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Homologous recombination defects and how they affect replication fork maintenance. 同源重组缺陷及其对复制叉维持的影响
Pub Date : 2019-04-03 eCollection Date: 2018-01-01 DOI: 10.3934/genet.2018.4.192
Mi Young Son, Paul Hasty

Homologous recombination (HR) repairs DNA double strand breaks (DSBs) and stabilizes replication forks (RFs). RAD51 is the recombinase for the HR pathway. To preserve genomic integrity, RAD51 forms a filament on the 3' end of a DSB and on a single-stranded DNA (ssDNA) gap. But unregulated HR results in undesirable chromosomal rearrangements. This review describes the multiple mechanisms that regulate HR with a focus on those mechanisms that promote and contain RAD51 filaments to limit chromosomal rearrangements. If any of these pathways break down and HR becomes unregulated then disease, primarily cancer, can result.

摘要同源重组(HR)修复DNA双链断裂(DSBs)并稳定复制叉(RFs)。RAD51是HR途径的重组酶。为了保持基因组的完整性,RAD51在DSB的3〃末端和单链DNA(ssDNA)间隙上形成细丝。但不受调控的HR会导致不理想的染色体重排。这篇综述描述了调节HR的多种机制,重点是那些促进并含有RAD51丝以限制染色体重排的机制。如果这些途径中的任何一种被破坏,HR变得不受控制,那么可能会导致疾病,主要是癌症。
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引用次数: 0
Cd2+ + Cr6+ causes toxic effects on chromosomal development of microspore in Carthamus tinctorius Cd2+ + Cr6+对红花小孢子染色体发育有毒性作用
Pub Date : 2019-03-29 DOI: 10.3934/genet.2019.1.1
N. Mittal, A. Srivastava
Abstract Intra-category hybrids of Carthamus tinctorius were analyzed for the genetic toxicity in detail for effect of Cd2+ + Cr6+ on reproductive biology of Carthamus tinctorius. Five partially tolerant and five non-tolerant accessions of Carthamus tinctorius after screening were crossed to produce intra-category hybrid. These two heavy metals in combination influenced antagonistically first as well as second meiotic divisions inducing various kinds of anomalies and reduced the number of pollen grains per anther and significantly increased pollen sterility. A differential response for the amount of meiotic irregularity was recorded between different treated sets of hybrids in (Cd + Cr) treated sets. This could be due to differential response of the genotypes for the same concentration of (Cd + Cr). These two heavy metals in combination reduced the number of pollen grains per anther and significantly increased pollen sterility.
摘要详细分析了Cd2++Cr6+对红花繁殖生物学的影响。筛选出5份红花部分耐受性材料和5份红花非耐受性材料进行杂交,形成类内杂交种。这两种重金属组合对第一次和第二次减数分裂产生拮抗作用,导致各种异常,减少了每个花药的花粉粒数,显著提高了花粉的不育性。在(Cd+Cr)处理组中,不同处理组的杂交种对减数分裂不规则数量的差异反应被记录下来。这可能是由于基因型对相同浓度(Cd+Cr)的不同反应。这两种重金属的组合减少了每个花药的花粉粒数,显著提高了花粉的不育性。
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引用次数: 2
Starless bias and parameter-estimation bias in the likelihood-based phylogenetic method 基于似然的系统发育方法中的无星偏差和参数估计偏差
Pub Date : 2018-12-01 DOI: 10.3934/genet.2018.4.212
X. Xia
Abstract I analyzed various site pattern combinations in a 4-OTU case to identify sources of starless bias and parameter-estimation bias in likelihood-based phylogenetic methods, and reported three significant contributions. First, the likelihood method is counterintuitive in that it may not generate a star tree with sequences that are equidistant from each other. This behaviour, dubbed starless bias, happens in a 4-OTU tree when there is an excess (i.e., more than expected from a star tree and a substitution model) of conflicting phylogenetic signals supporting the three resolved topologies equally. Special site pattern combinations leading to rejection of a star tree, when sequences are equidistant from each other, were identified. Second, fitting gamma distribution to model rate heterogeneity over sites is strongly confounded with tree topology, especially in conjunction with the starless bias. I present examples to show dramatic differences in the estimated shape parameter Α between a star tree and a resolved tree. There may be no rate heterogeneity over sites (with the estimated Α > 10000) when a star tree is imposed, but Α < 1 (suggesting strong rate heterogeneity over sites) when an (incorrect) resolved tree is imposed. Thus, the dependence of “rate heterogeneity” on tree topology implies that “rate heterogeneity” is not a sequence-specific feature, cautioning against interpreting a small Α to mean that some sites are under strong purifying selection and others not. Thirdly, because there is no existing (and working) likelihood method for evaluating a star tree with continuous gamma-distributed rate, I have implemented the method for JC69 in a self-contained R script for a four-OTU tree (star or resolved), in addition to another R script assuming a constant rate over sites. These R scripts should be useful for teaching and exploring likelihood methods in phylogenetics.
