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The transcription factor RUNT-like regulates pupal cuticle development via promoting a pupal cuticle protein transcription 转录因子RUNT-like通过促进蛹的角质层蛋白转录调控蛹的角质层发育
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-12 DOI: 10.1371/journal.pgen.1011393
Ke-Yan Jin, Xiao-Pei Wang, Yu-Qin Di, Yu-Meng Zhao, Jin-Xing Wang, Xiao-Fan Zhao
Holometabolous insects undergo morphological remodeling from larvae to pupae and to adults with typical changes in the cuticle; however, the mechanism is unclear. Using the lepidopteran agricultural insect Helicoverpa armigera, cotton bollworm, as a model, we revealed that the transcription factor RUNT-like (encoded by Runt-like) regulates the development of the pupal cuticle via promoting a pupal cuticle protein gene (HaPcp) expression. The HaPcp was highly expressed in the epidermis and wing during metamorphosis and was found being involved in pupal cuticle development by RNA interference (RNAi) analysis in larvae. Runt-like was also strongly upregulated in the epidermis and wing during metamorphosis. Knockdown of Runt-like produced similar phenomena, a failure of abdomen yellow envelope and wing formation, to those following HaPcp knockdown. The insect molting hormone 20-hydroxyecdysonen (20E) upregulated HaPcp transcription via RUNT-like. 20E upregulated Runt-like transcription via nuclear receptor EcR and the transcription factor FOXO. Together, RUNT-like and HaPCP are involved in pupal cuticle development during metamorphosis under 20E regulation.
全代谢昆虫从幼虫到蛹再到成虫都会经历形态重塑,其角质层会发生典型的变化,但其机制尚不清楚。我们以鳞翅目农业昆虫棉铃虫(Helicoverpa armigera)为模型,揭示了转录因子 RUNT-like(由 Runt-like 编码)通过促进蛹角质层蛋白基因(HaPcp)的表达来调控蛹角质层的发育。在幼虫的变态过程中,HaPcp在表皮和翅膀中高度表达,通过RNA干扰(RNAi)分析发现,HaPcp参与了蛹角质层的发育。Runt-like 在变态过程中也在表皮和翅膀中强烈上调。敲除 Runt-like 会产生与敲除 HaPcp 类似的现象,即腹部黄色包膜和翅膀无法形成。昆虫蜕皮激素 20-羟基蜕皮素(20E)通过 RUNT-like 上调 HaPcp 的转录。20E 通过核受体 EcR 和转录因子 FOXO 上调 Runt-like 的转录。在 20E 的调控下,RUNT-like 和 HaPCP 共同参与了蛹变态过程中的角质层发育。
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引用次数: 0
Subfunctionalization of NRC3 altered the genetic structure of the Nicotiana NRC network NRC3 的次功能化改变了烟草 NRC 网络的遗传结构
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-12 DOI: 10.1371/journal.pgen.1011402
Ching-Yi Huang, Yu-Seng Huang, Yu Sugihara, Hung-Yu Wang, Lo-Ting Huang, Juan Carlos Lopez-Agudelo, Yi-Feng Chen, Kuan-Yu Lin, Bing-Jen Chiang, AmirAli Toghani, Jiorgos Kourelis, Chun-Hsiung Wang, Lida Derevnina, Chih-Hang Wu
Nucleotide-binding domain and leucine-rich repeat (NLR) proteins play crucial roles in immunity against pathogens in both animals and plants. In solanaceous plants, activation of several sensor NLRs triggers their helper NLRs, known as NLR-required for cell death (NRC), to form resistosome complexes to initiate immune responses. While the sensor NLRs and downstream NRC helpers display diverse genetic compatibility, molecular evolutionary events leading to the complex network architecture remained elusive. Here, we showed that solanaceous NRC3 variants underwent subfunctionalization after the divergence of Solanum and Nicotiana, altering the genetic architecture of the NRC network in Nicotiana. Natural solanaceous NRC3 variants form three allelic groups displaying distinct compatibilities with the sensor NLR Rpi-blb2. Ancestral sequence reconstruction and analyses of natural and chimeric variants identified six key amino acids involved in sensor-helper compatibility. These residues are positioned on multiple surfaces of the resting NRC3 homodimer, collectively contributing to their compatibility with Rpi-blb2. Upon activation, Rpi-blb2-compatible NRC3 variants form membrane-associated punctate and high molecular weight complexes, and confer resistance to the late blight pathogen Phytophthora infestans. Our findings revealed how mutations in NRC alleles lead to subfunctionalization, altering sensor-helper compatibility and contributing to the increased complexity of the NRC network.
