Genetics最新文献_第7页

Noggin proteins are multifunctional extracellular regulators of cell signaling 诺金蛋白是细胞信号传导的多功能细胞外调节因子

IF 3.3 3区生物学

Genetics

Pub Date : 2022-03-31 DOI: 10.1093/genetics/iyac049

Prashath Karunaraj, O. Tidswell, E. Duncan, M. Lovegrove, Grace Jefferies, T. K. Johnson, C. Beck, P. Dearden

Abstract Noggin is an extracellular cysteine knot protein that plays a crucial role in vertebrate dorsoventral patterning. Noggin binds and inhibits the activity of bone morphogenetic proteins via a conserved N-terminal clip domain. Noncanonical orthologs of Noggin that lack a clip domain (“Noggin-like” proteins) are encoded in many arthropod genomes and are thought to have evolved into receptor tyrosine kinase ligands that promote Torso/receptor tyrosine kinase signaling rather than inhibiting bone morphogenic protein signaling. Here, we examined the molecular function of noggin/noggin-like genes (ApNL1 and ApNL2) from the arthropod pea aphid using the dorso-ventral patterning of Xenopus and the terminal patterning system of Drosophila to identify whether these proteins function as bone morphogenic protein or receptor tyrosine kinase signaling regulators. Our findings reveal that ApNL1 from the pea aphid can regulate both bone morphogenic protein and receptor tyrosine kinase signaling pathways, and unexpectedly, that the clip domain is not essential for its antagonism of bone morphogenic protein signaling. Our findings indicate that ancestral noggin/noggin-like genes were multifunctional regulators of signaling that have specialized to regulate multiple cell signaling pathways during the evolution of animals.

摘要Noggin是一种细胞外半胱氨酸结蛋白，在脊椎动物背腔模式中起着至关重要的作用。Noggin通过一个保守的N-末端片段结构域结合并抑制骨形态发生蛋白的活性。许多节肢动物基因组中编码了缺乏片段结构域的Noggin的非经典直向同源物（“Noggin-like”蛋白），并被认为已进化为受体酪氨酸激酶配体，促进Torso/受体酪氨酸激酶信号传导，而不是抑制骨形态发生蛋白信号传导。在这里，我们使用非洲爪蟾的背腹侧模式和果蝇的末端模式系统来检测节肢动物豌豆蚜的noggin/noggin样基因（ApNL1和ApNL2）的分子功能，以确定这些蛋白质是作为骨形态发生蛋白还是受体酪氨酸激酶信号调节因子。我们的研究结果表明，来自豌豆蚜的ApNL1可以调节骨形态发生蛋白和受体酪氨酸激酶信号通路，出乎意料的是，片段结构域对其拮抗骨形态发生蛋白质信号传导并不重要。我们的发现表明，祖先的noggin/noggin样基因是信号传导的多功能调节因子，在动物进化过程中专门调节多种细胞信号通路。

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引用次数: 0

Variation in cytonuclear expression accommodation among allopolyploid plants 异源多倍体植物细胞核表达调节的变异

IF 3.3 3区生物学

Genetics

Pub Date : 2022-03-12 DOI: 10.1101/2022.03.10.483839

C. Grover, Evan S. Forsythe, Joel Sharbrough, Emma R. Miller, Justin L. Conover, R. DeTar, Carolina Chavarro, Mark A. Arick, D. Peterson, S. Leal-Bertioli, Daniel B. Sloan, J. Wendel

Cytonuclear coevolution is a common feature among plants, which coordinates gene expression and protein products between the nucleus and organelles. Consequently, lineage-specific differences may result in incompatibilities between the nucleus and cytoplasm in hybrid taxa. Allopolyploidy is also a common phenomenon in plant evolution. The hybrid nature of allopolyploids may result in cytonuclear incompatibilities, but the massive nuclear redundancy created during polyploidy affords additional avenues for resolving cytonuclear conflict (i.e., cytonuclear accommodation). Here we evaluate expression changes in organelle-targeted nuclear genes for six allopolyploid lineages that represent four genera (i.e., Arabidopsis, Arachis, Chenopodium, and Gossypium) and encompass a range in polyploid ages. Because incompatibilities between the nucleus and cytoplasm could potentially result in biases toward the maternal homoeolog and/or maternal expression level, we evaluate patterns of homoeolog usage, expression bias, and expression level dominance in cytonuclear genes relative to the background of non-cytonuclear expression changes and to the diploid parents. Although we find subsets of cytonuclear genes in most lineages that match our expectations of maternal preference, these observations are not consistent among either allopolyploids or categories of organelle-targeted genes. Our results indicate that cytonuclear expression accommodation may be a subtle and/or variable phenomenon that does not capture the full range of mechanisms by which allopolyploid plants resolve nuclear-cytoplasmic incompatibilities.

