Natural variants

自然变种
  • 文章类型: Journal Article
    缓生根瘤菌以与农业上重要的作物共生固定大气氮而闻名。本研究集中于两组菌株,每个都包含亲本菌株的八个天然变体,日本根瘤菌SEMIA586(=CNPSO17)或重氮根瘤菌SEMIA566(=CNPSO10)。CNPSo17和CNPSo10在1960-1970年代南部地区的作物扩张开始时被用作巴西大豆作物的商业接种剂。从这些亲本菌株衍生的变体是在1980年代后期通过菌株选择计划获得的,该计划旨在鉴定适合中西部Cerrado地区新种植前沿的优良菌株,具有较高的生物固氮能力和竞争力。这里,我们旨在检测可能与BNF相关的遗传变异,结核占用的竞争力,并适应巴西塞拉多土壤的压力条件。为所有菌株产生高质量的基因组组装体。核心基因组系统发育表明,各组菌株密切相关,正如高平均核苷酸同一性值所证实的那样。然而,水平基因转移导致的变异累积差异,基因组重排,和核苷酸多态性。与重氮芽孢杆菌组相比,日本芽孢杆菌组呈现更大的pangenome和更多的核苷酸多态性,可能是由于其对Cerrado土壤的适应时间较长。有趣的是,日本芽孢杆菌组的五个菌株携带两个质粒。考虑到观察到的BNF能力差异,讨论了两组中发现的遗传变异性,结核占用的竞争力,和环境适应。IMPORTANCEToday,巴西是研究和使用大豆作物生物固氮的全球领导者。由于巴西土壤自然没有与大豆相容的缓生根瘤菌,建立了菌株选择程序,从外国分离物开始。选择寻找适应当地的气候条件,固氮效率更高,和强大的结核占用竞争力。我们分析了日本根瘤菌和重氮根瘤菌的两个亲本菌株的基因组,以及来自每个亲本菌株的八个变异菌株。我们在五个菌株中检测到两个质粒,以及一些遗传差异,这些差异可能与适应巴西Cerrado生物群落土壤的压力条件有关。我们还检测到特定区域的遗传变异,这些变异可能会影响共生固氮。我们的分析有助于对根瘤菌进化的新见解,和一些确定的差异可以作为遗传标记来帮助菌株选择程序。
    Bradyrhizobium is known for fixing atmospheric nitrogen in symbiosis with agronomically important crops. This study focused on two groups of strains, each containing eight natural variants of the parental strains, Bradyrhizobium japonicum SEMIA 586 (=CNPSo 17) or Bradyrhizobium diazoefficiens SEMIA 566 (=CNPSo 10). CNPSo 17 and CNPSo 10 were used as commercial inoculants for soybean crops in Brazil at the beginning of the crop expansion in the southern region in the 1960s-1970s. Variants derived from these parental strains were obtained in the late 1980s through a strain selection program aimed at identifying elite strains adapted to a new cropping frontier in the central-western Cerrado region, with a higher capacity of biological nitrogen fixation (BNF) and competitiveness. Here, we aimed to detect genetic variations possibly related to BNF, competitiveness for nodule occupancy, and adaptation to the stressful conditions of the Brazilian Cerrado soils. High-quality genome assemblies were produced for all strains. The core genome phylogeny revealed that strains of each group are closely related, as confirmed by high average nucleotide identity values. However, variants accumulated divergences resulting from horizontal gene transfer, genomic rearrangements, and nucleotide polymorphisms. The B. japonicum group presented a larger pangenome and a higher number of nucleotide polymorphisms than the B. diazoefficiens group, possibly due to its longer adaptation time to the Cerrado soil. Interestingly, five strains of the B. japonicum group carry two plasmids. The genetic variability found in both groups is discussed considering the observed differences in their BNF capacity, competitiveness for nodule occupancy, and environmental adaptation.IMPORTANCEToday, Brazil is a global leader in the study and use of biological nitrogen fixation with soybean crops. As Brazilian soils are naturally void of soybean-compatible bradyrhizobia, strain selection programs were established, starting with foreign isolates. Selection searched for adaptation to the local edaphoclimatic conditions, higher efficiency of nitrogen fixation, and strong competitiveness for nodule occupancy. We analyzed the genomes of two parental strains of Bradyrhizobium japonicum and Bradyrhizobium diazoefficiens and eight variant strains derived from each parental strain. We detected two plasmids in five strains and several genetic differences that might be related to adaptation to the stressful conditions of the soils of the Brazilian Cerrado biome. We also detected genetic variations in specific regions that may impact symbiotic nitrogen fixation. Our analysis contributes to new insights into the evolution of Bradyrhizobium, and some of the identified differences may be applied as genetic markers to assist strain selection programs.