摘要我分析了一个4-OTU病例中的各种位点模式组合,以确定基于似然的系统发育方法中无星偏倚和参数估计偏倚的来源,并报告了三个重要贡献。首先,似然法是违反直觉的,因为它可能不会生成序列彼此等距的星树。这种行为被称为无星偏倚,发生在4-OTU树中,当存在过量(即,来自星树和替代模型的超出预期的)冲突的系统发育信号时,这些信号同样支持三种已解决的拓扑结构。当序列彼此等距时,识别出了导致星树被拒绝的特殊位点模式组合。其次,拟合伽马分布以模拟站点上的速率异质性与树拓扑结构非常混淆,尤其是与无星偏差相结合。我举了一些例子来说明星形树和解析树之间估计的形状参数Α的显著差异。当使用星型树时,可能不存在站点间的速率异质性(估计的Α>10000),但当使用(不正确的)解析树时,Α<1(表明站点间的强烈速率异质性)。因此,“速率异质性”对树拓扑结构的依赖性意味着“速率异构性”不是序列特异性特征,提醒不要将小的Α解释为一些位点处于强纯化选择之下,而另一些位点则没有。第三,由于没有现有的(有效的)似然方法来评估具有连续伽玛分布速率的星树,除了假设站点上的速率不变的另一个R脚本外,我还在四个OTU树(星或已解析)的独立R脚本中实现了JC69的方法。这些R脚本应该对系统发育学中的可能性方法的教学和探索有用。
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引用次数: 1
Correction: Time-dependent modulation of FoxO activity by HDAC inhibitor in oncogene-transformed E1A+Ras cells. 更正:HDAC抑制剂对癌基因转化的E1A+Ras细胞中FoxO活性的时间依赖性调节。
Pub Date : 2018-09-13 eCollection Date: 2018-01-01 DOI: 10.3934/genet.2018.3.191
Alisa Morshneva, Olga Gnedina, Svetlana Svetlikova, Valery Pospelov, Maria Igotti

[This corrects the article DOI: 10.3934/genet.2018.1.41.].

