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Polyploids broadly generate novel haplotypes from trans-specific variation in Arabidopsis arenosa and Arabidopsis lyrata. 拟南芥和拟南芥多倍体广泛地从跨特异性变异中产生新的单倍型。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-23 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011521
Magdalena Bohutínská, Eliška Petříková, Tom R Booker, Cristina Vives Cobo, Jakub Vlček, Gabriela Šrámková, Alžběta Poupětová, Jakub Hojka, Karol Marhold, Levi Yant, Filip Kolář, Roswitha Schmickl

Polyploidy, the result of whole genome duplication (WGD), is widespread across the tree of life and is often associated with speciation and adaptability. It is thought that adaptation in autopolyploids (within-species polyploids) may be facilitated by increased access to genetic variation. This variation may be sourced from gene flow with sister diploids and new access to other tetraploid lineages, as well as from increased mutational targets provided by doubled DNA content. Here, we deconstruct in detail the origins of haplotypes displaying the strongest selection signals in established, successful autopolyploids, Arabidopsis lyrata and Arabidopsis arenosa. We see strong signatures of selection in 17 genes implied in meiosis, cell cycle, and transcription across all four autotetraploid lineages present in our expanded sampling of 983 sequenced genomes. Most prominent in our results is the finding that the tetraploid-characteristic haplotypes with the most robust signals of selection were completely absent in all diploid sisters. In contrast, the fine-scaled variant 'mosaics' in the tetraploids originated from highly diverse evolutionary sources. These include widespread novel reassortments of trans-specific polymorphism from diploids, new mutations, and tetraploid-specific inter-species hybridization-a pattern that is in line with the broad-scale acquisition and reshuffling of potentially adaptive variation in tetraploids.

多倍体是全基因组复制(WGD)的结果,在生命之树中广泛存在,通常与物种形成和适应性有关。据认为,自多倍体(种内多倍体)的适应可能通过增加获得遗传变异的途径而得到促进。这种变异可能来自姐妹二倍体的基因流动和对其他四倍体谱系的新获取,也可能来自DNA含量加倍所提供的突变靶点增加。在这里,我们详细解构了在已建立的、成功的自多倍体拟南芥(拟南芥lyrata)和砂南芥(Arabidopsis arenosa)中显示最强选择信号的单倍型的起源。我们在扩大的983个测序基因组样本中发现,在所有四种同源四倍体谱系中,在减数分裂、细胞周期和转录过程中,17个基因存在强烈的选择特征。在我们的结果中最突出的是发现具有最强大选择信号的四倍体特征单倍型在所有二倍体姐妹中完全不存在。相比之下,四倍体中的精细变异“马赛克”起源于高度多样化的进化来源。这包括二倍体跨特异性多态性的广泛新重组、新突变和四倍体特异性种间杂交——这种模式与四倍体潜在适应性变异的大规模获取和重组相一致。
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引用次数: 0
Multiple independent genetic code reassignments of the UAG stop codon in phyllopharyngean ciliates. 叶根咽目纤毛虫UAG停止密码子的多重独立遗传密码重分配。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-17 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011512
Jamie McGowan, Thomas A Richards, Neil Hall, David Swarbreck

The translation of nucleotide sequences into amino acid sequences, governed by the genetic code, is one of the most conserved features of molecular biology. The standard genetic code, which uses 61 sense codons to encode one of the 20 standard amino acids and 3 stop codons (UAA, UAG, and UGA) to terminate translation, is used by most extant organisms. The protistan phylum Ciliophora (the 'ciliates') are the most prominent exception to this norm, exhibiting the grfeatest diversity of nuclear genetic code variants and evidence of repeated changes in the code. In this study, we report the discovery of multiple independent genetic code changes within the Phyllopharyngea class of ciliates. By mining publicly available ciliate genome datasets, we discovered that three ciliate species from the TARA Oceans eukaryotic metagenome dataset use the UAG codon to putatively encode leucine. We identified novel suppressor tRNA genes in two of these genomes which are predicted to decode the reassigned UAG codon to leucine. Phylogenomics analysis revealed that these three uncultivated taxa form a monophyletic lineage within the Phyllopharyngea class. Expanding our analysis by reassembling published phyllopharyngean genome datasets led to the discovery that the UAG codon had also been reassigned to putatively code for glutamine in Hartmannula sinica and Trochilia petrani. Phylogenomics analysis suggests that this occurred via two independent genetic code change events. These data demonstrate that the reassigned UAG codons have widespread usage as sense codons within the phyllopharyngean ciliates. Furthermore, we show that the function of UAA is firmly fixed as the preferred stop codon. These findings shed light on the evolvability of the genetic code in understudied microbial eukaryotes.

