PLoS Genetics最新文献

{"title":"The MIR157-SPL15 module regulates flowering and inflorescence development in Arabidopsis thaliana under short days and in Arabis alpina.","authors":"Adrian Roggen, Alba Lloret, Yohanna Miotto, Kang Wang, Kerstin Luxa, Vidya Oruganti, Serena Della Pina, Annabel D van Driel, Youbong Hyun, Bruno Huettel, George Coupland","doi":"10.1371/journal.pgen.1011799","DOIUrl":"10.1371/journal.pgen.1011799","url":null,"abstract":"<p><p>The plant life cycle progresses through distinct phases defined by the morphology of the organs formed on the shoot. In Arabidopsis, age-dependent reduction in the related microRNAs miR156 and miR157 controls transitions from juvenile to adult vegetative phase and from adult to reproductive phase. However, whether these miRNA isoforms have specific contributions remains unclear. To compare their roles, we used Trans-kingdom, rapid, affordable Purification of RISCs (TraPR) for small RNA sequencing, CRISPR-Cas9, and confocal imaging. We show that in shoot apices, levels of miR156 in RNA-induced silencing complexes (RISCs) decline more rapidly than those of miR157, so that miR157 is more abundant than miR156 in RISCs of older plants undergoing floral transition and inflorescence development. Accordingly, confocal microscopy analysis showed that MIR156A and MIR156C are not detectably expressed in shoot apices of older plants, whereas at this stage MIR157C is expressed in upper stems, and MIR157D is expressed in axils of inflorescence leaves. Arabidopsis flowers much earlier under long days (LDs) than short days (SDs). CRISPR-induced mir157c mutations but not mir156ac mutations accelerated flowering under SDs, and altered inflorescence leaf morphology. Notably, mir157c mutations also caused early flowering in Arabis alpina, a perennial relative of Arabidopsis, indicating that the repression of flowering by this paralogue is evolutionarily conserved. SPL15 transcription factor promotes flowering under SDs and its mRNA is a target of miR156/miR157. SPL15 abundance was higher in apices of mir157 cd mutants under SDs, and spl15 mutations partially suppressed the early flowering of mir157c mutants and this effect was enhanced by spl4 mutation. We show by genetic analysis that the florigen FLOWERING LOCUS T overcomes the requirement for SPL15 in LDs but not SDs, contributing to the increased importance of the MIR157C-SPL15 module under SDs. We conclude that MIR157 genes have important evolutionarily conserved roles in repressing floral transition and modulating inflorescence development of older plants under SDs.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011799"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975371","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}

{"title":"Genetic variation in the FMO and GSTO gene clusters impacts arsenic metabolism in humans.","authors":"Lizeth I Tamayo, Lin Tong, Tetiana Davydiuk, Donald Vander Griend, Syed Emdadul Haque, Tariqul Islam, Farzana Jasmine, Muhammad G Kibriya, Joseph Graziano, Lin Chen, X Chris Le, Habibul Ahsan, Mary V Gamble, Brandon L Pierce","doi":"10.1371/journal.pgen.1011826","DOIUrl":"10.1371/journal.pgen.1011826","url":null,"abstract":"<p><strong>Background: </strong>In Bangladesh, > 50 million individuals are chronically exposed to inorganic arsenic (iAs) through drinking water, increasing risk for cancer and other iAs-related diseases. Previous studies show that individuals' ability to metabolize and eliminate iAs, and their risk of toxicity, is influenced by genetic variation in the AS3MT and FTCD gene regions.</p><p><strong>Methods: </strong>To identify additional loci influencing arsenic metabolism, we used data from Bangladeshi individuals to conduct genome-wide association analyses of the relative abundances of arsenic species measured in both urine (n = 6,540) and blood (n = 976). These species include iAs, monomethylated arsenic (MMA) and dimethylated arsenic (DMA) species.</p><p><strong>Results: </strong>In analyses of urine arsenic species, we identified a novel association signal in the FMO gene cluster (1q24.3), with the lead SNP residing in FMO3 (MMA% P = 4.2x10-16). In analyses of blood arsenic species, we identified an additional signal in the FMO cluster, with the lead SNP residing in FMO4 (DMA% P = 2.3x10-22) and a novel signal at 10q25.1, with the lead SNP in GSTO1 (DMA% P = 5.3x10-13). Lead SNPs at FMO3 and GSTO1 are associated with the splicing of FMO3 and GSTO1, respectively, in multiple tissue types, but also contain missense variants. The lead SNPs at FMO4 are associated with FMO4 expression level in multiple tissue types. These newly identified SNPs did not show a clear association with risk for arsenic-induced skin lesions (P > 0.05), based on 3,448 cases and 5,207 controls.</p><p><strong>Conclusion: </strong>We identified novel loci influencing arsenic metabolites measured in both urine and blood. FMOs are involved in the oxidation of xenobiotics but have no known direct role in arsenic metabolism, while GSTO1 has a well-established role in catalyzing the reduction of arsenic species. The novel associations we report appear specific to blood or urine, with no detectable impact on skin toxicity risk, pointing to complexities in arsenic metabolism and its genetic contributors that require further study.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011826"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975668","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}