[这更正了文章DOI:10.3934/genet.2018.1.41.]。
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引用次数: 0
Panic disorders: The role of genetics and epigenetics 惊恐障碍:遗传学和表观遗传学的作用
Pub Date : 2018-07-02 DOI: 10.3934/genet.2018.3.177
Eun Jeong Kim, Yong-Ku Kim
Abstract Panic disorder is characterized by symptoms with abrupt surges of fear with palpitations, sweating, trembling, heat sensations. Considering its disease burden on each individual and on society, understanding its etiology is important. Though no one specific etiology has been known, like other psychiatric disorders, multiple factors such as genetic, environmental, neurobiological, psychopathological factors have been suggested. In this article, we reviewed currently known etiologies and related study results, regarding especially genetic and epigenetic aspects of the panic disorder. Early studies, including twin studies, family studies, adoption studies suggested highly familial trait of panic disorder. Linkage studies, either, found panic disorder is not a single gene disorder but confirmed existence of multiple related genes. Chromosome and candidate gene studies found few related genes, NPY, ADORA2A, COMT, IKBKE. Newer method, genome-wide association studies (GWAS) have been searching for newer genes. No genome-wide significant genes, however, were detected, confirming previously known candidate genes, NPY5R on 4q31.3-32, BDKRB2 on 14q32, instead. Epigenetic modification has also been studied on many different psychiatric disorders. Monoamine oxidase A (MAOA) hypomethylation, taken together with negative life events, showed relation with panic disorder. Glutamate decarbodylases 1 (GAD1) hypomethylation was also specific on panic disorder patients. Relation with noradrenaline transporter (NET) gene SLC6a2 promoter methylation has also been studied. In conclusion, no specific gene or epigenetic pattern can fully explain etiology of panic disorder. Few genes and epigenetic patterns, however, showed strong association with panic disorder compared to healthy controls. Considering its multivariable background, further studies with larger populations can confirm current results and clarify etiologies of panic disorder.
摘要惊恐障碍的特点是突然出现恐惧,伴有心悸、出汗、颤抖和灼热感。考虑到其对每个人和社会的疾病负担,了解其病因很重要。尽管没有一种特定的病因是已知的,就像其他精神疾病一样,但已经提出了多种因素,如遗传、环境、神经生物学和精神病理学因素。在这篇文章中,我们回顾了目前已知的病因和相关研究结果,特别是关于惊恐障碍的遗传和表观遗传学方面。早期的研究,包括双胞胎研究、家庭研究和收养研究,都表明恐慌症具有高度的家族特征。连锁研究也发现,恐慌症不是一种单一的基因疾病,而是证实了多种相关基因的存在。染色体和候选基因研究发现很少有相关基因,如NPY、ADORA2A、COMT、IKBKE。新的方法,全基因组关联研究(GWAS)一直在寻找新的基因。然而,没有检测到全基因组的显著基因,证实了先前已知的候选基因,4q31.3-32上的NPY5R,14q32上的BDKRB2。表观遗传学修饰也被研究用于许多不同的精神疾病。单胺氧化酶A(MAOA)低甲基化,加上负性生活事件,与惊恐障碍有关。谷氨酸脱羧酶1(GAD1)低甲基化在惊恐障碍患者中也是特异性的。还研究了去甲肾上腺素转运蛋白(NET)基因SLC6a2启动子甲基化的关系。总之,并没有特定的基因或表观遗传学模式可以完全解释惊恐障碍的病因。然而,与健康对照组相比,很少有基因和表观遗传学模式与恐慌症有强烈的相关性。考虑到其多变量背景,对更多人群的进一步研究可以证实目前的结果,并阐明恐慌症的病因。
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引用次数: 11
The role of long non-coding RNAs in cardiac development and disease. 长非编码RNA在心脏发育和疾病中的作用。
Pub Date : 2018-03-26 eCollection Date: 2018-01-01 DOI: 10.3934/genet.2018.2.124
Carlos García-Padilla, Amelia Aránega, Diego Franco

Cells display a set of RNA molecules at one time point, reflecting thus the cellular transcriptional steady state, configuring therefore its transcriptome. It is basically composed of two different classes of RNA molecules; protein-coding RNAs (cRNAs) and protein non-coding RNAs (ncRNAs). Sequencing of the human genome and subsequently the ENCODE project identified that more than 80% of the genome is transcribed in some type of RNA. Importantly, only 3% of these transcripts correspond to protein-coding RNAs, pointing that ncRNAs are as important or even more as cRNAs. ncRNAs have pivotal roles in development, differentiation and disease. Non-coding RNAs can be classified into two distinct classes according to their length; i.e., small (<200 nt) and long (>200 nt) noncoding RNAs. The structure, biogenesis and functional roles of small non-coding RNA have been widely studied, particularly for microRNAs (miRNAs). In contrast to microRNAs, our current understanding of long non-coding RNAs (lncRNAs) is limited. In this manuscript, we provide state-of-the art review of the functional roles of long non-coding RNAs during cardiac development as well as an overview of the emerging role of these ncRNAs in distinct cardiac diseases.

