Genetics最新文献

{"title":"Vitamin B12 partially rescues embryonic cell migration defects in Caenorhabditis elegans ephrin mutants by improving propionic acid breakdown and one-carbon cycle metabolism.","authors":"Tushar H Ganjawala, Erin Hsiao, Prativa Amom, Radmehr Molaei, Samantha Goodwin, Amanda L Zacharias","doi":"10.1093/genetics/iyaf054","DOIUrl":"10.1093/genetics/iyaf054","url":null,"abstract":"<p><p>Successful cell migration followed by cell adhesion and tissue remodeling is required for organogenesis in a number of tissues, many of which are susceptible to gene-environment interactions resulting in congenital anomalies. In Caenorhabditis elegans embryogenesis, one such event is the closure of the ventral cleft, an essential first step in morphogenesis; this process depends on ephrin signaling, but no single gene mutation is fully penetrant embryonic lethal, likely due to redundancy with semaphorin and Robo signaling. We exposed hermaphrodites mutant for vab-1, the C. elegans ephrin receptor, to various environmental conditions and found vitamin B12 supplementation could partially rescue the embryonic lethality of multiple alleles, improving survival by 58%. Vitamin B12 improved the frequency of ventral cleft closure by promoting cell positions more similar to wild type and increasing cell migration. We found vitamin B12 partially rescued the embryonic lethality of other ephrin pathway mutants as well as semaphorin and robo mutants, but not mutants with ventral cleft defects due to cell adhesion or cell fate defects. We found rescue by vitamin B12 depends on its functions in both mitochondrial propionic acid breakdown and the one-carbon cycle, and antioxidant treatment can also partially rescue ephrin pathway mutants. These results are distinct from the larval response to vitamin B12, which depends only on the one-carbon cycle, emphasizing the unique metabolism of embryos and particularly the metabolic needs of migrating cells. Overall, our findings highlight the C. elegans embryo as a model system to investigate gene-environment interactions and developmental metabolism.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximity labeling identification of plasma membrane eisosome proteins in Candida albicans.","authors":"Carla E Lanze, John D Haley, James B Konopka","doi":"10.1093/genetics/iyaf077","DOIUrl":"10.1093/genetics/iyaf077","url":null,"abstract":"<p><p>The ability of Candida albicans to resist stressful conditions in the host and grow invasively into tissues contributes to the virulence of this human fungal pathogen. Plasma membrane subdomains known as the MCC (membrane compartment of Can1) or eisosomes are important for these processes. MCC/eisosome domains are furrow-shaped invaginations of the plasma membrane that are about 250 nm long and 50 nm deep. To identify proteins that localize to these domains, a proximity labeling method was used in which the TurboID variant of the BirA biotin ligase was fused to Sur7 and Lsp1, 2 proteins that localize to eisosomes and are important for virulence. This resulted in biotinylation of nearby proteins, permitting their identification. Analysis of 19 candidate proteins by tagging with the green fluorescent protein identified 7 proteins that detectably overlapped with MCC/eisosomes. Deletion mutant analysis showed that one of these, a poorly studied protein known as Ker1, was important for hyphal growth in liquid culture, invasive growth into agar medium, and resistance to stress caused by copper and cell wall perturbing agents. Altogether, these approaches identified novel MCC/eisosome proteins and show that TurboID can be applied to better define the molecular mechanisms of C. albicans pathogenesis and aid in discovery of targets for novel therapeutic strategies.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parameters that influence bipartite reporter system expression in Caenorhabditis elegans.","authors":"Emma Knoebel, Anna Brinck, Michael L Nonet","doi":"10.1093/genetics/iyaf076","DOIUrl":"10.1093/genetics/iyaf076","url":null,"abstract":"<p><p>The development of bipartite reporter systems in Caenorhabditis elegans has lagged by more than a decade behind its adoption in Drosophila, the other invertebrate model commonly used to dissect biological mechanisms. Here, we characterize many parameters that influence expression in recently developed C. elegans bipartite systems. We examine how DNA binding site number and spacing influence expression and characterize how these expression parameters vary in distinct tissue types. Furthermore, we examine how both basal promoters and 3' UTR influence the specificity and level of expression. These studies provide both a framework for the rational design of driver and reporter transgenes and molecular and genetic tools for the creation, characterization, and optimization of bipartite system components for expression in other cell types.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 multigenerational population-growth assay to capture subtle fitness phenotypes in C. elegans and other nematodes.","authors":"Sophia C Tintori, Derin Çağlar, Matthew V Rockman","doi":"10.1093/genetics/iyaf073","DOIUrl":"10.1093/genetics/iyaf073","url":null,"abstract":"<p><p>Heritable fitness differences between individuals are the currency of evolution but can be challenging to quantify with precision. A slight probabilistic fitness advantage to one relatively healthy individual over another is often too subtle to detect in a single generation. For this reason, we have developed an assay to quantify and compare heritable fitness traits in nematodes by allowing their differences to amplify during unrestricted exponential population growth over multiple generations. This method employs continuous imaging as populations expand, and an automated program to detect the time of resource exhaustion. Expanding on our earlier applications, we here describe, motivate, and validate the method's experimental parameters and introduce a new R package to facilitate image processing and statistical analyses. We demonstrate the utility of this method by using it to identify natural differences in mutagen sensitivity between wild isolates of Caenorhabditis elegans. This tool is immediately adaptable to any strain of C. elegans or similar nematode and can be used to quantify fitness differences in the face of any experimental condition that can be created on a petri dish.