由遗传密码控制的核苷酸序列到氨基酸序列的翻译是分子生物学中最保守的特征之一。标准遗传密码使用61个意义密码子编码20个标准氨基酸中的一个,并使用3个终止密码子(UAA, UAG和UGA)来终止翻译,这是大多数现存生物体所使用的。原生动物门纤毛虫(“纤毛虫”)是这一规范的最突出的例外,表现出核遗传密码变异的最大多样性和密码反复变化的证据。在这项研究中,我们报告了在phyllophyngea类纤毛虫中发现的多个独立的遗传密码变化。通过挖掘公开可用的纤毛虫基因组数据集,我们发现来自TARA Oceans真核元基因组数据集的三个纤毛虫物种使用UAG密码子来推测编码亮氨酸。我们在其中两个基因组中发现了新的tRNA抑制基因,这些基因预计将解码重新分配的UAG密码子到亮氨酸。系统基因组学分析表明,这三个未被栽培的类群形成了根咽亚纲的单系谱系。通过重组已发表的phyllophyngean基因组数据集来扩展我们的分析,发现在Hartmannula sinica和Trochilia petrani中,UAG密码子也被重新分配到谷氨酰胺的推定编码上。系统基因组学分析表明,这是通过两个独立的遗传密码变化事件发生的。这些数据表明,重分配的UAG密码子在phyllophyngean纤毛虫中作为意义密码子广泛使用。此外,我们证明了UAA作为首选停止密码子的功能是牢固固定的。这些发现揭示了未被充分研究的真核微生物遗传密码的可进化性。
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引用次数: 0
A Taybi-Linder syndrome-related RTTN variant impedes neural rosette formation in human cortical organoids. 一种与Taybi-Linder综合征相关的RTTN变异阻碍了人类皮质类器官中神经花环的形成。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-16 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011517
Justine Guguin, Ting-Yu Chen, Silvestre Cuinat, Alicia Besson, Eloïse Bertiaux, Lucile Boutaud, Nolan Ardito, Miren Imaz Murguiondo, Sara Cabet, Virginie Hamel, Sophie Thomas, Bertrand Pain, Patrick Edery, Audrey Putoux, Tang K Tang, Sylvie Mazoyer, Marion Delous

Taybi-Linder syndrome (TALS) is a rare autosomal recessive disorder characterized by severe microcephaly with abnormal gyral pattern, severe growth retardation and bone abnormalities. It is caused by pathogenic variants in the RNU4ATAC gene. Its transcript, the small nuclear RNA U4atac, is involved in the excision of ~850 minor introns. Here, we report a patient presenting with TALS features but no pathogenic variants were found in RNU4ATAC, instead the homozygous RTTN c.2953A>G variant was detected by whole-exome sequencing. After deciphering the impact of the variant on the RTTN protein function at centrosome in engineered RTTN-depleted RPE1 cells and patient fibroblasts, we analysed neural stem cells (NSC) derived from CRISPR/Cas9-edited induced pluripotent stem cells and revealed major cell cycle and mitotic abnormalities, leading to aneuploidy, cell cycle arrest and cell death. In cortical organoids, we discovered an additional function of RTTN in the self-organisation of NSC into neural rosettes, by observing delayed apico-basal polarization of NSC. Altogether, these defects contributed to a marked delay of rosette formation in RTTN-mutated organoids, thus impeding their overall growth and shedding light on mechanisms leading to microcephaly.