细胞在一个时间点上显示一组RNA分子,从而反映细胞转录稳定状态,从而配置其转录组。它基本上由两类不同的RNA分子组成;蛋白质编码RNA(cRNA)和蛋白质非编码RNA(ncRNA)。人类基因组测序和随后的ENCODE项目发现,超过80%的基因组在某种类型的RNA中转录。重要的是,这些转录物中只有3%对应于蛋白质编码RNA,这表明ncRNA与cRNA一样重要,甚至更重要。ncRNA在发育、分化和疾病中起着关键作用。非编码RNA根据其长度可分为两类;即小的(200nt)非编码RNA。小型非编码RNA的结构、生物发生和功能作用已被广泛研究,尤其是微小RNA(miRNA)。与微小RNA相比,我们目前对长非编码RNA(lncRNA)的理解是有限的。在这篇手稿中,我们对长非编码RNA在心脏发育过程中的功能作用进行了最新的综述,并概述了这些ncRNA在不同心脏疾病中的新作用。
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引用次数: 18
Preferable location of chromosomes 1, 29, and X in bovine spermatozoa. 牛精子中染色体1、29和X的优选位置
Pub Date : 2018-03-21 eCollection Date: 2018-01-01 DOI: 10.3934/genet.2018.2.113
Vadim Chagin, Andrei Zalensky, Igor Nazarov, Olga Mudrak

Chromosome positioning in sperm nucleus may have a functional significance by influencing the sequence of post-fertilization events. In this study we present data on preferential locations of chromosomes 1, 29 and X in Bos taurus spermatozoa. Here we demonstrate that the position of X chromosome in the sperm nucleus is more restricted as compared to the position of chromosome 1, which is about of the same size. Our data support the concept of the functional significance of genome architecture in male germline cells.

染色体在精子核中的定位可能通过影响受精后事件的顺序而具有功能意义。在这项研究中,我们提供了牛精子中染色体1、29和X的优先位置的数据。在这里,我们证明了X染色体在精子核中的位置比1染色体的位置更受限制,这是大约相同的大小。我们的数据支持基因组结构在男性生殖系细胞中的功能意义的概念。
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引用次数: 0
Towards an advanced cell-based in vitro glioma model system. 建立一种先进的基于细胞的体外神经胶质瘤模型系统。
Pub Date : 2018-03-19 eCollection Date: 2018-01-01 DOI: 10.3934/genet.2018.2.91
Valeriia Mikhailova, Valeriia Gulaia, Vladlena Tiasto, Stanislav Rybtsov, Margarita Yatsunskaya, Alexander Kagansky

The modulation of tumor growth and development in vitro has always been one of the key factors in the research of the malignant transformation, including gliomas, prevalent and most deadly cancers of the brain. Indeed, cellular and molecular biology research employing in vitro model cell-based systems have great potential to advance both the mechanistic understanding and the treatment of human glial tumors, as it facilitates not only the understanding of glioma biology and its regulatory mechanisms Additionally they promise to afford the screening of the putative anti-tumor agents and alternative treatment approaches in a personalized manner, i.e. by virtue of using the patient-derived tumor material for such tests. However, in order to become reliable and representative, glioma model systems need to move towards including most inherent cancer features such as local hypoxia, specific genetic aberrations, native tumor microenvironment, and the three-dimensional extracellular matrix. This review starts with a brief introduction on the general epidemiological and molecular characteristics of gliomas followed by an overview of the cell-based in vitro models currently used in glioma research. As a conclusion, we suggest approaches to move to innovative cell-based in vitro glioma models. We consider that main criteria for selecting these approaches should include the adequate resemblance to the key in vivo characteristics, robustness, cost-effectiveness and ease to use, as well as the amenability to high throughput handling to allow the standardized drug screening.