核苷酸结合域和富亮氨酸重复(NLR)蛋白在动物和植物对抗病原体的免疫中发挥着至关重要的作用。在茄科植物中,几种传感器 NLR 的激活会触发它们的辅助 NLR(即细胞死亡所需的 NLR(NRC)),形成抗原体复合物,启动免疫反应。虽然传感器 NLRs 和下游 NRC 辅助器显示出不同的遗传兼容性,但导致复杂网络结构的分子进化事件仍然难以捉摸。在这里,我们发现茄科植物的 NRC3 变体在茄科植物和烟草植物分化后经历了亚功能化,改变了烟草植物 NRC 网络的遗传结构。天然茄科植物 NRC3 变体形成了三个等位基因群,与传感器 NLR Rpi-blb2 具有不同的兼容性。通过对天然变体和嵌合变体的祖先序列重建和分析,确定了涉及传感器-助手兼容性的六个关键氨基酸。这些残基位于静止的 NRC3 同源二聚体的多个表面,共同促成了它们与 Rpi-blb2 的兼容性。激活后,与 Rpi-blb2 兼容的 NRC3 变体会形成与膜相关的点状高分子量复合物,并对晚疫病病原体 Phytophthora infestans 产生抗性。我们的研究结果揭示了 NRC 等位基因的突变是如何导致亚功能化、改变传感器-助手的兼容性并增加 NRC 网络的复杂性的。
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引用次数: 0
Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function MEF2C 的直接靶标富含与精神分裂症和认知功能相关的基因,并参与神经元发育和线粒体功能
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-11 DOI: 10.1371/journal.pgen.1011093
Deema Ali, Aodán Laighneach, Emma Corley, Saahithh Redddi Patlola, Rebecca Mahoney, Laurena Holleran, Declan P. McKernan, John P. Kelly, Aiden P. Corvin, Brian Hallahan, Colm McDonald, Gary Donohoe, Derek W. Morris
Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.
肌细胞增强因子 2C (MEF2C) 是一种转录因子,在神经发生和突触发育过程中起着至关重要的作用。遗传研究发现,MEF2C 是一个影响认知和神经精神疾病风险的基因,包括自闭症谱系障碍(ASD)和精神分裂症(SCZ)。在此,我们利用代表早期和晚期神经发育阶段的人源神经干细胞(NSCs)和谷氨酸能诱导神经元(iNs)研究了MEF2C参与这些表型的情况。在这些细胞模型中,MEF2C的功能先前已被直接或间接突变破坏,并使用RNA-seq对基因表达进行了检测。我们将这些RNA-seq数据与MEF2C ChIP-seq数据整合在一起,以确定NSCs和iNs模型中MEF2C直接靶基因的失调情况。几个MEF2C直接靶基因组富集于基于SNP的智力、教育程度和SCZ遗传性,并富集于在ASD和/或发育障碍中报告的含有罕见从头突变的基因。这些基因组富集在产前和成年大脑的兴奋性和抑制性神经元中,并参与了广泛的生物过程,包括神经元的生成、分化和发育,以及线粒体功能和能量产生。我们观察到 MEF2C 的一个 SNP(rs6893807,与智商有关)对目标基因 BNIP3L 的表达产生了反式表达量性状位点(eQTL)效应。BNIP3L 是 SCZ 最大的全基因组关联研究中的优先风险基因,在线粒体中具有有丝分裂吞噬功能。总之,我们的分析表明,MEF2C的直接或间接破坏会使包含与SCZ风险和认知功能相关的多个等位基因的基因集失调,并将神经元发育和线粒体功能与这些表型的病因学联系起来。
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引用次数: 0
Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers 糖基化通路之间普遍存在进化率协变,并指向潜在的疾病调节因子
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-11 DOI: 10.1371/journal.pgen.1011406
Holly J. Thorpe, Raghavendran Partha, Jordan Little, Nathan L. Clark, Clement Y. Chow
Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets.
