Proceedings of the National Academy of Sciences of the United States of America最新文献

Accurate, scalable, and fully automated inference of species trees from raw genome assemblies using ROADIES 准确的，可扩展的，和完全自动化的推断物种树从原始基因组组装使用roads

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2500553122

Anshu Gupta, Siavash Mirarab, Yatish Turakhia

{"title":"Accurate, scalable, and fully automated inference of species trees from raw genome assemblies using ROADIES","authors":"Anshu Gupta, Siavash Mirarab, Yatish Turakhia","doi":"10.1073/pnas.2500553122","DOIUrl":"https://doi.org/10.1073/pnas.2500553122","url":null,"abstract":"Current genome sequencing initiatives across a wide range of life forms offer significant potential to enhance our understanding of evolutionary relationships and support transformative biological and medical applications. Species trees play a central role in many of these applications; however, despite the widespread availability of genome assemblies, accurate inference of species trees remains challenging due to the limited automation, substantial domain expertise, and computational resources required by conventional methods. To address this limitation, we present ROADIES, a fully automated pipeline to infer species trees starting from raw genome assemblies. In contrast to the prominent approach, ROADIES incorporates a unique strategy of randomly sampling segments of the input genomes to generate gene trees. This eliminates the need for predefining a set of loci, limiting the analyses to a fixed number of genes, and performing the cumbersome gene annotation and/or whole genome alignment steps. ROADIES also eliminates the need to infer orthology by leveraging existing discordance-aware methods that allow multicopy genes. Using the genomic datasets from large-scale sequencing efforts across four diverse life forms (placental mammals, pomace flies, birds, and budding yeasts), we show that ROADIES infers species trees that are comparable in quality to the state-of-the-art studies but in a fraction of the time and effort, including on challenging datasets with rampant gene tree discordance and complex polyploidy. With its speed, accuracy, and automation, ROADIES has the potential to vastly simplify species tree inference, making it accessible to a broader range of scientists and applications.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"11 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic interplay between niche variation and flight adaptability drove a hundred million years’ dispersion in iconic lacewings 生态位变化和飞行适应性之间的动态相互作用推动了标志性草蛉长达上亿年的分散

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2414549122

Haohong Ou, Jingtao Yang, Honglong Wang, Nuoyao Kang, Shumin Li, Yuting Chen, Zihao Peng, Xianzhe Xiang, Michael S. Engel, Shaun L. Winterton, Dong Ren, Qiang Yang, Chaofan Shi

{"title":"Dynamic interplay between niche variation and flight adaptability drove a hundred million years’ dispersion in iconic lacewings","authors":"Haohong Ou, Jingtao Yang, Honglong Wang, Nuoyao Kang, Shumin Li, Yuting Chen, Zihao Peng, Xianzhe Xiang, Michael S. Engel, Shaun L. Winterton, Dong Ren, Qiang Yang, Chaofan Shi","doi":"10.1073/pnas.2414549122","DOIUrl":"https://doi.org/10.1073/pnas.2414549122","url":null,"abstract":"The form and change of animal biogeography reflects the long-term interplay between organisms and their environment, involving physiological limitation, dispersal capability, and adaptive evolution versus plate tectonics, global climatic shifts, and changing landscapes. This is especially manifest for lineages with extended geological histories, which, therefore, evokes questions as to the associated processes producing such patterns. Insects, as the earliest flying animals, have exceptional abilities for expanding their range and habitats and to avoid detrimental conditions. They are ideal for exploring historical biogeography augmented via adaptation. Here, we employ beaded lacewings as a model to explore such patterns and likely processes, particularly given that they differ notably from the commonly observed pattern of a latitudinal diversity gradient. Furthermore, owing to their good fossil record it can be observed that their distributions varied remarkably through time. Ecological niche modeling and evaluation demonstrate their niche variation and niche breadth expansion intermittently accompanying global climate change. However, different niche relevant variables changed under patterns of either phylogenetic conservatism or evolutionary lability. By assessing wing morphological disparity and modeling flight aerodynamics, we uncovered a continuous improvement of flight efficiency through beaded-lacewing history as well as a Paleogene divergence in strategy, which reveals a long-term associated path with the niche variation. Our results unveil the adaptive evolution and dispersal history of beaded lacewings through 170 My, achieved by dynamic strategies in niche shift and flight adaptation as responses to a changing planet.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"44 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bayesian phylodynamic inference of population dynamics with dormancy 种群动态与休眠的贝叶斯系统动力学推断

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2501394122

Lorenzo Cappello, Wai Tung ‘Jack’ Lo, Joy Z. Zhang, Peiyu Xu, Daniel Barrow, Ishani Chopra, Andrew G. Clark, Martin T. Wells, Jaehee Kim

