PLoS GeneticsPub Date : 2023-07-01DOI: 10.1101/2022.10.13.512103
Thomas W. Willis, C. Wallace
{"title":"Accurate detection of shared genetic architecture from GWAS summary statistics in the small-sample context","authors":"Thomas W. Willis, C. Wallace","doi":"10.1101/2022.10.13.512103","DOIUrl":"https://doi.org/10.1101/2022.10.13.512103","url":null,"abstract":"Assessment of the genetic similarity between two phenotypes can provide insight into a common genetic aetiology and inform the use of pleiotropy-informed, cross-phenotype analytical methods to identify novel genetic associations. The genetic correlation is a well-known means of quantifying and testing for genetic similarity between traits, but its estimates are subject to comparatively large sampling error. This makes it unsuitable for use in a small-sample context. We discuss the use of a nonparametric test of genetic similarity first introduced by Li et al. for application to GWAS summary statistics. We establish that the null distribution of the test statistic is modelled better by an extreme value distribution than a transformation of the standard exponential distribution as originally recommended by Li and colleagues. We show with simulation studies and real data from GWAS of 18 phenotypes from the UK Biobank that the test is to be preferred for use with small sample sizes, particularly when genetic effects are few and large, outperforming the genetic correlation and another nonparametric statistical test of independence. We find the test suitable for the detection of genetic similarity in the rare disease context. Author summary The genome-wide association study (GWAS) is a method used to identify genetic variants which contribute to the risk of developing disease. These genetic variants are frequently shared between conditions, such that the study of the genetic basis of one disease can be informed by knowledge of another, similar disease. This approach can be productive where the disease in question is rare such that a GWAS has less power to associate variants with the disease, but there exist larger GWAS of similar diseases. Existing methods do not measure genetic similarity precisely when patients are few. Here we assess a previously published method of testing for genetic similarity between pairs of diseases using GWAS data, the ‘GPS’ test, against three other methods with the use of real and simulated data. We present a new computational procedure for carrying out the test and show that the GPS test is superior to its comparators in identifying genetic similarity when the sample size is small and when the genetic similarity signal is less strong. Use of the test will enable accurate detection of genetic similarity and the study of rarer conditions using data from better-characterised diseases.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45888773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010827
Huanfeng Hao, Li Song, Luoying Zhang
{"title":"Wolfram syndrome 1 regulates sleep in dopamine receptor neurons by modulating calcium homeostasis.","authors":"Huanfeng Hao, Li Song, Luoying Zhang","doi":"10.1371/journal.pgen.1010827","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010827","url":null,"abstract":"<p><p>Sleep disruptions are quite common in psychological disorders, but the underlying mechanism remains obscure. Wolfram syndrome 1 (WS1) is an autosomal recessive disease mainly characterized by diabetes insipidus/mellitus, neurodegeneration and psychological disorders. It is caused by loss-of function mutations of the WOLFRAM SYNDROME 1 (WFS1) gene, which encodes an endoplasmic reticulum (ER)-resident transmembrane protein. Heterozygous mutation carriers do not develop WS1 but exhibit 26-fold higher risk of having psychological disorders. Since WS1 patients display sleep abnormalities, we aimed to explore the role of WFS1 in sleep regulation so as to help elucidate the cause of sleep disruptions in psychological disorders. We found in Drosophila that knocking down wfs1 in all neurons and wfs1 mutation lead to reduced sleep and dampened circadian rhythm. These phenotypes are mainly caused by lack of wfs1 in dopamine 2-like receptor (Dop2R) neurons which act to promote wake. Consistently, the influence of wfs1 on sleep is blocked or partially rescued by inhibiting or knocking down the rate-limiting enzyme of dopamine synthesis, suggesting that wfs1 modulates sleep via dopaminergic signaling. Knocking down wfs1 alters the excitability of Dop2R neurons, while genetic interactions reveal that lack of wfs1 reduces sleep via perturbation of ER-mediated calcium homeostasis. Taken together, we propose a role for wfs1 in modulating the activities of Dop2R neurons by impinging on intracellular calcium homeostasis, and this in turn influences sleep. These findings provide a potential mechanistic insight for pathogenesis of diseases associated with WFS1 mutations.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010827"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010856
Haoxian Zhou, Chen Xie, Yujie Xie, Yunru He, Yanlian Chen, Canfeng Zhang, Yan Zhang, Yong Zhao, Haiying Liu