糖基化途径(如N-连接糖基化、O-连接糖基化和GPI锚合成)中的突变会导致先天性糖基化紊乱(CDG)。先天性糖基化障碍通常表现为癫痫发作、肌张力低下和发育迟缓,但临床表现差异很大,症状会影响身体的各个系统。这种变异性表明,修饰基因可能会影响表型。由于生理和临床症状相似,CDG 之间可能存在共同的遗传修饰基因。在这里,我们以进化为工具,找出 CDG 和糖基化基因之间的共同修饰基因。从酵母到哺乳动物,蛋白质糖基化在进化上是保守的。进化速率共变(ERC)可以识别具有相似进化速率的蛋白质,这表明它们具有共同的生物功能和途径。利用ERC,我们在相同和不同糖基化途径的蛋白质之间发现了强烈的进化速率特征。对与GPI锚合成蛋白显示出显著ERC的蛋白质进行全基因组分析,发现了与ncRNA修饰蛋白和DNA修复蛋白之间的强烈特征。我们还根据 GPI 锚合成酶在细胞中的亚定位确定了强烈的 ERC 模式。对得分最高的候选基因进行的功能测试验证了基因之间的相互作用,并确定了 CDG 基因的新型基因修饰因子。通过对疾病基因和生物通路进行ERC分析,可以快速确定潜在遗传修饰因子的优先次序,从而更好地了解疾病的病理生理学和新型治疗靶点。
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引用次数: 0
Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells 紫外线挑战下的酵母细胞需要组蛋白变体 H2A.Z 来实现高效的转录耦合 NER 和基因组完整性
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-10 DOI: 10.1371/journal.pgen.1011300
Hélène Gaillard, Toni Ciudad, Andrés Aguilera, Ralf E. Wellinger
The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblocks and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeast Saccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z is needed for proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.
活细胞的基因组不断受到 DNA 损伤的挑战,这些损伤干扰了转录和复制等细胞过程。多种机制协同作用,确保了 DNA 的充分修复、基因表达和基因组稳定性。大块 DNA 病变,如紫外线或 DNA 破坏剂 4-硝基氧化喹啉诱导的病变,是转录和复制的路障,因此对细胞新陈代谢构成重大威胁。当这些损伤位于活性基因的转录链上时,转录偶联核苷酸切除修复(TC-NER)会对其进行处理,这是一种尚未完全被理解的 NER 子途径。在这里,我们通过对酵母进行基因筛选,发现组蛋白变体H2A.Z是紫外线照射后保护转录和DNA完整性的重要成分。在缺乏 H2A.Z 的情况下,TC-NER 的修复功能严重受损,RNA 聚合酶 II 的清除率降低,导致双链断裂增加。因此,H2A.Z 是高效 TC-NER 的必要条件,在紫外线辐照后维持基因组稳定性方面发挥着重要作用。
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引用次数: 0
The NF-κB Factor Relish maintains blood progenitor homeostasis in the developing Drosophila lymph gland NF-κB因子Relish维持发育中果蝇淋巴腺中血液祖细胞的平衡
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-09 DOI: 10.1371/journal.pgen.1011403
Parvathy Ramesh, Satish Kumar Tiwari, Md Kaizer, Deepak Jangra, Kaustuv Ghosh, Sudip Mandal, Lolitika Mandal
Post-larval hematopoiesis in Drosophila largely depends upon the stockpile of progenitors present in the blood-forming organ/lymph gland of the larvae. During larval stages, the lymph gland progenitors gradually accumulate reactive oxygen species (ROS), which is essential to prime them for differentiation. Studies have shown that ROS triggers the activation of JNK (c-Jun Kinase), which upregulates fatty acid oxidation (FAO) to facilitate progenitor differentiation. Intriguingly, despite having ROS, the entire progenitor pool does not differentiate simultaneously in the late larval stages. Using expression analyses, genetic manipulation and pharmacological approaches, we found that the Drosophila NF-κB transcription factor Relish (Rel) shields the progenitor pool from the metabolic pathway that inducts them into the differentiation program by curtailing the activation of JNK. Although ROS serves as the metabolic signal for progenitor differentiation, the input from ROS is monitored by the developmental signal TAK1, which is regulated by Relish. This developmental circuit ensures that the stockpile of ROS-primed progenitors is not exhausted entirely. Our study sheds light on how, during development, integrating NF-κB-like factors with metabolic pathways seem crucial to regulating cell fate transition during development.