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  • 文章类型: Journal Article
    在抗病毒药物靶向的基因组区域中突变的天然存在的SARS-CoV-2变体尚未被广泛研究。这项研究调查了严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的RNA依赖性RNA聚合酶(RdRp)复合物亚基和非结构蛋白(Nsp)5积累可能影响疗效的天然突变的潜力。抗病毒药物。为了这个目标,使用IlluminaMiSeq平台分析了从来自意大利南部的4155个未服用药物的个体中分离的SARS-CoV-2基因组序列。对4155个样品的测序显示以下病毒变体分布:71.2%Delta,22.2%Omicron,和6.4%的阿尔法。在Nsp12序列中,我们发现84个氨基酸取代。最常见的是P323L,在3777/4155(91%)样本中检测到,其中2906/3777(69.9%)也显示组合中的G671S取代。此外,我们在Nsp5,Nsp7和Nsp8基因组区域中鉴定了28,14和24个不同的氨基酸取代,分别。值得注意的是,V186F和A191V替换,影响Nsp5(抗病毒药物Paxlovid的靶标)活性位点附近的残基,在157/4155(3.8%)和3/4155(0.07%)样本中发现,分别。总之,RdRp复合物亚基和Nsp5基因组区域表现出对积累的天然突变的易感性。这种易感性对抗病毒药物的疗效构成潜在风险,因为这些突变可能会损害药物抑制病毒复制的能力。
    Naturally occurring SARS-CoV-2 variants mutated in genomic regions targeted by antiviral drugs have not been extensively studied. This study investigated the potential of the RNA-dependent RNA polymerase (RdRp) complex subunits and non-structural protein (Nsp)5 of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to accumulate natural mutations that could affect the efficacy of antiviral drugs. To this aim, SARS-CoV-2 genomic sequences isolated from 4155 drug-naive individuals from southern Italy were analyzed using the Illumina MiSeq platform. Sequencing of the 4155 samples showed the following viral variant distribution: 71.2% Delta, 22.2% Omicron, and 6.4% Alpha. In the Nsp12 sequences, we found 84 amino acid substitutions. The most common one was P323L, detected in 3777/4155 (91%) samples, with 2906/3777 (69.9%) also showing the G671S substitution in combination. Additionally, we identified 28, 14, and 24 different amino acid substitutions in the Nsp5, Nsp7, and Nsp8 genomic regions, respectively. Of note, the V186F and A191V substitutions, affecting residues adjacent to the active site of Nsp5 (the target of the antiviral drug Paxlovid), were found in 157/4155 (3.8%) and 3/4155 (0.07%) samples, respectively. In conclusion, the RdRp complex subunits and the Nsp5 genomic region exhibit susceptibility to accumulating natural mutations. This susceptibility poses a potential risk to the efficacy of antiviral drugs, as these mutations may compromise the drug ability to inhibit viral replication.
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  • 文章类型: Journal Article
    阳光调节转录程序,并在整个植物发育过程中触发基因组的形成。在到达地球表面的不同太阳光波长中,UV-B(280-315nm)控制数百个基因的表达,用于光形态发生反应,并且还诱导干扰基因组完整性和转录程序的光损伤的形成。细胞遗传学和基于深度学习的分析相结合,可以确定UV-B诱导的光产物的位置,并量化UV-B辐射对适应各种UV-B方案的不同拟南芥天然变体中组成性异染色质含量的影响。我们确定UV-B诱导的光致富集在色心内。此外,我们发现UV-B辐射促进组成性异染色质动力学,这在具有不同异染色质含量的拟南芥生态型中有所不同。最后,我们发现色心形状的正确恢复,在DNA修复后,依靠UV-B光感受器,抗紫外线位置8(UVR8)。这些发现揭示了UV-B暴露和感知在拟南芥组成性异染色质含量调节中的作用。
    Sunlight regulates transcriptional programs and triggers the shaping of the genome throughout plant development. Among the different sunlight wavelengths that reach the surface of the Earth, UV-B (280-315 nm) controls the expression of hundreds of genes for the photomorphogenic responses and also induces the formation of photodamage that interfere with genome integrity and transcriptional programs. The combination of cytogenetics and deep-learning-based analyses allowed determining the location of UV-B-induced photoproducts and quantifying the effects of UV-B irradiation on constitutive heterochromatin content in different Arabidopsis natural variants acclimated to various UV-B regimes. We identified that UV-B-induced photolesions are enriched within chromocenters. Furthermore, we uncovered that UV-B irradiation promotes constitutive heterochromatin dynamics that differs among the Arabidopsis ecotypes having divergent heterochromatin contents. Finally, we identified that the proper restoration of the chromocenter shape, upon DNA repair, relies on the UV-B photoreceptor, UV RESISTANCE LOCUS 8 (UVR8). These findings shed the light on the effect of UV-B exposure and perception in the modulation of constitutive heterochromatin content in Arabidopsis thaliana.