{"title":"Identification of gene-sex hormone interactions associated with type 2 diabetes among men and women.","authors":"Amonae Dabbs-Brown, Chang Liu, Qin Hui, Peter W F Wilson, Jin J Zhou, Marta Gwinn, Yan V Sun","doi":"10.1371/journal.pgen.1011470","DOIUrl":"10.1371/journal.pgen.1011470","url":null,"abstract":"<p><strong>Background and objectives: </strong>Type 2 diabetes affects an increasing number of people worldwide. Although genome-wide association studies (GWAS) of type 2 diabetes have identified hundreds of loci, their interactions with other risk factors aren't well understood. We investigated genetic interactions with three sex hormones (total testosterone, bioavailable testosterone, and sex hormone binding globulin (SHBG)) to identify additional type 2 diabetes-related loci that were undetected in traditional GWAS.</p><p><strong>Methods: </strong>The study population consisted of white European UK Biobank participants. Individuals with type 1 diabetes were excluded. We examined sex-stratified interactions of polygenic risk score (PRS) for type 2 diabetes with sex hormone levels. We analyzed sex-stratified, genome-wide SNP × sex hormone interactions, adjusting for age and the top ten principal ancestry components.</p><p><strong>Results: </strong>We found significant (P < 0.05) interactions for each of the sex hormones with PRS in both men and women, with the most significant being between SHBG and PRS in women (OR 0.88; 95% CI: 0.85-0.90; P = 1.09E-18). We identified 3 SNP × sex hormone interactions in men and 14 in women that achieved genome-wide significance (GWS; P < 5 × 10-8). Applying a 2-degree of freedom test, we identified GWS loci (10 in men and 23 in women) that were not GWS when testing marginal genetic effects alone.</p><p><strong>Conclusion: </strong>Including interaction terms in GWAS may identify additional risk loci and improve the understanding of genetic architecture for type 2 diabetes. Different genetic interactions with sex hormones in men and women emphasize the importance of sex-stratified analysis in sex differential diseases.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 9","pages":"e1011470"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975718","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}

{"title":"Igf2 adult-specific skeletal muscle enhancer activity revealed in mice with intergenic CTCF boundary deletion.","authors":"Joanne L Thorvaldsen, Aimee M Juan, Yemin Lan, Christopher Krapp, Marisa S Bartolomei","doi":"10.1371/journal.pgen.1011834","DOIUrl":"10.1371/journal.pgen.1011834","url":null,"abstract":"<p><p>Precise, monoallelic expression of imprinted genes is governed by cis regulatory elements called imprinting control regions (ICRs) and enhancer-promoter (E-P) interactions shaped by local chromatin architecture. The Igf2/H19 locus employs allele-specific CTCF binding at the ICR to instruct enhancer accessibility to maternal H19 and paternal Igf2 promoters. Here, we investigate the CTCF-bound centrally conserved domain (CCD), intergenic to H19 and Igf2, and an adjacent widely expressed lncRNA. Using transgenic mice, deletion alleles reinforced CCD as a neonatal muscle-specific repressor of maternal Igf2. However, deletion of the abutting lncRNA did not affect Igf2 levels. Unexpectedly, in adult skeletal muscle where Igf2 is normally repressed, absence of CCD resulted in remarkable, high-level activation of Igf2 from both parental alleles. Through multimodal chromatin analyses, we identified a conserved putative adult skeletal muscle enhancer (PaSME) insulated between chromatin domains at ICR and CCD. We propose that removal of CCD allows PaSME to drive robust abnormal Igf2 activation on both alleles in adult skeletal muscle. Thus, we uncover CCD as a developmental biallelic muscle-specific repressor, adding a new layer of architectural regulation to the extensively studied Igf2/H19 locus.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011834"},"PeriodicalIF":3.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975647","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}

{"title":"On the role of the terminal oxidase cytochrome bd in hyper-resistance of Listeria monocytogenes to the macrodiolide antibiotic tartrolon B.","authors":"Vitaliy B Borisov, Elena Forte","doi":"10.1371/journal.pgen.1011803","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011803","url":null,"abstract":"","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011803"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975738","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}