细胞核协同进化是植物的共同特征，它协调细胞核和细胞器之间的基因表达和蛋白质产物。因此，谱系特异性差异可能导致杂交类群细胞核和细胞质之间的不相容性。异源多倍体也是植物进化中的一种常见现象。异源多倍体的杂交性质可能导致细胞核不相容，但多倍体过程中产生的大量细胞核冗余为解决细胞核冲突（即细胞核调节）提供了额外的途径。在这里，我们评估了六个异源多倍体谱系的细胞器靶向核基因的表达变化，这些谱系代表四个属（即拟南芥、Arachis、藜属和棉属），并涵盖了一系列多倍体年龄。由于细胞核和细胞质之间的不相容性可能导致对母体同源性和/或母体表达水平的偏见，我们评估了与非细胞核表达变化背景和二倍体亲本相比，细胞核基因中同源性使用、表达偏见和表达水平优势的模式。尽管我们在大多数谱系中发现了与我们对母体偏好的预期相匹配的细胞核基因亚群，但这些观察结果在异源多倍体或细胞器靶向基因类别中并不一致。我们的研究结果表明，细胞核表达调节可能是一种微妙和/或可变的现象，不能捕捉到异多倍体植物解决核质不相容性的全部机制。

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引用次数: 3

Taking flight: an educational primer for use with "A novel mechanism for activation of myosin regulatory light chain by protein kinase C-delta in Drosophila". 飞行：用于“果蝇蛋白激酶C-delta激活肌球蛋白调节轻链的新机制”的教育性引物

IF 3.3 3区生物学

Genetics

Pub Date : 2022-03-03 DOI: 10.1093/genetics/iyab187

Scott J Nowak, Krista C Dobi

Muscles are required for animal movement, feeding, heartbeat, and reproduction. Disruption of muscle function can lead to mobility impairments and diseases like muscular dystrophy and cardiac myopathy; therefore, research in this area has significant implications for public health. Recent work by Vaziri and colleagues has taken genetic, cell biological, and biochemical approaches to identify Protein kinase C-d (Pkcδ) as a novel regulator of the essential myosin light chain 2 (MLC2) by phosphorylation. The authors determine which residues of MLC2 are modified by Pkcδ and show that phosphorylation by Pkcδ is required for proper sarcomere assembly and function. This study underscores the importance of Drosophila melanogaster as a model system for muscle function and highlights how protein phosphorylation is a vital part of post-translational gene regulation.

肌肉是动物运动、进食、心跳和繁殖所必需的。肌肉功能的破坏会导致行动障碍和肌肉萎缩症和心肌病等疾病;因此，这一领域的研究对公共卫生具有重要意义。Vaziri及其同事最近的工作采用遗传学，细胞生物学和生化方法鉴定了蛋白激酶C-d (Pkcδ)通过磷酸化作为必需肌球蛋白轻链2 (MLC2)的新型调节剂。作者确定了MLC2的哪些残基被Pkcδ修饰，并表明Pkcδ的磷酸化是正常的肌节组装和功能所必需的。这项研究强调了黑腹果蝇作为肌肉功能模型系统的重要性，并强调了蛋白质磷酸化是翻译后基因调控的重要组成部分。

引用次数: 0

Fisher's historic 1922 paper On the dominance ratio. 费舍尔1922年的历史性论文《论优势比》

IF 3.3 3区生物学

Genetics

Pub Date : 2022-03-03 DOI: 10.1093/genetics/iyac006

Brian Charlesworth

R.A. Fisher's 1922 paper On the dominance ratio has a strong claim to be the foundation paper for modern population genetics. It greatly influenced subsequent work by Haldane and Wright, and contributed 3 major innovations to the study of evolution at the genetic level. First, the introduction of a general model of selection at a single locus, which showed how variability could be maintained by heterozygote advantage. Second, the use of the branching process approach to show that a beneficial mutation has a substantial chance of loss from the population, even when the population size is extremely large. Third, the invention of the concept of a probability distribution of allele frequency, caused by random sampling of allele frequencies due to finite population size, and the first use of a diffusion equation to investigate the properties of such a distribution. Although Fisher was motivated by an inference that later turned out to lack strong empirical support (a substantial contribution of dominance to quantitative trait variability), and his use of a diffusion equation was marred by a technical mistake, the paper introduced concepts and methods that pervade much subsequent work in population genetics.