{"title":"Bayesian phylodynamic inference of population dynamics with dormancy","authors":"Lorenzo Cappello, Wai Tung ‘Jack’ Lo, Joy Z. Zhang, Peiyu Xu, Daniel Barrow, Ishani Chopra, Andrew G. Clark, Martin T. Wells, Jaehee Kim","doi":"10.1073/pnas.2501394122","DOIUrl":"https://doi.org/10.1073/pnas.2501394122","url":null,"abstract":"Many organisms employ reversible dormancy, or seedbank, in response to environmental fluctuations. This life-history strategy alters fundamental ecoevolutionary forces, leading to distinct patterns of genetic diversity. Two models of dormancy have been proposed based on the average duration of dormancy relative to coalescent timescales: weak seedbank, induced by scheduled seasonality (e.g., plants, invertebrates), and strong seedbank, where individuals stochastically switch between active and dormant states (e.g., bacteria, fungi). The weak seedbank coalescent is statistically equivalent to the Kingman coalescent with a scaled mutation rate, allowing the use of existing inference methods. In contrast, the strong seedbank coalescent differs fundamentally, as only active lineages can coalesce, while dormant lineages cannot. Additionally, dormant individuals typically mutate at a slower rate than active ones. Consequently, despite the significant role of dormancy in the ecoevolutionary dynamics of many organisms, no methods currently exist for inferring population dynamics involving dormancy and associated parameters. We present a Bayesian framework for jointly inferring a latent genealogy, seedbank parameters, and evolutionary parameters from molecular sequence data under the strong seedbank coalescent. We derive the exact probability density of genealogies sampled under the strong seedbank coalescent, characterize the corresponding likelihood function, and present efficient computational algorithms for its evaluation based on our theoretical framework. We develop a tailored Markov chain Monte Carlo sampler and implement our inference framework as a package SeedbankTree within BEAST2. Our work provides both a theoretical foundation and practical inference framework for studying the population genetic and genealogical impacts of dormancy.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"53 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Why does AI hinder democratization? 为什么人工智能会阻碍民主化？

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2423266122

C. Y. Cyrus Chu, Juin-Jen Chang, Chang-Ching Lin

{"title":"Why does AI hinder democratization?","authors":"C. Y. Cyrus Chu, Juin-Jen Chang, Chang-Ching Lin","doi":"10.1073/pnas.2423266122","DOIUrl":"https://doi.org/10.1073/pnas.2423266122","url":null,"abstract":"This paper examines the relationship between democratization and the development of AI and information and communication technology (ICT). Our empirical evidence shows that in the past 10 y, the advancement of AI/ICT has hindered the development of democracy in many countries around the world. Given that both the state rulers and civil society groups can use AI/ICT, the key that determines which side would benefit more from the advancement of these technologies hinges upon “technology complementarity.” In general, AI/ICT would be more complementary to the government rulers because they are more likely than civil society groups to access various administrative big data. Empirically, we propose three hypotheses and use statistical tests to verify our argument. Theoretically, we prove a proposition, showing that when the above-mentioned complementarity assumption is true, the AI/ICT advancements would enable rulers in authoritarian and fragile democratic countries to achieve better control over civil society forces, which leads to the erosion of democracy. Our analysis explains the recent ominous development in some fragile-democracy countries.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"138 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Induced B cell receptor diversity predicts PD-1 blockade immunotherapy response 诱导的B细胞受体多样性预测PD-1阻断免疫治疗反应

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2501269122

Yonglu Che, Jinwoo Lee, Farah Abou-Taleb, Kerri E. Rieger, Ansuman T. Satpathy, Anne Lynn S. Chang, Howard Y. Chang

