focused on SARS-CoV-2, it is likely that recurrent artifactual iSNVs will be problematic for other viruses as mass-sequencing becomes increasingly routine. Together, these findings highlight the importance of explicit, dataset-aware artifact control for robust inference from within-host variation, particularly as genomic studies increasingly seek to exploit sub-consensus diversity in rapidly evolving pathogens.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13533334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795470","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}

引用次数: 0

On the origin of animals and placental mammals: a critique of literalist readings of the fossil record. 动物和胎盘哺乳动物的起源：对化石记录的字面解读的批判。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-09-01 DOI: 10.1093/molbev/msag211

Sandra Álvarez-Carretero, Ziheng Yang, Philip C J Donoghue, Mario Dos Reis

{"title":"On the origin of animals and placental mammals: a critique of literalist readings of the fossil record.","authors":"Sandra Álvarez-Carretero, Ziheng Yang, Philip C J Donoghue, Mario Dos Reis","doi":"10.1093/molbev/msag211","DOIUrl":"10.1093/molbev/msag211","url":null,"abstract":"The fossil record is incomplete, as evidenced by the pervasive presence of ghost lineages throughout the Tree of Life. For example, across placental mammals, at least 720 Myr of basal lineages are ghost lineages, that is, lineages that have left no fossil evidence of their past history. In contrast, some studies have suggested that the fossil record is a faithful temporal archive of evolutionary history and thus the times of diversification of clades must be close to the ages of their oldest fossils. Such literalist interpretations have been contradicted by analysis of molecular datasets which, in many cases, indicate that groups including placental mammals and animals may have originated at times substantially older than their fossil records. Some of those studies have further argued that, in the case of animals and placental mammals, molecular clocks are uninformative, suffer from characteristic pathologies, and thus cannot distinguish between recent and ancient hypotheses of diversification. Here, we reexamine these two cases and show, using Bayesian model selection theory, that the explosive diversification models previously proposed for animals and placental mammals have a posterior probability of ∼0. We show the characteristic pathologies purportedly discovered do not exist, highlight errors in previous analyses, and provide advice on best practice for molecular-clock dating analysis.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795463","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}

引用次数: 0

Conserved water molecules shape the pathogenicity of missense variants in human proteins. 保守的水分子塑造了人类蛋白质错义变异的致病性。

IF 6.4 1区生物学

Molecular biology and evolution Pub Date : 2026-08-31 DOI: 10.1093/molbev/msag217

Janez Konc, Karmen Recer, Tanja Kunej, Dušanka Janežič

{"title":"Conserved water molecules shape the pathogenicity of missense variants in human proteins.","authors":"Janez Konc, Karmen Recer, Tanja Kunej, Dušanka Janežič","doi":"10.1093/molbev/msag217","DOIUrl":"https://doi.org/10.1093/molbev/msag217","url":null,"abstract":"Conserved water molecules (CWMs) are tightly bound solvent molecules that occupy well-defined, recurrent positions in protein structures. Although they are known to influence protein stability, function, and ligand binding, their role in shaping the effects of human missense variants remains largely unexplored. Here, we demonstrate that CWMs are a previously underappreciated determinant of missense variant pathogenicity. By predicting ligand-binding and CWM sites across human PDB structures and mapping missense variants to these sites and the remaining protein surface, we found that pathogenic variants were significantly enriched at CWM sites, whether overlapping or outside other ligand-binding regions. This enrichment exceeded that observed for binding sites as a whole, indicating a broader role for water-mediated interactions in modulating variant effects. To explore a mechanistic basis for this association, we performed molecular dynamics simulations of human lysosomal acid glucosylceramidase (GCase), encoded by GBA1 and implicated in Gaucher disease and Parkinson's disease risk. Selective destabilization of a CWM site in wild-type GCase produced structural and dynamical changes resembling those observed in the pathogenic L444P variant, whereas stabilization of this site in L444P shifted several measures toward wild-type behavior. These results suggest that disruption of a single CWM can contribute to long-range structural remodeling observed in a disease-associated variant. Together, our findings identify CWMs as a novel structural constraint shaping the distribution and effects of pathogenic missense variants. Incorporating water-mediated interactions into structural models provides a generalizable framework for interpreting human genetic variation and its contribution to disease.","PeriodicalId":18730,"journal":{"name":"Molecular biology and evolution","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865219","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}

引用次数: 0