果蝇的产后造血在很大程度上取决于幼虫造血器官/淋巴腺中的祖细胞储备。在幼虫阶段,淋巴腺祖细胞会逐渐积累活性氧(ROS),这对祖细胞的分化至关重要。研究表明,ROS 会引发 JNK(c-Jun 激酶)活化,从而上调脂肪酸氧化(FAO),促进祖细胞分化。耐人寻味的是,尽管存在 ROS,但整个祖细胞池在幼虫晚期并不会同时分化。通过表达分析、遗传操作和药理学方法,我们发现果蝇的 NF-κB 转录因子 Relish(Rel)通过抑制 JNK 的活化,使祖细胞池免受新陈代谢途径的影响,从而使它们进入分化程序。尽管 ROS 是祖细胞分化的代谢信号,但 ROS 的输入受到发育信号 TAK1 的监控,而 TAK1 则受 Relish 的调控。这一发育回路确保了ROS刺激的祖细胞储备不会完全耗尽。我们的研究揭示了在发育过程中,NF-κB 类因子与代谢途径的整合似乎对调节细胞命运的转变至关重要。
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引用次数: 0
Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction CCDC93 基因变异与中枢收缩压升高、动脉松弛功能受损和线粒体功能障碍有关
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2024-09-09 DOI: 10.1371/journal.pgen.1011151
Nitin Kumar, Min-Lee Yang, Pengfei Sun, Kristina L. Hunker, Jianping Li, Jia Jia, Fangfang Fan, Jinghua Wang, Xianjia Ning, Wei Gao, Ming Xu, Jifeng Zhang, Lin Chang, Yuqing E. Chen, Yong Huo, Yan Zhang, Santhi K. Ganesh
Genetic studies of blood pressure (BP) traits to date have been performed on conventional measures by brachial cuff sphygmomanometer for systolic BP (SBP) and diastolic BP, integrating several physiologic occurrences. Genetic associations with central SBP (cSBP) have not been well-studied. Genetic discovery studies of BP have been most often performed in European-ancestry samples. Here, we investigated genetic associations with cSBP in a Chinese population and functionally validated the impact of a novel associated coiled-coil domain containing 93 (CCDC93) gene on BP regulation. An exome-wide association study (EWAS) was performed using a mixed linear model of non-invasive cSBP and peripheral BP traits in a Han Chinese population (N = 5,954) from Beijing, China genotyped with a customized Illumina ExomeChip array. We identified four SNP-trait associations with three SNPs, including two novel associations (rs2165468-SBP and rs33975708-cSBP). rs33975708 is a coding variant in the CCDC93 gene, c.535C>T, p.Arg179Cys (MAF = 0.15%), and was associated with increased cSBP (β = 29.3 mmHg, P = 1.23x10-7). CRISPR/Cas9 genome editing was used to model the effect of Ccdc93 loss in mice. Homozygous Ccdc93 deletion was lethal prior to day 10.5 of embryonic development. Ccdc93+/- heterozygous mice were viable and morphologically normal, with 1.3-fold lower aortic Ccdc93 protein expression (P = 0.0041) and elevated SBP as compared to littermate Ccdc93+/+ controls (110±8 mmHg vs 125±10 mmHg, P = 0.016). Wire myography of Ccdc93+/- aortae showed impaired acetylcholine-induced relaxation and enhanced phenylephrine-induced contraction. RNA-Seq transcriptome analysis of Ccdc93+/- mouse thoracic aortae identified significantly enriched pathways altered in fatty acid metabolism and mitochondrial metabolism. Plasma free fatty acid levels were elevated in Ccdc93+/- mice (96±7mM vs 124±13mM, P = 0.0031) and aortic mitochondrial dysfunction was observed through aberrant Parkin and Nix protein expression. Together, our genetic and functional studies support a novel role of CCDC93 in the regulation of BP through its effects on vascular mitochondrial function and endothelial function.
