GeneticsPub Date : 2024-09-18DOI: 10.1093/genetics/iyae153
Lisa E Kursel,Kaan Goktepe,Ofer Rog
{"title":"The structural role of Skp1 in the synaptonemal complex is conserved in nematodes.","authors":"Lisa E Kursel,Kaan Goktepe,Ofer Rog","doi":"10.1093/genetics/iyae153","DOIUrl":"https://doi.org/10.1093/genetics/iyae153","url":null,"abstract":"The synaptonemal complex (SC) is a meiotic interface that assembles between parental chromosomes and is essential for gamete formation. While the dimensions and ultrastructure of the SC are conserved across eukaryotes, its protein components are highly divergent. Recently, an unexpected component of the SC has been described in the nematode C. elegans: the Skp1-related proteins SKR-1/2, which are components of the Skp1, Cullin, F-box (SCF) ubiquitin ligase. Here, we find that the role of SKR-1 in the SC is conserved in P. pacificus. The P. pacificus Skp1 ortholog, Ppa-SKR-1, colocalizes with other SC proteins throughout meiotic prophase, where it occupies the middle of the SC. Like in C. elegans, the dimerization interface of Ppa-SKR-1 is required for its SC function. A dimerization mutant, ppa-skr-1F105E, fails to assemble SC and produces almost no progeny. Interestingly, the evolutionary trajectory of SKR-1 contrasts with other SC proteins. Unlike most SC proteins, SKR-1 is highly conserved in nematodes. Our results suggest that the structural role of SKR-1 in the SC has been conserved since the common ancestor of C. elegans and P. pacificus, and that rapidly evolving SC proteins have maintained the ability to interact with SKR-1 for at least 100 million years.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253656","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}
GeneticsPub Date : 2024-09-13DOI: 10.1093/genetics/iyae132
Ralf Kölling
{"title":"Interaction between ESCRT-III proteins and the yeast SERINC homolog Tms1.","authors":"Ralf Kölling","doi":"10.1093/genetics/iyae132","DOIUrl":"https://doi.org/10.1093/genetics/iyae132","url":null,"abstract":"The endosomal sorting complex required for transport (ESCRT)-III is involved in membrane remodeling and abscission during intraluminal vesicle (ILV) formation at endosomes. Our data now suggest that ESCRT-III function could be connected to lipid remodeling of the endosomal membrane. This notion is based on our finding that ESCRT-III proteins bind to the yeast serine incorporator (SERINC) homolog Tms1. Human SERINC3 and SERINC5 are HIV-1 restriction factors and have been shown to act as scramblases, flipping phospholipids between membrane leaflets. Due to the extraordinarily high sequence conservation between Tms1 and human SERINCs, it is likely that Tms1 is also a scramblase. While deletion of TMS1 had only a moderate effect on the sorting of multivesicular body (MVB) cargo proteins, the simultaneous deletion of a component of the Vps55/Vps68 complex led to a strong synergistic phenotype. This pronounced synergism suggests that Tms1 and Vps55/Vps68 perform a parallel function at endosomes. Vps55/Vps68 loosely resembles Tms1 in its overall structure. Thus, it is possible that Vps55/Vps68 is also a scramblase. Since both Vps55 and Tms1 physically interact with ESCRT-III proteins, we propose that the recruitment of a scramblase plays a crucial role in ESCRT-III-dependent membrane remodeling at endosomes.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253347","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}
GeneticsPub Date : 2024-09-11DOI: 10.1093/genetics/iyae147
Lu Lu,Allison L Abbott
{"title":"Role of male gonad-enriched microRNAs in sperm production in C. elegans.","authors":"Lu Lu,Allison L Abbott","doi":"10.1093/genetics/iyae147","DOIUrl":"https://doi.org/10.1093/genetics/iyae147","url":null,"abstract":"Germ cell development and gamete production in animals require small RNA pathways. While studies indicate that microRNAs (miRNAs) are necessary for normal sperm production and function, the specific roles for individual miRNAs are largely unknown. Here, we use small RNA sequencing of dissected gonads and functional analysis of new loss of function alleles to identify functions for miRNAs in the control of fecundity and sperm production in Caenorhabditis elegans (C. elegans) males and hermaphrodites. We describe a set of 29 male gonad-enriched miRNAs and identify a set of individual miRNAs (mir-58.1 and mir-235) and a miRNA cluster (mir-4807-4810.1) that are required for optimal sperm production at 20°C and a set of miRNAs (mir-49, mir-57, mir-83, mir-261, and mir-357/358) that are required for sperm production at 25°C. We observed defects in meiotic progression in mutants missing mir-58.1, mir-83, mir-235, and mir-4807-4810.1, which may contribute to the observed defects in sperm production. Further, analysis of multiple mutants of these miRNAs suggested genetic interactions between these miRNAs. This study provides insights on the regulatory roles of miRNAs that promote optimal sperm production and fecundity in males and hermaphrodites.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142200844","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}
GeneticsPub Date : 2024-09-10DOI: 10.1093/genetics/iyae148
Ruoyu He,Jinwen Fu,Jingchen Ren,Wei Pan