肿瘤体外生长发育的调节一直是恶性转化研究的关键因素之一,包括胶质瘤、常见和最致命的脑癌。事实上,采用体外模型细胞系统的细胞和分子生物学研究在促进对人类神经胶质瘤的机制理解和治疗方面具有巨大潜力,因为它不仅有助于理解神经胶质瘤生物学及其调控机制。此外,他们承诺以个性化的方式,即通过使用患者来源的肿瘤材料进行此类测试,提供推定的抗肿瘤药物和替代治疗方法的筛选。然而,为了变得可靠和具有代表性,神经胶质瘤模型系统需要包括大多数固有的癌症特征,如局部缺氧、特异性遗传畸变、原生肿瘤微环境和三维细胞外基质。本文首先简要介绍了胶质瘤的一般流行病学和分子特征,然后概述了目前用于胶质瘤研究的基于细胞的体外模型。作为结论,我们建议采用创新的基于细胞的体外神经胶质瘤模型。我们认为,选择这些方法的主要标准应包括与体内关键特征的足够相似性、稳健性、成本效益和易用性,以及高通量处理的适应性,以实现标准化药物筛选。
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引用次数: 12
The possible function of Flp1 in homologous recombination repair in Saccharomyces cerevisiae Flp1在酿酒酵母同源重组修复中的可能功能
Pub Date : 2018-03-18 DOI: 10.3934/genet.2018.2.161
H. Phung, H. Nguyen, D. Nguyen
Abstract Saccharomyces cerevisiae Mus81 is a structure-selective endonuclease which constitutes an alternative pathway in parallel with the helicase-topoisomerase Sgs1-Top3-Rmi1 complex to resolve a number of DNA intermediates during DNA replication, repair, and homologous recombination. Previously, it was showed that the N-terminal region of Mus81 was required for its in vivo function in a redundant manner with Sgs1; mus81Δ120N mutant that lacks the first 120 amino acid residues at the N-terminus exhibited synthetic lethality in combination with the loss of SGS1. In this study, the physiologically important role of the N-terminal region of Mus81 in processing toxic intermediates was further investigated. We examined the cellular defect of sgs1Δmus81Δ100N cells and observed that although viable, the cells became very sensitive to DNA damaging agents. A single-copy suppressor screening to seek for a factor(s) that could rescue the drug sensitivity of sgs1Δmus81Δ100N cells was performed and revealed that Flp1, a site-specific recombinase 1 encoded on the 2-micron plasmid was a suppressor. Moreover, Flp1 overexpression could partially suppress the drug sensitivity of mus81Δ cells at 37 °C. Our findings suggest a possible function of Flp1 in coordination with Mus81 and Sgs1 to jointly resolve the branched-DNA structures generated in cells attempting to repair DNA damages.