迄今为止,对血压(BP)特征的遗传研究都是通过肱动脉袖带血压计对收缩压(SBP)和舒张压进行传统测量,并综合了几种生理现象。与中心收缩压(cSBP)相关的遗传学研究还不多。有关血压的遗传发现研究多在欧洲裔样本中进行。在此,我们在中国人群中调查了 cSBP 的遗传关联,并从功能上验证了一个新的相关盘卷结构域含 93(CCDC93)基因对血压调节的影响。在中国北京的一个汉族人群(N = 5954)中,使用定制的 Illumina ExomeChip 阵列对无创 cSBP 和外周血压性状进行了混合线性模型分析,并开展了一项外显子全关联研究(EWAS)。rs33975708是CCDC93基因的编码变异,c.535C>T,p.Arg179Cys(MAF = 0.15%),与cSBP升高有关(β = 29.3 mmHg,P = 1.23x10-7)。CRISPR/Cas9基因组编辑被用来模拟小鼠Ccdc93缺失的影响。同基因 Ccdc93 缺失在胚胎发育第 10.5 天之前是致死的。与同窝 Ccdc93+/+ 对照组相比,Ccdc93+/- 杂合子小鼠存活率高且形态正常,主动脉 Ccdc93 蛋白表达量降低 1.3 倍(P = 0.0041),SBP 升高(110±8 mmHg vs 125±10 mmHg,P = 0.016)。Ccdc93+/- 主动脉的线性肌电图显示,乙酰胆碱诱导的松弛功能受损,而苯肾上腺素诱导的收缩功能增强。对Ccdc93+/-小鼠胸主动脉进行的RNA-Seq转录组分析发现,脂肪酸代谢和线粒体代谢的通路发生了显著的富集。Ccdc93+/-小鼠血浆游离脂肪酸水平升高(96±7mM vs 124±13mM,P = 0.0031),并且通过Parkin和Nix蛋白的异常表达观察到主动脉线粒体功能障碍。总之,我们的遗传和功能研究支持 CCDC93 通过影响血管线粒体功能和内皮功能在血压调节中发挥新的作用。
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引用次数: 0
Review and further developments in statistical corrections for Winner's Curse in genetic association studies. 遗传关联研究中赢家诅咒统计校正的回顾和进一步发展。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-09-18 eCollection Date: 2023-09-01 DOI: 10.1371/journal.pgen.1010546
Amanda Forde, Gibran Hemani, John Ferguson

Genome-wide association studies (GWAS) are commonly used to identify genomic variants that are associated with complex traits, and estimate the magnitude of this association for each variant. However, it has been widely observed that the association estimates of variants tend to be lower in a replication study than in the study that discovered those associations. A phenomenon known as Winner's Curse is responsible for this upward bias present in association estimates of significant variants in the discovery study. We review existing Winner's Curse correction methods which require only GWAS summary statistics in order to make adjustments. In addition, we propose modifications to improve existing methods and propose a novel approach which uses the parametric bootstrap. We evaluate and compare methods, first using a wide variety of simulated data sets and then, using real data sets for three different traits. The metric, estimated mean squared error (MSE) over significant SNPs, was primarily used for method assessment. Our results indicate that widely used conditional likelihood based methods tend to perform poorly. The other considered methods behave much more similarly, with our proposed bootstrap method demonstrating very competitive performance. To complement this review, we have developed an R package, 'winnerscurse' which can be used to implement these various Winner's Curse adjustment methods to GWAS summary statistics.