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  • 文章类型: Journal Article
    β-微管蛋白(TUBB)蛋白是微管细胞骨架的组成部分之一,在中枢神经系统中起着至关重要的作用。TUBB的遗传变异导致皮质发育不良,与轴突引导和神经元迁移有关的发育性大脑缺陷。在这项研究中,我们评估致病变异(Q15K,Y222F,M299V,V353I,和E401K)的TUBB蛋白,并与非致病性变体G235S进行比较,以确定它们对蛋白动力学的影响,从而导致皮质发育不良。在分析的变体中,Q15K,Y222F,M299V,和E401K被发现具有有害作用。然后,对变体结构进行建模,并评估其与已知辅因子鸟苷-5'-三磷酸(GTP)的亲和力,结果显示变体与野生型(-7.428kcal/mol)相比,不同的结合能介于(-7.436至-6.950kcal/mol)之间。最后,对每个变异体的分子动力学模拟进行了研究,结果显示致病性变异体和非致病性变异体的轨迹存在差异.我们的分析表明,TUBB结构的氨基酸残基的变化显着影响蛋白质的柔韧性及其与已知辅因子的相互作用。总的来说,我们的研究结果为TUBB变异体与其结构动力学之间的关系提供了见解,这些结构动力学可能导致导致皮质发育不良的多种效应.
    Beta-tubulin (TUBB) protein is one of the components of the microtubule cytoskeleton that plays a critical role in the central nervous system. Genetic variants of TUBB cause cortical dysplasia, a developmental brain defect implicated in axonal guidance and the neuron migration. In this study, we assess pathogenic variants (Q15K, Y222F, M299V, V353I, and E401K) of TUBB protein and compared with non-pathogenic variant G235S to determine their impact on protein dynamic to cause cortical dysplasia. Among the analyzed variants, Q15K, Y222F, M299V, and E401K were noticed to have deleterious effect. Then, variant structures were modeled and their affinity with their known cofactor Guanosine-5\'-triphosphate (GTP) was assessed which showed diverse binding energies ranged between (-7.436 to -6.950 kcal/mol) for the variants compared to wild-type (-7.428 kcal/mol). Finally, the molecular dynamics simulation of each variant was investigated which showed difference in trajectory between the pathogenic and non-pathogenic variant. Our analysis suggests change in amino acid residue of TUBB structure has notably affects the protein flexibility and their interactions with known cofactor. Overall, our findings provide insight on the relationship between TUBB variants and their structural dynamics that may cause diverse effects leading to cortical dysplasia.
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  • 文章类型: Journal Article
    Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, Gα, Gβ, and Gγ. Gα is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with Gα switches G protein into basal or active states, respectively. Genetic alteration in Gα could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of Gαs are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of Gαs are associated with McCune-Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the Gαs subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of Gαs, others induced drastic conformational changes in Gαs, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of Gα and iPPSDs.
