IF 3.3 3区生物学

Genetics Pub Date : 2025-05-29 DOI: 10.1093/genetics/iyaf101

Alexander Stein, Benjamin Werner

{"title":"On the patterns of genetic intra-tumour heterogeneity before and after treatment.","authors":"Alexander Stein, Benjamin Werner","doi":"10.1093/genetics/iyaf101","DOIUrl":"https://doi.org/10.1093/genetics/iyaf101","url":null,"abstract":"Genetic intra-tumour heterogeneity (gITH) is a universal property of all cancers. It emerges from the interplay of cell division, mutation accumulation and selection with important implications for the evolution of treatment resistance. Theoretical and data-driven approaches extensively studied gITH in ageing somatic tissues or cancers at detection. Yet, the expected patterns of gITH during and after treatment are less well understood. Here, we use stochastic birth-death processes to investigate the expected patterns of gITH across different treatment scenarios. We consider homogeneous treatment response with shrinking, growing and stable disease, and follow up investigating heterogeneous treatment response with sensitive and resistant cell types. We derive analytic expressions for the site frequency spectrum, the total mutational burden and the single-cell mutational burden distribution that we validate with computer simulations. We find that the site frequency spectrum after homogeneous treatment response retains its characteristic power-law tail, while emergent resistant clones cause peaks corresponding to their sizes. The frequency of the largest resistant clone is subdominant and independent of the population size at detection, whereas the relative total number of resistant cells increases with detection size. Furthermore, the growth dynamics under treatment determine whether the total mutational burden is dominated by preexisting or newly acquired mutations, suggesting different possible treatment strategies.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173698","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}

引用次数: 0

Likelihoods for a general class of ARGs under the SMC. 在SMC下一般类型ARGs的可能性。

IF 3.3 3区生物学

Genetics Pub Date : 2025-05-29 DOI: 10.1093/genetics/iyaf103

Gertjan Bisschop, Jerome Kelleher, Peter Ralph

{"title":"Likelihoods for a general class of ARGs under the SMC.","authors":"Gertjan Bisschop, Jerome Kelleher, Peter Ralph","doi":"10.1093/genetics/iyaf103","DOIUrl":"https://doi.org/10.1093/genetics/iyaf103","url":null,"abstract":"Ancestral recombination graphs (ARGs) are the focus of much ongoing research interest. Recent progress in inference has made ARG-based approaches feasible across of range of applications, and many new methods using inferred ARGs as input have appeared. This progress on the long-standing problem of ARG inference has proceeded in two distinct directions. First, the Bayesian inference of ARGs under the Sequentially Markov Coalescent (SMC), is now practical for tens-to-hundreds of samples. Second, approximate models and heuristics can now scale to sample sizes two to three orders of magnitude larger. Although these heuristic methods are reasonably accurate under many metrics, one significant drawback is that the ARGs they estimate do not have the topological properties required to compute a likelihood under models such as the SMC under present-day formulations. In particular, heuristic inference methods typically do not estimate precise details about recombination events, which are currently required to compute a likelihood. In this paper we present a backwards-time formulation of the SMC (conventionally regarded as an along-the-genome process) and derive a straightforward definition of the likelihood of a general class of ARG under this model. We show that this formulation does not require precise details of recombination events to be estimated, and is robust to the presence of polytomies. We discuss the possibilities for ARG inference that this new formulation opens.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173695","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}

引用次数: 0

The structural role of Skp1 in the synaptonemal complex is conserved in nematodes. Skp1在突触神经复合体中的结构作用在线虫中是保守的。

IF 3.3 3区生物学

Genetics Pub Date : 2024-09-18 DOI: 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":"6 1","pages":""},"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}

引用次数: 0

Interaction between ESCRT-III proteins and the yeast SERINC homolog Tms1. ESCRT-III 蛋白与酵母 SERINC 同源物 Tms1 之间的相互作用。

IF 3.3 3区生物学

Genetics Pub Date : 2024-09-13 DOI: 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":"152 1","pages":""},"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}

引用次数: 0

Role of male gonad-enriched microRNAs in sperm production in C. elegans. 雄性性腺富集的 microRNA 在秀丽隐杆线虫精子生成中的作用

IF 3.3 3区生物学

Genetics Pub Date : 2024-09-11 DOI: 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":"16 1","pages":""},"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}

引用次数: 0

Trait Imputation Enhances Nonlinear Genetic Prediction for Some Traits. 性状置换增强了某些性状的非线性遗传预测能力

IF 3.3 3区生物学

Genetics Pub Date : 2024-09-10 DOI: 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":"11 1","pages":""},"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}

引用次数: 0

Robust and heritable knockdown of gene expression using a self-cleaving ribozyme in Drosophila. 在果蝇中使用自裂解核糖酶稳健并可遗传地敲除基因表达。

IF 3.3 3区生物学

Genetics Pub Date : 2024-05-03 DOI: 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":"8 1","pages":""},"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}

引用次数: 0

The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease. Dmc1 重组酶与 Mlh1-Mlh3 内切酶发生物理作用，并促进减数分裂交叉功能。

IF 3.3 3区生物学

Genetics Pub Date : 2024-04-24 DOI: 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":"11 12","pages":""},"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}

引用次数: 0

Osiris gene family defines the cuticle nanopatterns of Drosophila. Osiris 基因家族确定了果蝇角质层的纳米形态。

IF 3.3 3区生物学

Genetics Pub Date : 2024-04-23 DOI: 10.1093/genetics/iyae065

Zhengkuan Sun, Sachi Inagaki, Keita Miyoshi, Kuniaki Saito, Shigeo Hayashi

引用次数: 0

Ploidy inference from single-cell data: application to human and mouse cell atlases. 从单细胞数据推断倍性：应用于人类和小鼠细胞图谱。

IF 3.3 3区生物学

Genetics Pub Date : 2024-04-23 DOI: 10.1093/genetics/iyae061

Fumihiko Takeuchi, Norihiro Kato

引用次数: 0

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