R.A.Fisher 1922年的论文《优势比》有力地宣称是现代群体遗传学的基础论文。它极大地影响了霍尔丹和赖特随后的工作，并为遗传学层面的进化研究贡献了3项重大创新。首先，在单个基因座引入了一个通用的选择模型，该模型显示了如何通过杂合子优势来保持变异性。其次，使用分支过程方法来表明，即使种群规模非常大，有益的突变也有很大的机会从种群中消失。第三，发明了等位基因频率的概率分布的概念，这是由于有限的群体规模对等位基因的频率进行随机抽样引起的，并且首次使用扩散方程来研究这种分布的性质。尽管Fisher的动机是一个后来被证明缺乏强有力的经验支持的推论（显性对数量性状变异性的重大贡献），并且他对扩散方程的使用受到了一个技术错误的破坏，但该论文介绍了在群体遗传学的许多后续工作中普遍存在的概念和方法。

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引用次数: 0

The wing imaginal disc 翅膀想象盘

IF 3.3 3区生物学

Genetics

Pub Date : 2022-02-21 DOI: 10.1093/genetics/iyac020

B. Tripathi, K. Irvine

Abstract The Drosophila wing imaginal disc is a tissue of undifferentiated cells that are precursors of the wing and most of the notum of the adult fly. The wing disc first forms during embryogenesis from a cluster of ∼30 cells located in the second thoracic segment, which invaginate to form a sac-like structure. They undergo extensive proliferation during larval stages to form a mature larval wing disc of ∼35,000 cells. During this time, distinct cell fates are assigned to different regions, and the wing disc develops a complex morphology. Finally, during pupal stages the wing disc undergoes morphogenetic processes and then differentiates to form the adult wing and notum. While the bulk of the wing disc comprises epithelial cells, it also includes neurons and glia, and is associated with tracheal cells and muscle precursor cells. The relative simplicity and accessibility of the wing disc, combined with the wealth of genetic tools available in Drosophila, have combined to make it a premier system for identifying genes and deciphering systems that play crucial roles in animal development. Studies in wing imaginal discs have made key contributions to many areas of biology, including tissue patterning, signal transduction, growth control, regeneration, planar cell polarity, morphogenesis, and tissue mechanics.

摘要果蝇的翅膀想象盘是一种未分化细胞的组织，这些细胞是成年苍蝇翅膀和大部分notum的前体。翼盘在胚胎发生过程中首先由位于第二胸段的一簇～30个细胞形成，这些细胞内陷形成囊状结构。它们在幼虫阶段经历广泛的增殖，形成约35000个细胞的成熟幼虫翼盘。在这段时间里，不同的细胞命运被分配到不同的区域，翼盘形成了复杂的形态。最后，在蛹期，翅盘经历形态发生过程，然后分化形成成虫的翅膀和绒毛。虽然翼盘的大部分包括上皮细胞，但它也包括神经元和神经胶质，并与气管细胞和肌肉前体细胞有关。翼盘相对简单易用，再加上果蝇丰富的遗传工具，使其成为识别基因和破译在动物发育中发挥关键作用的系统的首要系统。对翅膀想象盘的研究在生物学的许多领域做出了关键贡献，包括组织模式、信号转导、生长控制、再生、平面细胞极性、形态发生和组织力学。

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引用次数: 19

The 2021 Genetics Society of America Medal: Douglas Koshland 2021年美国遗传学会奖章:道格拉斯·科什兰

IF 3.3 3区生物学

Genetics

Pub Date : 2022-02-13 DOI: 10.1093/genetics/iyab232

D. Koshland

Abstract The Genetics Society of America Medal honors an individual member of the Society for outstanding contributions to the field of genetics in the last 15 years. Genetics Society of America established the Medal in 1981 to recognize members who exemplify the ingenuity of the Genetics Society of America membership through elegant and highly meaningful contributions to modern genetics. The 2021 Genetics Society of America Medal has been awarded to Douglas Koshland of the University of California, Berkeley. His advances in chromosome biology have not only illuminated fundamental features of the structure of chromosomes but also provided tools for many others to use.