{"title":"Induced B cell receptor diversity predicts PD-1 blockade immunotherapy response","authors":"Yonglu Che, Jinwoo Lee, Farah Abou-Taleb, Kerri E. Rieger, Ansuman T. Satpathy, Anne Lynn S. Chang, Howard Y. Chang","doi":"10.1073/pnas.2501269122","DOIUrl":"https://doi.org/10.1073/pnas.2501269122","url":null,"abstract":"Immune checkpoint inhibitors such as anti-Programmed Death-1 antibodies (aPD-1) can be effective in treating advanced cancers. However, many patients do not respond, and the mechanisms underlying these differences remain incompletely understood. In this study, we profile a cohort of patients with locally advanced or metastatic basal cell carcinoma undergoing aPD-1 therapy using single-cell RNA sequencing, high-definition spatial transcriptomics in tumors and draining lymph nodes, and spatial immunoreceptor profiling, with long-term clinical follow-up. We find that successful responses to PD-1 inhibition are characterized by an induction of B cell receptor (BCR) clonal diversity after treatment initiation. These induced BCR clones spatially colocalize with T cell clones, facilitate their activation, and traffic alongside them between tumor and draining lymph nodes to enhance tumor clearance. Furthermore, we validated aPD-1-induced BCR diversity as a predictor of clinical response in a larger cohort of glioblastoma, melanoma, and head and neck squamous cell carcinoma patients, suggesting that this is a generalizable predictor of treatment response across many types of cancers. We find that pretreatment tumors harbor a characteristic gene expression signature that portends a higher probability of inducing BCR clonal diversity after aPD-1 therapy, and we develop a machine learning model that predicts PD-1-induced BCR clonal diversity from baseline tumor RNA sequencing. These findings underscore a dynamic role of B cell diversity during immunotherapy, highlighting its importance as a prognostic marker and a potential target for intervention in non-responders.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"43 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Using pledges to improve the effectiveness of environmental information campaigns: The case of biowaste recycling 利用承诺提高环保宣传活动的成效：以生物废物回收为例

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2414578122

Eduard Alonso-Paulí, Pau Balart, Lara Ezquerra, Iñigo Hernandez-Arenaz

引用次数: 0

Accurate identification and mechanistic evaluation of pathogenic missense variants with Rhapsody-2 利用Rhapsody-2对致病性错义变异进行准确鉴定和机制评价

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2418100122

Anupam Banerjee, Anthony T. Bogetti, Ivet Bahar

{"title":"Accurate identification and mechanistic evaluation of pathogenic missense variants with Rhapsody-2","authors":"Anupam Banerjee, Anthony T. Bogetti, Ivet Bahar","doi":"10.1073/pnas.2418100122","DOIUrl":"https://doi.org/10.1073/pnas.2418100122","url":null,"abstract":"Understanding the effects of missense mutations or single amino acid variants (SAVs) on protein function is crucial for elucidating the molecular basis of diseases/disorders and designing rational therapies. We introduce here Rhapsody-2 , a machine learning tool for discriminating pathogenic and neutral SAVs, significantly expanding on a precursor limited by the availability of structural data. With the advent of AlphaFold2 as a powerful tool for structure prediction, Rhapsody-2 is trained on a significantly expanded dataset of 117,525 SAVs corresponding to 12,094 human proteins reported in the ClinVar database. Adopting a broad set of descriptors composed of sequence evolutionary, structural, dynamic, and energetics features in the training algorithm, Rhapsody-2 achieved an AUROC of 0.94 in 10-fold cross-validation when all SAVs of a particular test protein (mutant) were excluded from the training set. Benchmarking against a variety of testing datasets demonstrated the high performance of Rhapsody-2 . While sequence evolutionary descriptors play a dominant role in pathogenicity prediction, those based on structural dynamics provide a mechanistic interpretation. Notably, residues involved in allosteric communication and those distinguished by pronounced fluctuations in the high-frequency modes of motion or subject to spatial constraints in soft modes usually give rise to pathogenicity when mutated. Overall, Rhapsody-2 provides an efficient and transparent tool for accurately predicting the pathogenicity of SAVs and unraveling the mechanistic basis of the observed behavior, thus advancing our understanding of genotype-to-phenotype relations.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"8 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa 了解小胶质细胞中TAK1的缺乏：视网膜色素变性小鼠模型中光感受器保护的双重机制

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2423134122

Jing Zhang, Wei Yang, Jiangmei Wu, Bin Lin

{"title":"Understanding TAK1 deficiency in microglia: Dual mechanisms for photoreceptor protection in a mouse model of retinitis pigmentosa","authors":"Jing Zhang, Wei Yang, Jiangmei Wu, Bin Lin","doi":"10.1073/pnas.2423134122","DOIUrl":"https://doi.org/10.1073/pnas.2423134122","url":null,"abstract":"Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by the progressive loss of photoreceptors. Neuroinflammation has been implicated in the pathophysiology of RP and its progression. Previous studies have suggested that the transforming growth factor-beta-activated kinase 1 (TAK1) plays a pivotal role in regulating acute and chronic neuroinflammation. However, the functional role of TAK1 in neuroinflammation remains unclear in RP. Here, we observed TAK1 upregulation in activated microglia of the rd10 mouse model of RP. To create the conditional deletion of TAK1 in microglia, we backcrossed Cx3cr1 CreER/CreER mice and Tak1 fl/fl mice onto rd10 background. We found that both heterozygous (rd10;Cx3cr1 CreER/+ ;Tak1 fl/+ ) and homozygous (rd10;Cx3cr1 CreER/+ ;Tak1 fl/fl ) deletion of microglial TAK1 slowed down photoreceptor degeneration but with distinct mechanisms. The heterozygous TAK1 deficiency resulted in a reduction in the activation and proliferation of microglia and the release of proinflammatory cytokines by inhibiting STAT3 signaling. In contrast, the homozygous TAK1 deficiency induced apoptosis in microglia via the TNF/RIPK1/CASP3 signaling pathway, contributing to the reduction of microglia-mediated neurotoxicity and subsequent preservation of photoreceptors in RP. Overall, our findings highlight the crucial role of TAK1 in the survival and activation of microglia. We propose that targeting microglial TAK1, considering its expression levels and subsequent signal transduction, could offer a promising personalized therapeutic strategy for individuals with RP regardless of underlying genetic causes.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"97 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thermodynamic consistency of autocatalytic cycles 自催化循环的热力学一致性