全基因组关联研究(GWAS)通常用于识别与复杂性状相关的基因组变异,并估计每个变异的这种关联程度。然而,人们普遍观察到,在复制研究中,变异的关联估计往往低于发现这些关联的研究。一种被称为“赢家诅咒”的现象是发现研究中显著变异的关联估计中存在的这种向上偏差的原因。我们审查了现有的赢家诅咒修正方法,这些方法只需要GWAS摘要统计数据即可进行调整。此外,我们提出了改进现有方法的修改,并提出了一种使用参数自举的新方法。我们评估和比较了各种方法,首先使用各种模拟数据集,然后使用三种不同性状的真实数据集。该指标,即显著SNPs的估计均方误差(MSE),主要用于方法评估。我们的结果表明,广泛使用的基于条件似然的方法往往表现不佳。其他考虑的方法表现得更相似,我们提出的bootstrap方法表现出了非常有竞争力的性能。为了补充这篇综述,我们开发了一个R包“winnerssurce”,可用于实现GWAS汇总统计的各种Winners Curse调整方法。
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引用次数: 0
Genome-wide circadian gating of a cold temperature response in bread wheat. 面包小麦低温反应的全基因组昼夜节律门控。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-09-18 eCollection Date: 2023-09-01 DOI: 10.1371/journal.pgen.1010947
Calum A Graham, Pirita Paajanen, Keith J Edwards, Antony N Dodd

Circadian rhythms coordinate the responses of organisms with their daily fluctuating environments, by establishing a temporal program of gene expression. This schedules aspects of metabolism, physiology, development and behaviour according to the time of day. Circadian regulation in plants is extremely pervasive, and is important because it underpins both productivity and seasonal reproduction. Circadian regulation extends to the control of environmental responses through a regulatory process known as circadian gating. Circadian gating is the process whereby the circadian clock regulates the response to an environmental cue, such that the magnitude of response to an identical cue varies according to the time of day of the cue. Here, we show that there is genome-wide circadian gating of responses to cold temperatures in plants. By using bread wheat as an experimental model, we establish that circadian gating is crucial to the programs of gene expression that underlie the environmental responses of a crop of major socioeconomic importance. Furthermore, we identify that circadian gating of cold temperature responses are distributed unevenly across the three wheat subgenomes, which might reflect the geographical origins of the ancestors of modern wheat.

昼夜节律通过建立基因表达的时间程序,将生物体的反应与其日常波动的环境相协调。这会根据一天中的时间安排新陈代谢、生理、发育和行为。植物中的昼夜节律调节非常普遍,而且很重要,因为它支撑着生产力和季节性繁殖。昼夜节律调节通过一个称为昼夜节律门控的调节过程扩展到对环境反应的控制。昼夜节律门控是昼夜节律时钟调节对环境提示的反应的过程,因此对相同提示的反应幅度根据提示的时间而变化。在这里,我们展示了植物对低温反应的全基因组昼夜节律门控。通过使用面包小麦作为实验模型,我们确定昼夜节律门控对基因表达程序至关重要,而基因表达程序是具有重要社会经济意义的作物环境反应的基础。此外,我们发现,低温反应的昼夜节律门控在三个小麦亚基因组中分布不均,这可能反映了现代小麦祖先的地理起源。
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引用次数: 0
The proprotein convertase BLI-4 promotes collagen secretion prior to assembly of the Caenorhabditis elegans cuticle. 前蛋白转化酶BLI-4在秀丽隐杆线虫角质层组装之前促进胶原蛋白分泌。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-09-18 eCollection Date: 2023-09-01 DOI: 10.1371/journal.pgen.1010944
Susanna K Birnbaum, Jennifer D Cohen, Alexandra Belfi, John I Murray, Jennifer R G Adams, Andrew D Chisholm, Meera V Sundaram

Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.

一些类型的胶原蛋白,包括跨膜MACIT胶原蛋白和秀丽隐杆线虫角质层胶原蛋白,在一个类似于弗林蛋白酶或枯草杆菌蛋白酶/可辛(PCSK)家族的其他前蛋白转化酶的共有位点上被N-末端切割。这种切割可以从质膜释放跨膜胶原,并影响细胞外基质的组装或结构。然而,这种切割的功能后果尚不清楚,也缺乏特定PCSK作用的证据。在这里,我们使用内源性胶原融合荧光蛋白来观察秀丽隐杆线虫中第一个基于胶原的角质层的分泌和组装,然后测试PCSK BLI-4在这些过程中的作用。出乎意料的是,我们发现角质层胶原SQT-3和DPY-17在角质层基质组装前几个小时分泌到胚胎外空间。此外,这种早期分泌依赖于BLI-4/PCSK;在bli-4和切割位点突变体中,SQT-3和DPY-17不能有效分泌,而是形成大的细胞内点状。它们后来组装成角质层基质的过程减少了,但并没有完全阻断。这些数据揭示了胶原N末端处理在细胞内运输和体内基质组装控制中的作用。我们的观察结果还促使对秀丽隐杆线虫角质层基质组装和角质层前到角质层过渡的经典模型进行了修订,表明角质层组装是通过一系列调节步骤进行的,而不仅仅是通过顺序分泌和沉积。
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