摘要美国遗传学学会奖章表彰在过去15年中对遗传学领域做出杰出贡献的学会个人成员年。美国遗传学学会于1981年设立了该奖章，以表彰那些通过对现代遗传学做出优雅而有意义的贡献而体现美国遗传学学会会员独创性的成员。2021年美国遗传学学会奖章授予加州大学伯克利分校的Douglas Koshland。他在染色体生物学方面的进展不仅阐明了染色体结构的基本特征，还为许多其他人提供了使用的工具。

引用次数: 0

MOET: a web-based gene set enrichment tool at the Rat Genome Database for multiontology and multispecies analyses MOET：大鼠基因组数据库中用于多本体和多物种分析的基于网络的基因集富集工具

IF 3.3 3区生物学

Genetics

Pub Date : 2022-01-28 DOI: 10.1093/genetics/iyac005

M. Vedi, H. S. Nalabolu, Chien-Wei Lin, M. Hoffman, Jennifer R. Smith, K. Brodie, J. D. De Pons, W. Demos, A. Gibson, G. Hayman, M. L. Hill, M. Kaldunski, L. Lamers, S. Laulederkind, K. Thorat, J. Thota, M. Tutaj, M. Tutaj, Shur-Jen Wang, S. Zacher, M. Dwinell, A. Kwitek

Abstract Biological interpretation of a large amount of gene or protein data is complex. Ontology analysis tools are imperative in finding functional similarities through overrepresentation or enrichment of terms associated with the input gene or protein lists. However, most tools are limited by their ability to do ontology-specific and species-limited analyses. Furthermore, some enrichment tools are not updated frequently with recent information from databases, thus giving users inaccurate, outdated or uninformative data. Here, we present MOET or the Multi-Ontology Enrichment Tool (v.1 released in April 2019 and v.2 released in May 2021), an ontology analysis tool leveraging data that the Rat Genome Database (RGD) integrated from in-house expert curation and external databases including the National Center for Biotechnology Information (NCBI), Mouse Genome Informatics (MGI), The Kyoto Encyclopedia of Genes and Genomes (KEGG), The Gene Ontology Resource, UniProt-GOA, and others. Given a gene or protein list, MOET analysis identifies significantly overrepresented ontology terms using a hypergeometric test and provides nominal and Bonferroni corrected P-values and odds ratios for the overrepresented terms. The results are shown as a downloadable list of terms with and without Bonferroni correction, and a graph of the P-values and number of annotated genes for each term in the list. MOET can be accessed freely from https://rgd.mcw.edu/rgdweb/enrichment/start.html.

摘要大量基因或蛋白质数据的生物学解释是复杂的。本体分析工具在通过过度表达或丰富与输入基因或蛋白质列表相关的术语来寻找功能相似性方面是必不可少的。然而，大多数工具都受到其进行本体特定和物种有限分析的能力的限制。此外，一些丰富工具没有经常更新数据库中的最新信息，因此给用户提供了不准确、过时或无信息的数据。在这里，我们介绍了MOET或多本体丰富工具（2019年4月发布的v.1和2021年5月发布的v.2），这是一种利用大鼠基因组数据库（RGD）从内部专家管理和外部数据库（包括国家生物技术信息中心（NCBI）、小鼠基因组信息学（MGI），京都基因和基因组百科全书（KEGG）、基因本体论资源、UniProt GOA等。给定基因或蛋白质列表，MOET分析使用超几何检验来识别显著过度表达的本体术语，并为过度表达的术语提供标称和Bonferroni校正的P值和比值比。结果显示为带有和不带有Bonferroni校正的术语的可下载列表，以及列表中每个术语的P值和注释基因数量的图表。MOET可以从https://rgd.mcw.edu/rgdweb/enrichment/start.html.