{"title":"The actin module of endocytic internalization in Aspergillus nidulans: A critical role of the WISH/DIP/SPIN90 family protein Dip1.","authors":"Marisa Delgado, Mario Pinar, Paula Polonio, Sergio Fandiño, Eduardo A Espeso, Miguel A Peñalva","doi":"10.1371/journal.pgen.1011619","DOIUrl":"10.1371/journal.pgen.1011619","url":null,"abstract":"<p><p>Using fluorescent protein-tagged F-actin reporters we studied the actin cytoskeleton in Aspergillus nidulans. F-actin probes labeled endocytic patches, contractile actin rings and the Spitzenkörper (SPK), but not exocytic cables generated by the SPK-associated formin, illuminated only by tropomyosin. The SPK actin mesh contains tropomyosin and capping protein, but not fimbrin or Arp2/3, showing that it does not involve branched actin. Arp2/3 and fimbrin are recruited to endocytic patches at the end of their lifecycle, staying in them for 12-14 sec, coinciding with the burst of branched actin polymerization that powers vesicle internalization, whereas verprolin stays only during the first half of this actin phase. Hyphal growth requires endocytic recycling, which we exploited to assess the efficiency of endocytosis following genetic interventions. Ablation of SlaBSla2, Arp2/3, cofilin and fimbrin is lethal, whereas that of Srv2, verprolin and capping protein are debilitating, with the lifetime of actin in mutant patches roughly correlating with the extent of growth and endocytic defects. An outstanding problem is the origin of seed filaments required to prime Arp2/3 during endocytosis. Actin patches associate with cortical cables that give rise to long distance-moving \"actin worms\" that are different from tropomyosin-containing cables emanating from the SPK. Cables and worms are dependent on formin, yet inactivation of formin does not affect the F-actin patch lifecycle, arguing against formin playing an endocytic role. Ablation of the WISH/DIP/SPIN90 protein Dip1 priming Arp2/3 for the synthesis of linear actin delocalizes the endocytic machinery and severely impairs, but does not preclude, endocytosis. This establishes the existence of Dip1-independent mechanism(s) that synthesize seed filaments. Our data negate the possibility that this alternative mechanism results from a priming role of formin that is unmasked in dip1∆ cells, but do not exclude that cofilin-mediated filament severing could produce seed microfilaments for Arp2/3, as suggested for Schizosaccharomyces pombe.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011619"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12422587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975678","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}

{"title":"A systems genetics approach identifies roles for proteasome factors in heart development and congenital heart defects.","authors":"Gist H Farr, Whitaker Reid, Eva H Hasegawa, Azzam Azzam, Isabelle Young, Mona L Li, Aaron K Olson, David R Beier, Lisa Maves","doi":"10.1371/journal.pgen.1011579","DOIUrl":"10.1371/journal.pgen.1011579","url":null,"abstract":"<p><p>Congenital heart defects (CHDs) occur in about 1% of live births and are the leading cause of infant death due to birth defects. While there have been remarkable efforts to pursue large-scale whole-exome and genome sequencing studies on CHD patient cohorts, it is estimated that these approaches have thus far accounted for only about 50% of the genetic contribution to CHDs. We sought to take a new approach to identify genetic causes of CHDs. By combining analyses of genes that are under strong selective constraint along with published embryonic heart transcriptomes, we identified over 200 new candidate genes for CHDs. We utilized protein-protein interaction (PPI) network analysis to identify a functionally-related subnetwork consisting of known CHD genes as well as genes encoding proteasome factors, in particular POMP, PSMA6, PSMA7, PSMD3, and PSMD6. We used CRISPR targeting in zebrafish embryos to preliminarily identify roles for the PPI subnetwork genes in heart development. We then used CRISPR to create new mutant zebrafish strains for two of the proteasome genes in the subnetwork: pomp and psmd6. We show that loss of proteasome gene functions leads to defects in zebrafish heart development, including dysmorphic hearts, myocardial cell blebbing, and reduced outflow tracts. We also identified deficits in cardiac function in pomp and psmd6 mutants. These heart defects resemble those seen in zebrafish mutants for known CHD genes and other critical heart development genes. Our study provides a novel systems genetics approach to further our understanding of the genetic causes of human CHDs.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011579"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975717","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}