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal network inference of cis- and trans-gene regulation of expression quantitative trait loci across human tissues.","authors":"Jarred Kvamme, Md Bahadur Badsha, Evan A Martin, Jiayu Wu, Xiaoyue Wang, Audrey Qiuyan Fu","doi":"10.1093/genetics/iyaf064","DOIUrl":"10.1093/genetics/iyaf064","url":null,"abstract":"<p><p>Expression quantitative trait loci (eQTLs) have been identified for most genes in the human genome across tissues and cell types. While most of the eQTLs are near (i.e. cis) the associated genes on the linear genome, some can be far away or on different chromosomes (i.e. trans), with the regulatory mechanisms largely unknown. Here, we study regulation by eQTLs of their cis- and trans-genes across nearly 50 tissues and cell types, taking a causal network inference approach and leveraging the principle of Mendelian randomization. Specifically, we constructed trios consisting of an eQTL, its cis-gene and trans-gene. We then inferred the regulatory relationships, using the eQTL as an instrumental variable and accounting for confounding variables. We identify multiple types of regulatory networks for trios: across all the tissues, more than half of the trios are inferred to be conditionally independent, where the two genes are conditionally independent given the genotype of the eQTL (gene1←eQTL→gene2). Around 1.5% of the trios are inferred to be mediation (eQTL→mediator→target), around 1.3% fully connected among the three nodes, and just a handful v-structures (eQTL→gene1←gene2). The identifications are generally consistent with the statistical dependence patterns of each trio. Genes in trios of different regulatory types exhibit distinct functional enrichments. Interestingly, many mediation trios have the trans-gene as the mediator. Existing transcription factor databases and HiC data for genome spatial structure provide additional support for long-range cis-acting and trans-acting in some of the inferred trans-gene mediation trios.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of rad-51 separation of function allele suggests divergence of the synthesis-dependent strand annealing and double Holliday junction pathways prior to RAD-51 filament disassembly.","authors":"Joseph Oberlitner, Maggie Tinman, Aasthika Das, Emily Koury, Nicola Silva, Sarit Smolikove","doi":"10.1093/genetics/iyaf063","DOIUrl":"10.1093/genetics/iyaf063","url":null,"abstract":"<p><p>DNA double-strand breaks (DSBs) are formed in meiosis, so their repair in the homologous recombination (HR) pathway will lead to crossover formation, which is essential for successful chromosome segregation. HR contains 2 subpathways: synthesis-dependent strand annealing (SDSA) that creates noncrossover and double Holliday junction (dHJ) that generates crossovers. RAD-51 is a protein essential to the formation of all products of HR, as it assembles on the processed DSB, allowing the invasion of the single-stranded DNA into a region of homology. RAD-51 is removed by RAD-54.L after invasion to allow for repair to occur. Here, we investigate a separation of function allele of rad-51, rad-51::FLAG, as compared to 2 other RAD-51 alleles: rad-51::degron and GFP::rad-51. rad-51::FLAG displays slowed repair kinetics, resulting in an accumulation of RAD-51 foci. rad-51::FLAG worms also activate the DSB checkpoint, but to a less extant than that of rad-51 null mutants. In a proximity ligation assay, RAD-54.L and RAD-51 show enriched colocalization in rad-51::FLAG germlines (but not in rad-51::degron), consistent with stalling at the strand invasion step in HR. The defects in RAD-51 disassembly in rad-51::FLAG mutants lead to formation of chromosomal fragments, similar in their magnitude to ones observed in rad-51 or rad-54.L null mutants. However, rad-51::FLAG mutants (unlike a rad-51 null, GFP::rad-51 or rad-54.L null mutants) displayed no defects in the formation of crossover-designated sites (via GFP::COSA-1 localization). Given that rad-51::FLAG worms show checkpoint activation and chromosomal fragments, these results suggest that crossover repair concludes normally, while the noncrossover pathway is perturbed. This is strikingly different from rad-51::degron and GFP::rad-51 strains, which are proficient or deficient in both pathways, respectively. These results suggest that noncrossovers vs crossovers have distinct recombination intermediates and diverge prior to RAD-51 disassembly.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diploidy confers genomic instability in Schizosaccharomyces pombe.","authors":"Joshua M Park, Daniel F Pinski, Susan L Forsburg","doi":"10.1093/genetics/iyaf078","DOIUrl":"10.1093/genetics/iyaf078","url":null,"abstract":"<p><p>Whole genome duplication, or polyploidy, has been implicated in driving genome instability and tumorigenesis. Recent studies suggest that polyploidy in tumors promotes cancer genome evolution, progression, and chemoresistance resulting in worse prognosis of survival. The mechanisms by which whole genome duplications confer genome instability are not yet fully understood. In this study, we use Schizosaccharomyces pombe (fission yeast) diploids to investigate how whole genome duplication affects genome maintenance and response to stress. We find that S. pombe diploids are sensitive to replication stress and DNA damage, exhibit high levels of loss of heterozygosity, and become dependent on a group of ploidy-specific lethal genes for viability. These findings are observed in other eukaryotic models suggesting conserved consequences of polyploidy. We further investigate ploidy-specific lethal genes by depleting them using an auxin-inducible degron system to elucidate the mechanisms of genome maintenance in diploids. Overall, this work provides new insights on how whole genome duplications lead to genome instability.