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2421274122

Thomas Kosc, Denis Kuperberg, Etienne Rajon, Sylvain Charlat

{"title":"Thermodynamic consistency of autocatalytic cycles","authors":"Thomas Kosc, Denis Kuperberg, Etienne Rajon, Sylvain Charlat","doi":"10.1073/pnas.2421274122","DOIUrl":"https://doi.org/10.1073/pnas.2421274122","url":null,"abstract":"Autocatalysis is seen as a potential key player in the origin of life, and perhaps more generally in the emergence of Darwinian dynamics. Building on recent formalizations of this phenomenon, we tackle the computational challenge of exhaustively detecting minimal autocatalytic cycles (autocatalytic cores) in reaction networks and further evaluate the impact of thermodynamic constraints on their realization under mass action kinetics. We first characterize the complexity of the detection problem by proving its NP-completeness. This justifies the use of constraint solvers to list all cores in a given reaction network, and also to group them into compatible sets, composed of cores whose stoichiometric requirements are not contradictory. Crucially, we show that the introduction of thermodynamic realism does constrain the composition of these sets. Compatibility relationships among autocatalytic cores can indeed be disrupted when the reaction kinetics obey thermodynamic consistency throughout the network. On the contrary, these constraints have no impact on the realizability of isolated cores, unless upper or lower bounds are imposed on the concentrations of the reactants. Overall, by better characterizing the conditions of autocatalysis in complex reaction systems, this work brings us a step closer to assessing the contribution of this collective chemical behavior to the emergence of natural selection in the primordial soup.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"34 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Massive mutagenesis reveals an incomplete amyloid motif in Bri2 that turns amyloidogenic upon C-terminal extension 大量突变揭示了Bri2中一个不完整的淀粉样基序，该基序在c端延伸后变为淀粉样变性

IF 11.1 1区综合性期刊

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-05-02 DOI: 10.1073/pnas.2415521122

Mariano Martín, Benedetta Bolognesi

{"title":"Massive mutagenesis reveals an incomplete amyloid motif in Bri2 that turns amyloidogenic upon C-terminal extension","authors":"Mariano Martín, Benedetta Bolognesi","doi":"10.1073/pnas.2415521122","DOIUrl":"https://doi.org/10.1073/pnas.2415521122","url":null,"abstract":"Stop-loss mutations cause over twenty different diseases. The effects of stop-loss mutations can have multiple consequences that are, however, hard to predict. Stop-loss in ITM2B/BRI2 results in C-terminal extension of the encoded protein and, upon furin cleavage, in the production of two 34 amino acid long peptides, ADan and ABri, that accumulate as amyloids in the brains of patients affected by familial Danish and British Dementia. To systematically explore the consequences of Bri2 C-terminal extension, here, we use a yeast-based massively parallel assay to measure amyloid formation for 676 ADan substitutions and identify the region that forms the putative amyloid core of ADan fibrils, located between positions 20 and 26, where stop-loss occurs. Moreover, we measure amyloid formation for ~18,000 random C-terminal extensions of Bri2 and find that ~32% of these sequences can nucleate amyloids. We find that the amino acid composition of these nucleating sequences varies with peptide length and that short extensions of two specific amino acids (Aliphatics, Aromatics, and Cysteines) are sufficient to generate de novo amyloid cores. Overall, our results show that the C-terminus of Bri2 contains an incomplete amyloid motif that can turn amyloidogenic upon extension. C-terminal extension with de novo formation of amyloid motifs may thus be a widespread pathogenic mechanism resulting from stop-loss, highlighting the importance of determining the impact of these mutations for other sequences across the genome.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"35 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0