{"title":"ETS transcription factor pointed controls germline survival in Drosophila.","authors":"Alicia E Rosales-Nieves, Miriam Marín-Menguiano, Lourdes López-Onieva, Juan Garrido-Maraver, Acaimo González-Reyes","doi":"10.1371/journal.pgen.1011809","DOIUrl":"10.1371/journal.pgen.1011809","url":null,"abstract":"<p><p>Proper gonad development is a pre-requisite for gametogenesis and reproduction. During female gonad formation in Drosophila, the EGF receptor (EGFR) signalling pathway ensures the correct number of primordial germ cells (PGCs) populate the larval gonad. We study the gene pointed (pnt), which acts downstream of the EGFR receptor and belongs to the ETS transcription factor family, with a previously unknown function in gonadogenesis. We report that pnt is expressed in female larval gonads and later in the adult ovarian germline niche and that it is required to sustain proper gametogenesis. Loss of pnt function in female larval gonads, similar to the EGFR, induced PGC overproliferation. Conversely, we isolated a novel mutant allele gene, termed pntaga, which resulted in agametic gonads and ovaries. While pntaga embryos developed gonads containing a normal complement of PGCs, these are subsequently lost by apoptosis during late larval and pupal stages. Molecular characterization of pntaga revealed reduced expression levels of the different pnt isoforms, unveiling a complex autoregulatory network involving the three Pnt proteins. We propose that germline survival in Drosophila gonads requires a precise tuning of EGFR signalling to ensure the appropriate transcriptional activation of its target pnt.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011809"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975651","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}

{"title":"Circulating proteins associated with histological subtypes of lung cancer from genetic and population-based perspectives.","authors":"Zhangyan Lyu, Guojin Si, Mengbo Xing, Wenxuan Li, Ximin Gao, Meng Wang, Fengju Song, Kexin Chen","doi":"10.1371/journal.pgen.1011821","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011821","url":null,"abstract":"<p><p>Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, accounting for millions of deaths annually. Its major subtypes-lung squamous carcinoma (LUSC), lung adenocarcinoma, and small-cell LC-exhibit distinct risk factors and genetic susceptibilities, necessitating the use of subtype-specific biomarkers. Two-sample Mendelian randomization (MR) analyses were conducted using protein quantitative trait loci from the UK Biobank Pharma Proteomics Project and deCODE datasets. A robust analytical framework, including reverse MR, meta-analysis, summary-data-based MR tests, and colocalization, cisMR-cML, MR.CUE and phenotype scanning analyses were used to identify proteins associated with LC risk. We conducted a systematic review to contextualize our research findings. Follow-up analyses, including pathway enrichment, protein-protein interaction network analysis, and druggability evaluations, were used to explore the mechanisms and therapeutic potential of the identified proteins. Significant proteins were validated using population-level proteomic data from the UK Biobank (UKB). The results showed that twenty-five proteins were significantly associated with LC or its subtypes, including 15 novel findings. 60S ribosomal protein L14 (RPL14) and advanced glycosylation end-product-specific receptor (AGER) emerged as the strongest discovery, demonstrating consistent and significant associations across both MR and population-level analyses. RPL14 exhibited positive associations with overall LC risk (MR_meta: odds ratio [OR]: 2.012, 95% confidence interval [CI]: 1.297-3.119; UKB: OR: 1.509, 95% CI: 1.015-2.244). Similarly, AGER showed significant protective effects against LUSC risk (MR_meta: OR: 0.572, 95%CI: 0.368-0.889; UKB: OR: 0.366, 95% CI: 0.158-0.850). Pathway analysis revealed the involvement of these proteins in immune regulation and tumorigenesis. Among the 13 identified druggable targets, RPL14 and AGER showed therapeutic potential as approved or investigational drugs targeting these proteins. These findings offer new insights into the pathogenesis of LC and potential therapeutic targets.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011821"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975670","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}

{"title":"Idiosyncratic evolvability among single-point ribosomal mutants towards multi-aminoglycoside resistance.","authors":"Laura Sánchez-Maroto, Guillem A Devin, Pablo Gella, Alejandro Couce","doi":"10.1371/journal.pgen.1011832","DOIUrl":"10.1371/journal.pgen.1011832","url":null,"abstract":"<p><p>Newly-arising mutations can impact not only fitness but also an organism's capacity for further adaptation (i.e., its evolvability). Understanding what determines evolvability differences is of great interest from both fundamental and applied perspectives. A general pattern observed across multiple microbes is that evolvability tends to decline with genotype fitness (i.e., the \"rule of declining adaptability\"), typically attributed to epistatic rather than mutational differences among genotypes. Here, we investigate whether common rpsL point mutations in Escherichia coli, conferring streptomycin resistance, may potentiate or hinder adaptation towards secondary aminoglycosides. We find a version of the rule of declining adaptability in which initially more-fit genotypes experience higher effective beneficial mutation rates but smaller effect sizes than their less-fit counterparts. Genome sequencing reveals the ribosome and electron transport chain as primary targets for adaptation. Second-step mutations typically confer cross-resistance across aminoglycosides, and some even restore fitness costs in the absence of drugs. However, some genotypes deviate markedly from the overall pattern, being completely unable to develop resistance to the secondary aminoglycosides. Such idiosyncratic dead-ends, if common among other systems involving single-point mutants, would expand the pool of potential targets for strategies to promote evolutionary robustness in biotechnology and combat multidrug resistance in clinical microbiology.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011832"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975722","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}