Saccharomyces cerevisiae Mus81是一种结构选择性内切酶,它与解旋酶-拓扑异构酶Sgs1-Top3-Rmi1复合物平行构成了在DNA复制、修复和同源重组过程中分解许多DNA中间体的替代途径。先前的研究表明,Mus81的n端区域与Sgs1是冗余的,是其体内功能所必需的;mus81Δ120N突变体缺乏n端前120个氨基酸残基,在SGS1缺失的同时表现出合成致死性。在这项研究中,进一步研究了Mus81的n端区域在处理有毒中间体中的生理重要作用。我们检查了sgs1Δmus81Δ100N细胞的细胞缺陷,并观察到尽管存活,细胞对DNA损伤剂变得非常敏感。我们进行了单拷贝抑制因子筛选,以寻找能够挽救sgs1Δmus81Δ100N细胞药物敏感性的因子,并发现编码在2微米质粒上的位点特异性重组酶1 Flp1是一个抑制因子。此外,在37℃下,Flp1过表达可以部分抑制mus81Δ细胞的药物敏感性。我们的研究结果表明,Flp1可能与Mus81和Sgs1协同作用,共同解决细胞中产生的分支DNA结构,试图修复DNA损伤。
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引用次数: 0
Non-centrosomal MTs play a crucial role in organization of MT array in interphase fibroblasts 非中心体MT在间期成纤维细胞MT阵列的组织中起着至关重要的作用
Pub Date : 2018-03-15 DOI: 10.3934/genet.2018.2.141
Yekaterina Zvorykina, A. Tvorogova, A. Gladkikh, I. Vorobjev
Abstract Microtubules in interphase fibroblast-like cells are thought to be organized in a radial array growing from a centrosome-based microtubule-organizing center (MTOC) to the cell edges. However, many morphogenetic processes require the asymmetry of the microtubules (MT) array. One of the possible mechanisms of this asymmetry could be the presence of non-centrosomal microtubules in different intracellular areas. To evaluate the role of centrosome-born and non-centrosomal microtubules in the organization of microtubule array in motile 3T3 fibroblasts, we have performed the high-throughput analysis of microtubule growth in different functional zones of the cell and distinguished three subpopulations of growing microtubules (centrosome-born, marginal and inner cytoplasmic). Centrosome as an active microtubule-organizing center was absent in half of the cell population. However, these cells do not show any difference in microtubule growth pattern. In cells with active centrosome, it was constantly forming short (ephemeral) MTs, and ∼15–20 MT per minute grow outwards for a distance >1 µm. Almost no persistent growth of microtubules was observed in these cells with the average growth length of 5–6 µm and duration of growth periods within 30 s. However, the number of growing ends increased towards cell margin, especially towards the active edges. We found the peripheral cytoplasmic foci of microtubule growth there. During recovery from nocodazole treatment microtubules started to grow around the centrosome in a normal way and independently in all the cell areas. Within 5 minutes microtubules continued to grow mainly near the cell edge. Thus, our data confirm the negligible role of centrosome as MTOC in 3T3 fibroblasts and propose a model of non-centrosomal microtubules as major players that create the cell asymmetry in the cells with a mesenchymal type of motility. We suggest that increased density of dynamic microtubules near the active lamellum could be supported by microtubule-based microtubule nucleation.
间期成纤维细胞样细胞中的微管被认为是由中心体为基础的微管组织中心(MTOC)向细胞边缘呈放射状排列。然而,许多形态发生过程需要微管阵列的不对称性。这种不对称的可能机制之一可能是在不同的细胞内区域存在非中心体微管。为了评估着丝体微管和非着丝体微管在运动3T3成纤维细胞微管阵列组织中的作用,我们对细胞不同功能区的微管生长进行了高通量分析,并区分了生长微管的三个亚群(着丝体、细胞质边缘和细胞质内)。作为活跃的微管组织中心的中心体在一半的细胞群中缺失。然而,这些细胞在微管生长模式上没有表现出任何差异。在中心体活跃的细胞中,它不断形成短的(短暂的)MT,每分钟约15-20 MT向外生长,距离为10µm。这些细胞几乎未观察到微管的持续生长,平均生长长度为5-6µm,生长周期在30 s以内。生长端向细胞边缘方向增加,尤其是向活动边缘方向增加。我们在那里发现了微管生长的外周细胞质灶。在诺可达唑治疗恢复期间,微管开始在中心体周围正常生长,并在所有细胞区域独立生长。在5分钟内,微管主要在细胞边缘继续生长。因此,我们的数据证实了中心体在3T3成纤维细胞中作为MTOC的作用可以忽略不计,并提出了一个非中心体微管模型,该模型在具有间充质类型运动的细胞中产生细胞不对称。我们认为,活性薄片附近动态微管密度的增加可能是由基于微管的微管成核所支持的。
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引用次数: 0
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