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  • 文章类型: Journal Article
    G蛋白偶联受体(GPCRs)通过涉及其激活的一般机制介导几种信号通路,坚持一系列事件,导致释放负责细胞质作用和进一步调节的分子。GPCR基因的突变可严重改变这些生理功能。GPCRs亚家族A17(多巴胺,血清素,肾上腺素能和微量胺受体)与神经退行性疾病直接相关,因此,探索这些系统上的已知突变及其对结构和功能的影响至关重要。构建了一个全面而详细的计算框架-MUG(理解GPCRs的突变),说明报告的关键突变及其对GPCRs亚家族A17受体的影响。我们探索了总体上和亚家族A17的不同家族中发生的突变类型,以及它们在受体中的定位和对受体功能的潜在影响。考虑其致病性,进一步分析突变的残基。结果揭示了GPCR亚家族A17结构中突变的高度多样性,注意保守残基和结构域中大量的突变。突变的残基通常是在配体结合口袋和已知的活化微结构域处富集的疏水残基。这可能导致受体功能的破坏。MUG作为交互式Web应用程序可用于此数据集的管理和可视化。我们希望这个交互式数据库有助于探索GPCR突变,他们的影响力,以及它们的家族性和受体特异性效应,构成了在原子水平上阐明其结构和分子的第一步。
    G protein-coupled receptors (GPCRs) mediate several signaling pathways through a general mechanism that involves their activation, upholding a chain of events that lead to the release of molecules responsible for cytoplasmic action and further regulation. These physiological functions can be severely altered by mutations in GPCR genes. GPCRs subfamily A17 (dopamine, serotonin, adrenergic and trace amine receptors) are directly related with neurodegenerative diseases, and as such it is crucial to explore known mutations on these systems and their impact in structure and function. A comprehensive and detailed computational framework - MUG (Mutations Understanding GPCRs) - was constructed, illustrating key reported mutations and their effect on receptors of the subfamily A17 of GPCRs. We explored the type of mutations occurring overall and in the different families of subfamily A17, as well their localization within the receptor and potential effects on receptor functionality. The mutated residues were further analyzed considering their pathogenicity. The results reveal a high diversity of mutations in the GPCR subfamily A17 structures, drawing attention to the considerable number of mutations in conserved residues and domains. Mutated residues were typically hydrophobic residues enriched at the ligand binding pocket and known activating microdomains, which may lead to disruption of receptor function. MUG as an interactive web application is available for the management and visualization of this dataset. We expect that this interactive database helps the exploration of GPCR mutations, their influence, and their familywise and receptor-specific effects, constituting the first step in elucidating their structures and molecules at the atomic level.
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  • 文章类型: Journal Article
    根向重力影响根的水溶性。根向向重力与根向水的干扰强度在植物物种之间有所不同。然而,这些差异在单一植物物种中没有得到很好的比较。在这项研究中,我们比较了在静止条件下拟南芥的各种天然变体中的根水溶性。因此,在自然拟南芥变种中,我们在固定条件下检测到了一系列的根水溶性。几种拟南芥自然变种之间的根引力性和根水溶性的比较将降低根水溶性的自然变种分为两种类型;即一种类型的根引力性和根水溶性弱于Col-0,另一种类型的根引力性弱于Col-0,但与Col-0表达相似的根引力性。然而,通过倾斜旋转促进了所有检查过的拟南芥天然变体的根水溶性。这些结果表明,在拟南芥自然变种中,根向向重力与根向水的干扰是保守的。尽管根系向重力干扰的强度与根系向水的强度不同。
    Root gravitropism affects root hydrotropism. The interference intensity of root gravitropism with root hydrotropism differs among plant species. However, these differences have not been well compared within a single plant species. In this study, we compared root hydrotropism in various natural variants of Arabidopsis under stationary conditions. As a result, we detected a range of root hydrotropism under stationary conditions among natural Arabidopsis variants. Comparison of root gravitropism and root hydrotropism among several Arabidopsis natural variants classified natural variants that decreased root hydrotropism into two types; namely one type that expresses root gravitropism and root hydrotropism weaker than Col-0, and the other type that expresses weaker root hydrotropism than Col-0 but expresses similar root gravitropism with Col-0. However, root hydrotropism of all examined Arabidopsis natural variants was facilitated by clinorotation. These results suggested that the interference of root gravitropism with root hydrotropism is conserved among Arabidopsis natural variants, although the intensity of root gravitropism interference with root hydrotropism differs.