{"title":"Trait Imputation Enhances Nonlinear Genetic Prediction for Some Traits.","authors":"Ruoyu He,Jinwen Fu,Jingchen Ren,Wei Pan","doi":"10.1093/genetics/iyae148","DOIUrl":"https://doi.org/10.1093/genetics/iyae148","url":null,"abstract":"The expansive collection of genetic and phenotypic data within biobanks offers an unprecedented opportunity for biomedical research. However, the frequent occurrence of missing phenotypes presents a significant barrier to fully leveraging this potential. In our target application, on one hand, we have only a small and complete dataset with both genotypes and phenotypes to build a genetic prediction model, commonly called a polygenic (risk) score (PGS or PRS); on the other hand, we have a large dataset of genotypes (e.g. from a biobank) without the phenotype of interest. Our goal is to leverage the large dataset of genotypes (but without the phenotype) and a separate GWAS summary dataset of the phenotype to impute the phenotypes, which are then used as an individual-level dataset, along with the small complete dataset, to build a nonlinear model as PGS. More specifically, we trained some nonlinear models to 7 imputed and observed phenotypes from the UK Biobank data. We then trained an ensemble model to integrate these models for each trait, resulting in higher R2 values in prediction than using only the small complete (observed) dataset. Additionally, for 2 of the 7 traits, we observed that the nonlinear model trained with the imputed traits had higher R2 than using the imputed traits directly as the PGS, while for the remaining 5 traits, no improvement was found. These findings demonstrates the potential of leveraging existing genetic data and accounting for nonlinear genetic relationships to improve prediction accuracy for some traits.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142200846","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}
GeneticsPub Date : 2024-05-03DOI: 10.1093/genetics/iyae067
Kevin G Nyberg, Fritz Gerald Navales, Eren Keles, Joseph Q Nguyen, Laura M Hertz, Richard W Carthew
{"title":"Robust and heritable knockdown of gene expression using a self-cleaving ribozyme in Drosophila.","authors":"Kevin G Nyberg, Fritz Gerald Navales, Eren Keles, Joseph Q Nguyen, Laura M Hertz, Richard W Carthew","doi":"10.1093/genetics/iyae067","DOIUrl":"https://doi.org/10.1093/genetics/iyae067","url":null,"abstract":"The current toolkit for genetic manipulation in the model animal Drosophila melanogaster is extensive and versatile but not without its limitations. Here, we report a powerful and heritable method to knockdown gene expression in D. melanogaster using the self-cleaving N79 hammerhead ribozyme, a modification of a naturally occurring ribozyme found in the parasite Schistosoma mansoni. A 111 bp ribozyme cassette, consisting of the N79 ribozyme surrounded by insulating spacer sequences, was inserted into four independent long noncoding RNA genes as well as the male-specific splice variant of doublesex using scarless CRISPR/Cas9-mediated genome editing. Ribozyme-induced RNA cleavage resulted in robust destruction of 3' fragments typically exceeding 90%. Single molecule RNA fluorescence in situ hybridization results suggest that cleavage and destruction can even occur for nascent transcribing RNAs. Knockdown was highly specific to the targeted RNA, with no adverse effects observed in neighboring genes or the other splice variants. To control for potential effects produced by the simple insertion of 111 nucleotides into genes, we tested multiple catalytically inactive ribozyme variants and found that a variant with scrambled N79 sequence best recapitulated natural RNA levels. Thus, self-cleaving ribozymes offer a novel approach for powerful gene knockdown in Drosophila, with potential applications for the study of noncoding RNAs, nuclear-localized RNAs, and specific splice variants of protein-coding genes.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140826961","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}
GeneticsPub Date : 2024-04-24DOI: 10.1093/genetics/iyae066
Gianno Pannafino, Jun Jie Chen, Viraj Mithani, Lisette Payero, Michael Gioia, J. B. Crickard, Eric Alani
{"title":"The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease.","authors":"Gianno Pannafino, Jun Jie Chen, Viraj Mithani, Lisette Payero, Michael Gioia, J. B. Crickard, Eric Alani","doi":"10.1093/genetics/iyae066","DOIUrl":"https://doi.org/10.1093/genetics/iyae066","url":null,"abstract":"The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80 percent of meiotic crossovers result from Mlh1-Mlh3 and Exo1 acting to resolve double-Holliday junction (dHJ) intermediates in a biased manner. Little is known about how Mlh1-Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1-Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1-Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1, the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1-Mlh3's role in crossover resolution is presented.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140659003","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":"Osiris gene family defines the cuticle nanopatterns of Drosophila.","authors":"Zhengkuan Sun, Sachi Inagaki, Keita Miyoshi, Kuniaki Saito, Shigeo Hayashi","doi":"10.1093/genetics/iyae065","DOIUrl":"https://doi.org/10.1093/genetics/iyae065","url":null,"abstract":"Nanostructures of pores and protrusions in the insect cuticle modify molecular permeability and surface wetting, and help insects sense various environmental cues. However, the cellular mechanisms that modify cuticle nanostructures are poorly understood. Here, we elucidate how insect-specific Osiris family genes are expressed in various cuticle-secreting cells in the Drosophila head during the early stages of cuticle secretion and cover nearly the entire surface of the head epidermis. Furthermore, we demonstrate how each sense organ cell with various cuticular nanostructures expressed a unique combination of Osiris genes. Osiris gene mutations cause various cuticle defects in the corneal nipples and pores of the chemosensory sensilla. Thus, our study emphasizes on the importance of Osiris genes for elucidating cuticle nanopatterning in insects.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140802065","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}