{"title":"UBQLN1 deficiency mediates telomere shortening and IPF through interacting with RPA1.","authors":"Haoxian Zhou, Chen Xie, Yujie Xie, Yunru He, Yanlian Chen, Canfeng Zhang, Yan Zhang, Yong Zhao, Haiying Liu","doi":"10.1371/journal.pgen.1010856","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010856","url":null,"abstract":"<p><p>Premature telomere shortening is a known factor correlated to idiopathic pulmonary fibrosis (IPF) occurrence, which is a chronic, progressive, age-related disease with high mortality. The etiology of IPF is still unknown. Here, we found that UBQLN1 plays a key role in telomere length maintenance and is potentially relevant to IPF. UBQLN1 involves in DNA replication by interacting with RPA1 and shuttling it off from the replication fork. The deficiency of UBQLN1 retains RPA1 at replication fork, hinders replication and thus causes cell cycle arrest and genome instability. Especially at telomere regions of the genome, where more endogenous replication stress exists because of G rich sequences, UBQLN1 depletion leads to rapid telomere shortening in HeLa cells. It revealed that UBQLN1 depletion also shortens telomere length at mouse lung and accelerates mouse lung fibrosis. In addition, the UBQLN1 expression level in IPF patients is downregulated and correlated to poor prognosis. Altogether, these results uncover a new role of UBQLN1 in ensuring DNA replication and maintaining telomere stability, which may shed light on IPF pathogenesis and prevention.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010856"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10381042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10260432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010795
John L Goodier, Han Wan, Alisha O Soares, Laura Sanchez, John Michael Selser, Gavin C Pereira, Sadik Karma, Jose Luis García-Pérez, Haig H Kazazian, Marta M García Cañadas
{"title":"ZCCHC3 is a stress granule zinc knuckle protein that strongly suppresses LINE-1 retrotransposition.","authors":"John L Goodier, Han Wan, Alisha O Soares, Laura Sanchez, John Michael Selser, Gavin C Pereira, Sadik Karma, Jose Luis García-Pérez, Haig H Kazazian, Marta M García Cañadas","doi":"10.1371/journal.pgen.1010795","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010795","url":null,"abstract":"<p><p>Retrotransposons have generated about half of the human genome and LINE-1s (L1s) are the only autonomously active retrotransposons. The cell has evolved an arsenal of defense mechanisms to protect against retrotransposition with factors we are only beginning to understand. In this study, we investigate Zinc Finger CCHC-Type Containing 3 (ZCCHC3), a gag-like zinc knuckle protein recently reported to function in the innate immune response to infecting viruses. We show that ZCCHC3 also severely restricts human retrotransposons and associates with the L1 ORF1p ribonucleoprotein particle. We identify ZCCHC3 as a bona fide stress granule protein, and its association with LINE-1 is further supported by colocalization with L1 ORF1 protein in stress granules, dense cytoplasmic aggregations of proteins and RNAs that contain stalled translation pre-initiation complexes and form when the cell is under stress. Our work also draws links between ZCCHC3 and the anti-viral and retrotransposon restriction factors Mov10 RISC Complex RNA Helicase (MOV10) and Zinc Finger CCCH-Type, Antiviral 1 (ZC3HAV1, also called ZAP). Furthermore, collective evidence from subcellular localization, co-immunoprecipitation, and velocity gradient centrifugation connects ZCCHC3 with the RNA exosome, a multi-subunit ribonuclease complex capable of degrading various species of RNA molecules and that has previously been linked with retrotransposon control.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010795"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9836000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010798
Anastasia Shatilovich, Vamshidhar R Gade, Martin Pippel, Tarja T Hoffmeyer, Alexei V Tchesunov, Lewis Stevens, Sylke Winkler, Graham M Hughes, Sofia Traikov, Michael Hiller, Elizaveta Rivkina, Philipp H Schiffer, Eugene W Myers, Teymuras V Kurzchalia
{"title":"A novel nematode species from the Siberian permafrost shares adaptive mechanisms for cryptobiotic survival with C. elegans dauer larva.","authors":"Anastasia Shatilovich, Vamshidhar R Gade, Martin Pippel, Tarja T Hoffmeyer, Alexei V Tchesunov, Lewis Stevens, Sylke Winkler, Graham M Hughes, Sofia Traikov, Michael Hiller, Elizaveta Rivkina, Philipp H Schiffer, Eugene W Myers, Teymuras V Kurzchalia","doi":"10.1371/journal.pgen.1010798","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010798","url":null,"abstract":"<p><p>Some organisms in nature have developed the ability to enter a state of suspended metabolism called cryptobiosis when environmental conditions are unfavorable. This state-transition requires execution of a combination of genetic and biochemical pathways that enable the organism to survive for prolonged periods. Recently, nematode individuals have been reanimated from Siberian permafrost after remaining in cryptobiosis. Preliminary analysis indicates that these nematodes belong to the genera Panagrolaimus and Plectus. Here, we present precise radiocarbon dating indicating that the Panagrolaimus individuals have