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引用次数: 4

Recombination, selection, and the evolution of tandem gene arrays 串联基因阵列的重组、选择和进化

IF 3.3 3区生物学

Genetics

Pub Date : 2022-01-28 DOI: 10.1101/2022.01.26.477888

M. Otto, Yichen Zheng, T. Wiehe

Multi-gene families – immunity genes or sensory receptors, for instance – are often subject to diversifying selection. Allelic diversity may be favoured not only through balancing or frequency dependent selection at individual loci, but also by associating different alleles in multi copy gene families. Using a combination of analytical calculations and simulations, we explored a population genetic model of epistatic selection and unequal recombination, where a trade-off exists between the benefit of allelic diversity and the cost of copy abundance. Starting from the neutral case, where we showed that gene copy number is Gamma-distributed at equilibrium, we derived also mean and shape of the limiting distribution under selection. Considering a more general model which includes variable population size and population substructure, we explored by simulations mean fitness and some summary statistics of the copy number distribution. We determined the relative effects of selection, recombination and demographic parameters in maintaining allelic diversity and shaping mean fitness of a population. One way to control the variance of copy number is by lowering the rate of unequal recombination. Indeed, when encoding recombination by a rate modifier locus, we observe exactly this prediction. Finally, we analyzed the empirical copy number distribution of three genes in human and estimated recombination and selection parameters of our model.

多基因家族——例如免疫基因或感觉受体——经常受到多样化选择的影响。等位基因多样性不仅可以通过在单个基因座上进行平衡或频率依赖性选择，还可以通过在多拷贝基因家族中关联不同的等位基因。通过分析计算和模拟相结合，我们探索了上位选择和不平等重组的群体遗传模型，其中等位基因多样性的收益和拷贝丰度的成本之间存在权衡。从中性情况出发，我们证明了基因拷贝数在平衡时是伽玛分布的，我们还推导了在选择下极限分布的均值和形状。考虑到一个更通用的模型，包括可变种群规模和种群子结构，我们通过模拟平均适应度和一些拷贝数分布的汇总统计来探索。我们确定了选择、重组和人口统计学参数在保持等位基因多样性和形成群体平均适合度方面的相对影响。控制拷贝数变化的一种方法是降低不平等重组的速率。事实上，当用速率修饰基因座编码重组时，我们正好观察到了这一预测。最后，我们分析了三个基因在人类中的经验拷贝数分布，并估计了我们模型的重组和选择参数。

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引用次数: 6

2021 GENETICS Reviewer Index 2021年遗传学审稿人索引

IF 3.3 3区生物学

Genetics

Pub Date : 2021-12-01 DOI: 10.1093/genetics/iyab200

引用次数: 0

Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model. 在一种新的秀丽隐杆线虫模型中，与阿尔茨海默病相关的Tau修饰选择性地破坏了drp1独立的有丝分裂和有丝分裂酶体运输。

IF 3.3 3区生物学

Genetics

Pub Date : 2021-11-29 DOI: 10.21203/rs.3.rs-1096882/v1

Sanjib Guha, Anson Cheng, Trae Carroll, Dennisha King, Shon Koren, Sierra Swords, Keith Nehrke, Gail V W Johnson

Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer's disease (AD), with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in C. elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator Drp1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to AD pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and ML neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for Drp1-independent, Pink1-dependent, perhaps adaptive, mitophagy.

不适当磷酸化的tau积累到神经原纤维缠结（NFT）中是阿尔茨海默病（AD）的一个决定性特征，tau pT231是tau病理学的早期预兆。此前，我们证明在秀丽隐杆线虫中表达人类拟磷酸突变体tau（T231E）的单个基因组拷贝会驱动年龄依赖性神经退行性变。一个关键的发现是，与野生型tau不同，T231E完全选择性地抑制了氧化应激诱导的线粒体自噬。在这里，我们使用动态成像方法来分析线粒体和线粒体溶酶体（ML）形态、丰度、运输和应激诱导的线粒体自噬的T231E相关变化，作为线粒体分裂介质Drp1的功能，Drp1已被证明与高磷酸化的tau相互作用，并有助于AD的发病机制，一种公认的线粒体质量控制介质，与Parkin一起支持应激诱导的线粒体自噬。T231E以优异的选择性影响线粒体自噬和ML轴突运输，避免了大自噬以及溶酶体和自溶体运输。氧化应激诱导的线粒体自噬和T231E抑制线粒体自噬的能力都独立于drp-1，但至少部分依赖于pink-1。细胞器运输更为复杂，drp-1和pink-1突变体发挥独立作用，但通常支持线粒体自噬表型在T231E中具有更大生理影响的观点。总之，我们的研究结果完善了T231E导致神经退行性变的机制途径，证明了对模拟tau病相关翻译后修饰的突变的病理选择性，对含有受损线粒体的细胞器的生理选择性，以及对Drp1非依赖性、Pink1依赖性、可能是适应性的线粒体自噬的分子选择性。

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引用次数: 1