Genetics最新文献

{"title":"Intrinsically disordered arginine-glycine (RG) repeat domains tune sub-nucleolar compartmentalization in C. elegans.","authors":"Emily L Spaulding, Dustin L Updike","doi":"10.1093/genetics/iyaf067","DOIUrl":"https://doi.org/10.1093/genetics/iyaf067","url":null,"abstract":"<p><p>Intrinsically disordered arginine-glycine (RG) repeat domains are enriched in multilayered biomolecular condensates such as the nucleolus. C. elegans nucleolar RG repeats are dispensable for nucleolar accumulation and instead contribute to the organization of sub-nucleolar compartments. The sufficiency of RG repeats to facilitate sub-nucleolar compartmentalization is unclear. In this study, we drive expression of full-length RG repeats in the C. elegans germline to test their ability to localize to nucleoli and organize into nucleolar sub-compartments in vivo. We find that repeats accumulate within germ cell nucleoli but do not enrich in the correct sub-compartment. Our results suggest RG repeats may indirectly influence nucleolar organization by creating an environment favorable for sub-nucleolar compartmentalization of proteins primarily based on their function within the nucleolus.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796528","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}

{"title":"Dimensionality Reduction of Genetic Data using Contrastive Learning.","authors":"Filip Thor, Carl Nettelblad","doi":"10.1093/genetics/iyaf068","DOIUrl":"https://doi.org/10.1093/genetics/iyaf068","url":null,"abstract":"<p><p>We introduce a framework for using contrastive learning for dimensionality reduction on genetic datasets to create PCA-like population visualizations. Contrastive learning is a self-supervised deep learning method that uses similarities between samples to train the neural network to discriminate between samples. Many of the advances in these types of models have been made for computer vision, but some common methodology does not translate well from image to genetic data. We define a loss function that outperforms loss functions commonly used in contrastive learning, and a data augmentation scheme tailored specifically towards SNP genotype datasets. We compare the performance of our method to PCA and contemporary non-linear methods with respect to how well they preserve local and global structure, and how well they generalize to new data. Our method displays good preservation of global structure and has improved generalization properties over t-SNE, UMAP, and popvae, while preserving relative distances between individuals to a high extent. A strength of the deep learning framework is the possibility of projecting new samples and fine-tuning to new datasets using a pre-trained model without access to the original training data, and the ability to incorporate more domain-specific information in the model. We show examples of population classification on two datasets of dog and human genotypes.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804628","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}

{"title":"Analysis of rad-51 separation of function allele suggests divergence of the SDSA and dHJ 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":"https://doi.org/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 chromosomes segregation. HR contains two sub pathways: synthesis dependent strand annealing (SDSA) that creates non-crossover, 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 ssDNA 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 two 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 non-crossover 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 non-crossovers 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":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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 240k 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":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of regions required for allelic specificity at the cell wall remodeling allorecognition checkpoint in Neurospora crassa.","authors":"Adriana M Rico-Ramirez, N Louise Glass","doi":"10.1093/genetics/iyaf062","DOIUrl":"https://doi.org/10.1093/genetics/iyaf062","url":null,"abstract":"<p><p>Allorecognition is the ability of organisms/cells to differentiate self from non-self. In Neurospora crassa, allorecognition systems serve as checkpoints to restrict germling/hyphal fusion between genetically incompatible strains. The cell wall remodeling (cwr) checkpoint functions after chemotrophic interactions and is triggered upon cell/hyphal contact, regulating cell wall dissolution and subsequent cell fusion. The cwr region consists of two linked loci, cwr-1 and cwr-2, that are under severe linkage disequilibrium. Phylogenetic analyses of N. crassa populations showed that cwr-1/cwr-2 alleles fall into six different haplogroups (HGs). Strains containing deletions of cwr-1 and cwr-2 fuse with previously HG incompatible cells, indicating cwr negatively regulates cell fusion. CWR-1 encodes a chitin polysaccharide monooxygenase (PMO); the PMO domain confers allelic specificity by interacting in trans with the predicted transmembrane protein, CWR-2, from a different HG. However, catalytic activity of CWR-1 is not required for triggering a block in cell fusion. The CWR-1 L2 and LC regions of the PMO domain show high levels of structural variability between different HGs. CWR-1 chimeras containing a LC region from a different HG were sufficient to trigger a cell fusion block, suggesting that the complete PMO structure is necessary for allorecognition. Modeling of the transmembrane protein CWR-2 revealed allelic variability in the two major extracellular domains (ED2/ED4). Chimeras of CWR-2 with swapped ED2 or ED4 or ED2/ED4 domains from different cwr-2 HGs also altered allelic specificity. This work identified key regions of CWR-1 and CWR-2 that contribute to allorecognition specificity, providing insight into the molecular basis of this process.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781457","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}