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fork-barrier-independent roles of topoisomerase I in the ribosomal DNA.","authors":"Temistocles Molinar, Daniel Sultanov, Hannah Klein, Andreas Hochwagen","doi":"10.1093/genetics/iyaf052","DOIUrl":"10.1093/genetics/iyaf052","url":null,"abstract":"<p><p>Topoisomerase I, a nickase that allows swiveling of the DNA substrate, is highly enriched in the ribosomal DNA (rDNA) from yeast to humans, but its function at this locus remains poorly understood. S. cerevisiae mutants lacking topoisomerase I (top1) exhibit pronounced rDNA instability and accumulate bubbles of single-stranded DNA (ssDNA) on 35S ribosomal RNA genes, suggesting a role in relieving transcription-associated topological stress. However, Top1 cleavage complexes are most highly enriched in the rDNA-encoded replication fork barrier, a genetically encoded source of rDNA instability, and only weakly in the 35S promoter, leading to the proposal that top1-associated rDNA instability may be linked to the fork barrier. Here, we show that the rDNA instability phenotypes of top1 mutants, including increased formation of extrachromosomal rDNA circles, elevated genetic marker loss, and instability of critically short rDNA arrays, are independent of the replication fork barrier. In addition, we link Top1 binding at the 35S promoter to the formation of a DNA species with a long ssDNA tail, which originates in the 35S promoter region and is undetectable in top1 mutants. This DNA species is abundant in wild-type cells, occurs independently of S-phase, and may be the resolution product of the ssDNA bubbles seen in top1 mutants. Whether the formation of this DNA species is important for rDNA stability remains unclear, but our findings link Top1 to highly active DNA metabolism in the 35S promoter.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimation of heritabilities and genetic correlations by time slices using predictivity in large genomic models.","authors":"Ignacy Misztal, Gopal Gowane","doi":"10.1093/genetics/iyaf066","DOIUrl":"10.1093/genetics/iyaf066","url":null,"abstract":"<p><p>Under genomic selection, genetic parameters may change rapidly from generation to generation. Unless genetic parameters used for a selection index are current, the expected genetic gain may be unrealistic, possibly with a decline for antagonistic traits. Existing methods for parameter estimation are computationally unfeasible with large genomic data. We present formulas for estimating heritabilities and genetic correlations applicable for large models with any number of genotyped individuals. Heritabilities are calculated by combining 2 formulas for genomic accuracies: one that relies on predictivity and another that depends on the number of independent chromosome segments. Genetic correlations are calculated from predictivities across traits. We simulated data including 2 traits for 240,000 genotyped and phenotyped animals in 6 generations, namely, production trait with an initial heritability of 0.4 and a fitness trait with a fixed heritability set at 0.1 in each generation. Only the first trait (production) was selected, whereas the second trait (fitness) was constructed so that its genetic correlation with the first trait declined by about 0.1 per generation. Calculations were for 3-generation windows, with the first 2 generations treated as a reference population. Compared with realized values, the estimated heritabilities were within 0.02. Genetic correlations were within 0.15 with predictivity of production phenotype by prediction for fitness and within 0.05 with predictivity of the fitness phenotype by prediction for production. The proposed formulas enable the estimation of heritabilities and genetic correlations by time slices for models in which predictivities can be calculated and genetic evaluation is feasible.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of hybridization and gene flow on gene co-expression networks.","authors":"Rogini Runghen, Daniel I Bolnick","doi":"10.1093/genetics/iyaf057","DOIUrl":"10.1093/genetics/iyaf057","url":null,"abstract":"<p><p>Gene co-expression networks are a widely used tool for summarizing transcriptomic variation between individuals, and for inferring the transcriptional regulatory pathways that mediate genotype-phenotype relationships. However, these co-expression networks must be interpreted with caution, as they can arise from multiple processes. Here, we investigate one such process, using simulations to demonstrate that hybridization and gene flow between populations can greatly modify co-expression networks. Admixture between populations produces correlated expression between genes experiencing linkage disequilibrium. This correlated expression does not reflect functional relationships between genes but rather depends on migration rates and physical linkage on chromosomes. Given the prevalence of gene flow and hybridization between divergent populations in nature, these introgression effects likely represent a significant force in network evolution, even in populations where hybridization is historical rather than contemporary. These findings emphasize the critical importance of considering both evolutionary history and genomic architecture when analyzing gene co-expression networks in natural populations.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}