remained in cryptobiosis since the late Pleistocene (~46,000 years). Phylogenetic inference based on our genome assembly and a detailed morphological analysis demonstrate that they belong to an undescribed species, which we named Panagrolaimus kolymaensis. Comparative genome analysis revealed that the molecular toolkit for cryptobiosis in P. kolymaensis and in C. elegans is partly orthologous. We show that biochemical mechanisms employed by these two species to survive desiccation and freezing under laboratory conditions are similar. Our experimental evidence also reveals that C. elegans dauer larvae can remain viable for longer periods in suspended animation than previously reported. Altogether, our findings demonstrate that nematodes evolved mechanisms potentially allowing them to suspend life over geological time scales.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010798"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10219087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010857
Zhongqing Ren, Constantin N Takacs, Hugo B Brandão, Christine Jacobs-Wagner, Xindan Wang
{"title":"Organization and replicon interactions within the highly segmented genome of Borrelia burgdorferi.","authors":"Zhongqing Ren, Constantin N Takacs, Hugo B Brandão, Christine Jacobs-Wagner, Xindan Wang","doi":"10.1371/journal.pgen.1010857","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010857","url":null,"abstract":"<p><p>Borrelia burgdorferi, a causative agent of Lyme disease, contains the most segmented bacterial genome known to date, with one linear chromosome and over twenty plasmids. How this unusually complex genome is organized, and whether and how the different replicons interact are unclear. We recently demonstrated that B. burgdorferi is polyploid and that the copies of the chromosome and plasmids are regularly spaced in each cell, which is critical for faithful segregation of the genome to daughter cells. Regular spacing of the chromosome is controlled by two separate partitioning systems that involve the protein pairs ParA/ParZ and ParB/Smc. Here, using chromosome conformation capture (Hi-C), we characterized the organization of the B. burgdorferi genome and the interactions between the replicons. We uncovered that although the linear chromosome lacks contacts between the two replication arms, the two telomeres are in frequent contact. Moreover, several plasmids specifically interact with the chromosome oriC region, and a subset of plasmids interact with each other more than with others. We found that Smc and the Smc-like MksB protein mediate long-range interactions on the chromosome, but they minimally affect plasmid-chromosome or plasmid-plasmid interactions. Finally, we found that disruption of the two partition systems leads to chromosome restructuring, correlating with the mis-positioning of chromosome oriC. Altogether, this study revealed the conformation of a complex genome and analyzed the contribution of the partition systems and SMC family proteins to this organization. This work expands the understanding of the organization and maintenance of multipartite bacterial genomes.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010857"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9974566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010799
Aaron Kusmec, Lakshmi Attigala, Xiongtao Dai, Srikant Srinivasan, Cheng-Ting Eddy Yeh, Patrick S Schnable
{"title":"A genetic tradeoff for tolerance to moderate and severe heat stress in US hybrid maize.","authors":"Aaron Kusmec, Lakshmi Attigala, Xiongtao Dai, Srikant Srinivasan, Cheng-Ting Eddy Yeh, Patrick S Schnable","doi":"10.1371/journal.pgen.1010799","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010799","url":null,"abstract":"<p><p>Global climate change is increasing both average temperatures and the frequencies of extreme high temperatures. Past studies have documented a strong negative effect of exposures to temperatures >30°C on hybrid maize yields. However, these studies could not disentangle genetic adaptation via artificial selection from changes in agronomic practices. Because most of the earliest maize hybrids are no longer available, side-by-side comparisons with modern hybrids under current field conditions are generally impossible. Here, we report on the collection and curation of 81 years of public yield trial records covering 4,730 maize hybrids, which enabled us to model genetic variation for temperature responses among maize hybrids. We show that selection may have indirectly and inconsistently contributed to the genetic adaptation of maize to moderate heat stress over this time period while preserving genetic variance for continued adaptation. However, our results reveal the existence of a genetic tradeoff for tolerance to moderate and severe heat stress, leading to a decrease in tolerance to severe heat stress over the same time period. Both trends are particularly conspicuous since the mid-1970s. Such a tradeoff poses challenges to the continued adaptation of maize to warming climates due to a projected increase in the frequency of extreme heat events. Nevertheless, given recent advances in phenomics, enviromics, and physiological modeling, our results offer a degree of optimism for the capacity of plant breeders to adapt maize to warming climates, assuming appropriate levels of R&D investment.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010799"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10325116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10162727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010864