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  • 文章类型: Journal Article
    我们最近报道了两种小鼠品系在线粒体复合物I基因中携带不同的单核苷酸变异,即,B6-mtBPL小鼠携带m.11902T>C和B6-mtALR携带m.4738C>A。B6-mtBPL小鼠表现出更长的寿命和较低的代谢疾病易感性,尽管在稳态下线粒体功能存在轻度差异。由于线粒体DNA(mtDNA)中的天然多态性已知与肠道微生物组成的不同模式相关,我们进一步研究了这些小鼠菌株的肠道菌群组成。与小鼠表型一致,我们发现变形杆菌的丰度明显较低,与病理状况呈正相关,在B6-mtBPL中与B6-mtALR小鼠相比。对这些菌株之间显着差异的细菌属的功能特征的预测揭示了葡萄糖代谢途径的参与。来自B6-mtBPL和B6-mtALR小鼠的肝脏样品的全转录组分析证实了这些发现。因此,由mtDNA变异差异引起的宿主基因表达和肠道微生物变化都可能导致这些小鼠品系的衰老和代谢表型。由于肠道微生物群更容易调节,与mtDNA变体相比,这些mtDNA变体的鉴定,特定的肠道细菌种类和细菌代谢物可能是调节常见疾病的潜在干预措施,它们对具有不同mtDNA变体的个体有差异易感。
    We recently reported on two mouse strains carrying different single nucleotide variations in the mitochondrial complex I gene, i.e., B6-mtBPL mice carrying m.11902T>C and B6-mtALR carrying m.4738C>A. B6-mtBPL mice exhibited a longer lifespan and a lower metabolic disease susceptibility despite mild mitochondrial functional differences in steady-state. As natural polymorphisms in the mitochondrial DNA (mtDNA) are known to be associated with distinct patterns of gut microbial composition, we further investigated the gut microbiota composition in these mice strains. In line with mouse phenotypes, we found a significantly lower abundance of Proteobacteria, which is positively associated with pathological conditions, in B6-mtBPL compared to B6-mtALR mice. A prediction of functional profile of significantly differential bacterial genera between these strains revealed an involvement of glucose metabolism pathways. Whole transcriptome analysis of liver samples from B6-mtBPL and B6-mtALR mice confirmed these findings. Thus, both host gene expression and gut microbial changes caused by the mtDNA variant differences may contribute to the ageing and metabolic phenotypes observed in these mice strains. Since gut microbiota are easier to modulate, compared with mtDNA variants, identification of such mtDNA variants, specific gut bacterial species and bacterial metabolites may be a potential intervention to modulate common diseases, which are differentially susceptible to individuals with different mtDNA variants.
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  • 文章类型: Journal Article
    MarlaSokolowski是行为遗传学的真正先驱,在她对果蝇觅食位点的研究中,首次对自然发生的行为多态性进行了分子描述。随后发现该基因负责许多其他物种的行为变异和类型,无脊椎动物和哺乳动物(人类)。到达那里的路径是如何使用基因分析的力量的范例,包括一些相当深奥的技术,对基因进行归零,并描述其分子身份和多效性作用。
    Marla Sokolowski is a true pioneer in behavioral genetics, having made the first molecular delineation of a naturally occurring behavioral polymorphism in her work on the foraging locus in Drosophila melanogaster. The gene was subsequently found to be responsible for behavioral variants and types in many other species, both invertebrate and mammal (human). The path to get there is a paradigmatic example of how to use the power of genetic analysis, including some rather esoteric techniques, to zero in on a gene and delineate its molecular identity and its pleiotropic roles.
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  • 文章类型: Journal Article
    嗅觉受体(ORs)构成了一个很大的感觉蛋白家族,使我们能够识别环境中的各种化学挥发物。与关于人类嗅觉阈值的大量信息相比,数千种气味剂,遗传对嗅觉影响的研究仅限于几个例子。为了在结构水平上广泛注释突变的影响,在这里,我们分析了从公共领域收集的人类OR中的119,069个天然变体的汇编.
    OR突变根据其基因组和蛋白质环境进行分类,以及它们在几个人群中的发生频率。通过对G蛋白偶联受体(GPCR)家族的结构和功能的日益了解,可以估计自然变化的功能解释。OR所属的。我们的分析揭示了个体和种群之间嗅觉基因库的自然变异的非凡多样性,在结构保守的区域发生了大量的变化。特别注意与保守的GPCR激活机制相关的位置中的突变,这可能暗示嗅觉感知中的表型变异。交互式Web应用程序(hormdb,人类嗅觉受体突变数据库)是为该突变数据集的管理和可视化而开发的。
    我们对人类嗅觉受体的自然变体进行了拓扑注释和群体分析,并提供了一个交互式应用程序来探索人类OR突变数据。我们设想,随着这些受体的可用药理学数据量的增长,该信息的效用将增加。这个努力,与正在进行的其他感官受体遗传变化研究一起,可以塑造一个新兴的感官基因组学知识领域,食品和化妆品消费品制造商应该考虑这一点,以造福普通民众。
    Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain.
    OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset.
    We performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.
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