{"title":"Conserved components of the macroautophagy machinery in Caenorhabditis elegans.","authors":"Hong Zhang, Alicia Meléndez","doi":"10.1093/genetics/iyaf007","DOIUrl":"https://doi.org/10.1093/genetics/iyaf007","url":null,"abstract":"<p><p>Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and its subsequent delivery to lysosomes for degradation and recycling. In Caenorhabditis elegans, autophagy participates in diverse processes such as stress resistance, cell fate specification, tissue remodeling, aging, and adaptive immunity. Genetic screens in C. elegans have identified a set of metazoan-specific autophagy genes that form the basis for our molecular understanding of steps unique to the autophagy pathway in multicellular organisms. Suppressor screens have uncovered multiple mechanisms that modulate autophagy activity under physiological conditions. C. elegans also provides a model to investigate how autophagy activity is coordinately controlled at an organismal level. In this chapter, we will discuss the molecular machinery, regulation, and physiological functions of autophagy, and also methods utilized for monitoring autophagy during C. elegans development.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781455","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}

{"title":"Origin and establishment of the germline in Drosophila melanogaster.","authors":"Ruoyu Chen, Sherilyn Grill, Benjamin Lin, Mariyah Saiduddin, Ruth Lehmann","doi":"10.1093/genetics/iyae217","DOIUrl":"https://doi.org/10.1093/genetics/iyae217","url":null,"abstract":"<p><p>The continuity of a species depends on germ cells. Germ cells are different from all the other cell types of the body (somatic cells) as they are solely destined to develop into gametes (sperm or egg) to create the next generation. In this review, we will touch on 4 areas of embryonic germ cell development in Drosophila melanogaster: the assembly and function of germplasm, which houses the determinants for germ cell specification and fate and the mitochondria of the next generation; the process of pole cell formation, which will give rise to primordial germ cells (PGCs); the specification of pole cells toward the PGC fate; and finally, the migration of PGCs to the somatic gonadal precursors, where they, together with somatic gonadal precursors, form the embryonic testis and ovary.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781460","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}

{"title":"Replacement of Arabidopsis H2A.Z with human H2A.Z orthologs reveals extensive functional conservation and limited importance of the N-terminal tail sequence for Arabidopsis development.","authors":"Paja Sijacic, Dylan H Holder, Brianna D Silver, Ellen G Krall, Courtney G Willett, Maryam Foroozani, Roger B Deal","doi":"10.1093/genetics/iyaf065","DOIUrl":"https://doi.org/10.1093/genetics/iyaf065","url":null,"abstract":"<p><p>The incorporation of histone variants, distinct paralogs of core histones, into chromatin affects all DNA-templated processes in the cell, including the regulation of transcription. In recent years, much research has been focused on H2A.Z, an evolutionarily conserved H2A variant found in all eukaryotes. In order to investigate the functional conservation of H2A.Z histones during eukaryotic evolution we transformed h2a.z deficient Arabidopsis thaliana plants with each of the three human H2A.Z variants to assess their ability to rescue the mutant defects. We discovered that human H2A.Z.1 and H2A.Z.2.1 fully complement the phenotypic abnormalities of h2a.z plants despite significant divergence in the N-terminal tail sequences of Arabidopsis and human H2A.Zs. In contrast, the brain-specific splice variant H2A.Z.2.2 has a dominant-negative effect in wild-type plants, mimicking an H2A.Z deficiency phenotype. Furthermore, human H2A.Z.1 almost completely re-establishes normal H2A.Z chromatin occupancy in h2a.z plants and restores the expression of more than 84% of misexpressed genes. Finally, we used a series of N-terminal tail truncations of Arabidopsis HTA11 to reveal that the N-terminal tail of Arabidopsis H2A.Z is not necessary for normal plant development under optimal growth conditions but does play an important role in mounting proper abiotic stress responses.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781462","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}

{"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":"https://doi.org/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 (gene 1 ← eQTL → gene 2). 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 → gene 1 ← gene 2). 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":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new set of mutations in the second transmembrane helix of the Cox2p-W56R substantially improves its allotopic expression in Saccharomyces cerevisiae.","authors":"Kewin Gombeau, Stefan A Hoffmann, Yizhi Cai","doi":"10.1093/genetics/iyaf037","DOIUrl":"https://doi.org/10.1093/genetics/iyaf037","url":null,"abstract":"<p><p>The dual genetic control of mitochondrial respiratory function, combined with the high mutation rate of the mitochondrial genome (mtDNA), makes mitochondrial diseases among the most frequent genetic diseases in humans (1 in 5,000 in adults). With no effective treatments available, gene therapy approaches have been proposed. Notably, several studies have demonstrated the potential for nuclear expression of a healthy copy of a dysfunctional mitochondrial gene, referred to as allotopic expression, to help recover respiratory function. However, allotopic expression conditions require significant optimization. We harnessed engineering biology tools to improve the allotopic expression of the COX2-W56R gene in the budding yeast Saccharomyces cerevisiae. Through conducting random mutagenesis and screening of the impact of vector copy number, promoter, and mitochondrial targeting sequence, we substantially increased the mitochondrial incorporation of the allotopic protein and significantly increased recovery of mitochondrial respiration. Moreover, CN-PAGE analyses revealed that our optimized allotopic protein does not impact cytochrome c oxidase assembly, or the biogenesis of respiratory chain supercomplexes. Importantly, the most beneficial amino acid substitutions found in the second transmembrane helix (L93S and I102K) are conserved residues in the corresponding positions of human MT-CO2 (L73 and L75), and we propose that mirroring these changes could potentially help improve allotopic Cox2p expression in human cells. To conclude, this study demonstrates the effectiveness of using engineering biology approaches to optimise allotopic expression of mitochondrial genes in the baker's yeast.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781453","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}