Marco Fumasoni, Andrew W Murray
{"title":"Correction: Ploidy and recombination proficiency shape the evolutionary adaptation to constitutive DNA replication stress.","authors":"Marco Fumasoni, Andrew W Murray","doi":"10.1371/journal.pgen.1010864","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010864","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.pgen.1009875.].</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010864"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10381068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9891506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010834
Joshua M Lensmire, Michael R Wischer, Cristina Kraemer-Zimpel, Paige J Kies, Lo Sosinski, Elliot Ensink, Jack P Dodson, John C Shook, Phillip C Delekta, Christopher C Cooper, Daniel H Havlichek, Martha H Mulks, Sophia Y Lunt, Janani Ravi, Neal D Hammer
{"title":"The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition.","authors":"Joshua M Lensmire, Michael R Wischer, Cristina Kraemer-Zimpel, Paige J Kies, Lo Sosinski, Elliot Ensink, Jack P Dodson, John C Shook, Phillip C Delekta, Christopher C Cooper, Daniel H Havlichek, Martha H Mulks, Sophia Y Lunt, Janani Ravi, Neal D Hammer","doi":"10.1371/journal.pgen.1010834","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010834","url":null,"abstract":"Sulfur is an indispensable element for proliferation of bacterial pathogens. Prior studies indicated that the human pathogen, Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a previously uncharacterized five-gene locus comprising a putative ABC-transporter and γ–glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter the Glutathione import system (GisABCD). We confirm that Ggt is capable of cleaving GSH and GSSG γ–bonds and that this process is required for their use as nutrient sulfur sources. Additionally, we find that the enzyme is cell associated. Bioinformatic analyses reveal that only Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologues. Homologues are not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSH and promotes competition against other staphylococci commonly associated with the human microbiota.","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010834"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10219863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PLoS GeneticsPub Date : 2023-07-01DOI: 10.1371/journal.pgen.1010646
Ruben Iruegas, Katharina Pfefferle, Stephan Göttig, Beate Averhoff, Ingo Ebersberger
{"title":"Feature architecture aware phylogenetic profiling indicates a functional diversification of type IVa pili in the nosocomial pathogen Acinetobacter baumannii.","authors":"Ruben Iruegas, Katharina Pfefferle, Stephan Göttig, Beate Averhoff, Ingo Ebersberger","doi":"10.1371/journal.pgen.1010646","DOIUrl":"https://doi.org/10.1371/journal.pgen.1010646","url":null,"abstract":"<p><p>The Gram-negative bacterial pathogen Acinetobacter baumannii is a major cause of hospital-acquired opportunistic infections. The increasing spread of pan-drug resistant strains makes A. baumannii top-ranking among the ESKAPE pathogens for which novel routes of treatment are urgently needed. Comparative genomics approaches have successfully identified genetic changes coinciding with the emergence of pathogenicity in Acinetobacter. Genes that are prevalent both in pathogenic and a-pathogenic Acinetobacter species were not considered ignoring that virulence factors may emerge by the modification of evolutionarily old and widespread proteins. Here, we increased the resolution of comparative genomics analyses to also include lineage-specific changes in protein feature architectures. Using type IVa pili (T4aP) as an example, we show that three pilus components, among them the pilus tip adhesin ComC, vary in their Pfam domain annotation within the genus Acinetobacter. In most pathogenic Acinetobacter isolates, ComC displays a von Willebrand Factor type A domain harboring a finger-like protrusion, and we provide experimental evidence that this finger conveys virulence-related functions in A. baumannii. All three genes are part of an evolutionary cassette, which has been replaced at least twice during A. baumannii diversification. The resulting strain-specific differences in T4aP layout suggests differences in the way how individual strains interact with their host. Our study underpins the hypothesis that A. baumannii uses T4aP for host infection as it was shown previously for other pathogens. It also indicates that many more functional complexes may exist whose precise functions have been adjusted by modifying individual components on the domain level.</p>","PeriodicalId":20266,"journal":{"name":"PLoS Genetics","volume":"19 7","pages":"e1010646"},"PeriodicalIF":4.5,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10278800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}