GeneticsPub Date : 2024-04-23DOI: 10.1093/genetics/iyae061
Fumihiko Takeuchi, Norihiro Kato
{"title":"Ploidy inference from single-cell data: application to human and mouse cell atlases.","authors":"Fumihiko Takeuchi, Norihiro Kato","doi":"10.1093/genetics/iyae061","DOIUrl":"https://doi.org/10.1093/genetics/iyae061","url":null,"abstract":"Ploidy is relevant to numerous biological phenomena, including development, metabolism, and tissue regeneration. Single-cell RNA-seq and other omics studies are revolutionizing our understanding of biology, yet they have largely overlooked ploidy. This is likely due to the additional assay step required for ploidy measurement. Here, we developed a statistical method to infer ploidy from single-cell ATAC-seq data, addressing this gap. When applied to data from human and mouse cell atlases, our method enabled systematic detection of polyploidy across diverse cell types. This method allows for the integration of ploidy analysis into single-cell studies. Additionally, this method can be adapted to detect the proliferating stage in the cell cycle and copy number variations in cancer cells. The software is implemented as the scPloidy package of the R software and is freely available from CRAN.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140802128","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}
GeneticsPub Date : 2024-04-23DOI: 10.1093/genetics/iyae045
Vitoria K. Paolillo, Matthew E. Ochs, E. Lundquist
{"title":"MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans.","authors":"Vitoria K. Paolillo, Matthew E. Ochs, E. Lundquist","doi":"10.1093/genetics/iyae045","DOIUrl":"https://doi.org/10.1093/genetics/iyae045","url":null,"abstract":"Neurogenesis involves the precisely coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts in Caenorhabditis elegans, QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5/Hox transcription factor is necessary and sufficient for posterior Q lineage migration and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells from wild-type, mab-5 loss-of-function (lof), and mab-5 gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected by mab-5 included those involved in neurogenesis, neural development, and interaction with the extracellular matrix. cwn-1, which encodes a Wnt signaling molecule, showed a paired response to mab-5 in the Q cells: cwn-1 expression was reduced in mab-5(lof) and increased in mab-5(gof), suggesting that MAB-5 is required for cwn-1 expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20/Wnt in a noncanonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes, cwn-1, acts downstream of mab-5 in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669243","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}
GeneticsPub Date : 2024-04-18DOI: 10.1093/genetics/iyae055
Yang Ping Kuo, Oana Carja
{"title":"Evolutionary graph theory beyond single mutation dynamics: on how network structured populations cross fitness landscapes.","authors":"Yang Ping Kuo, Oana Carja","doi":"10.1093/genetics/iyae055","DOIUrl":"https://doi.org/10.1093/genetics/iyae055","url":null,"abstract":"Spatially-resolved datasets are revolutionizing knowledge in molecular biology, yet are under-utilized for questions in evolutionary biology. To gain insight from these large-scale datasets of spatial organization, we need mathematical representations and modeling techniques that can both capture their complexity, but also allow for mathematical tractability. Evolutionary graph theory utilizes the mathematical representation of networks as a proxy for heterogeneous population structure and has started to reshape our understanding of how spatial structure can direct evolutionary dynamics. However, previous results are derived for the case of a single new mutation appearing in the population and the role of network structure in shaping fitness landscape crossing is still poorly understood. Here we study how network structured populations cross fitness landscapes and show that even a simple extension to a two-mutational landscape can exhibit complex evolutionary dynamics that cannot be predicted using previous single-mutation results. We show how our results can be intuitively understood through the lens of how the two main evolutionary properties of a network, the amplification and acceleration factors, change the expected fate of the intermediate mutant in the population and further discuss how to link these models to spatially-resolved datasets of cellular organization.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623548","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}