泰比-林德综合征(Taybi-Linder Syndrome,TALS)是一种罕见的常染色体隐性遗传疾病,其特征是严重的小头畸形并伴有异常的回旋纹、严重的生长发育迟缓和骨骼异常。它是由 RNU4ATAC 基因的致病变体引起的。其转录本小核 RNA U4atac 参与约 850 个小内含子的切除。在此,我们报告了一名具有 TALS 特征的患者,但在 RNU4ATAC 基因中未发现致病变体,而是通过全外显子组测序检测到了同源的 RTTN c.2953A>G 变异。在解读了该变异对工程RTTN-depleted RPE1细胞和患者成纤维细胞中RTTN蛋白在中心体功能的影响后,我们分析了从CRISPR/Cas9编辑的诱导多能干细胞中提取的神经元干细胞(NSC),发现了主要的细胞周期和有丝分裂异常,导致非整倍体、细胞周期停滞和细胞死亡。在皮质器官组织中,我们发现了RTTN的另一个功能,即通过观察NSC的基底极化延迟,将NSC自组织成神经莲座。总之,这些缺陷导致RTTN突变的器官组织中的莲座形成明显延迟,从而阻碍了它们的整体生长,并揭示了导致小头畸形的机制。
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引用次数: 0
Spop deficiency impairs adipogenesis and promotes thermogenic capacity in mice. Spop缺乏损害小鼠的脂肪生成和促进产热能力。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-16 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011514
Qinghe Li, Yuhong Liu, Yuanyuan Wang, Qi Zhang, Na Zhang, Danli Song, Fei Wang, Qianmei Gao, Yuxin Chen, Gaomeng Zhang, Jie Wen, Guiping Zhao, Li Chen, Yu Gao

As the adaptor protein that determines substrate specificity of the Cul3-SPOP-Rbx1 E3 ligase complex, SPOP is involved in numerous biological processes. However, its physiological connections with adipogenesis and thermogenesis remain poorly understood. In the current study, we report that the conditional knockout of Spop in mice results in substantial changes in protein expression, including the upregulation of a critical factor associated with thermogenesis, UCP1. Loss of SPOP also led to defects in body weight gain. In addition, conditional knockout mice exhibited resistance to high-fat-diet-induced obesity. Proteomics analysis found that proteins upregulated in the knockout mice are primarily enriched for functions in glycolysis/gluconeogenesis, oxidative phosphorylation, and thermogenesis. Furthermore, Spop knockout mice were more resilient during cold tolerance assay compared with the wild-type controls. Finally, the knockout of SPOP efficiently impaired adipogenesis in primary preadipocytes and the expression of associated genes. Collectively, these findings demonstrate the critical roles of SPOP in regulating adipogenesis and thermogenic capacity in mice.

作为决定 Cul3-SPOP-Rbx1 E3 连接酶复合物底物特异性的适配蛋白,SPOP 参与了许多生物过程。然而,人们对其与脂肪生成和产热之间的生理联系仍然知之甚少。在目前的研究中,我们发现有条件地敲除小鼠的 Spop 会导致蛋白质表达发生重大变化,包括与产热相关的关键因子 UCP1 的上调。SPOP的缺失也会导致体重增加的缺陷。此外,条件性基因敲除小鼠对高脂饮食诱发的肥胖具有抵抗力。蛋白质组学分析发现,基因敲除小鼠体内上调的蛋白质主要富集于糖酵解/糖元生成、氧化磷酸化和产热功能中。此外,与野生型对照组相比,Spop基因敲除小鼠在耐寒试验中的恢复能力更强。最后,SPOP 基因敲除有效地阻碍了原代前脂肪细胞的脂肪生成和相关基因的表达。总之,这些发现证明了 SPOP 在调节小鼠脂肪生成和产热能力方面的关键作用。
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引用次数: 0
Adjusting for principal components can induce collider bias in genome-wide association studies. 调整主成分会导致全基因组关联研究中的对撞机偏差。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-16 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011242
Kelsey E Grinde, Brian L Browning, Alexander P Reiner, Timothy A Thornton, Sharon R Browning

Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.

主成分分析(PCA)被广泛用于控制全基因组关联研究(GWAS)中的群体结构。顶部主成分(PCs)通常反映了群体结构,但在决定需要多少个 PCs 以及确保 PCs 不会捕捉到其他假象(如具有非典型连锁不平衡(LD)的区域)方面存在挑战。针对后者,许多研究小组建议在 PCA 之前进行 LD 修剪或排除已知的高 LD 区域。然而,这些建议并没有得到普遍实施,对 GWAS 的影响也没有得到充分理解,尤其是在混杂人群中。在本文中,我们从妇女健康倡议 SNP 健康关联资源和两项跨奥美精准医学全基因组测序项目贡献研究(杰克逊心脏研究和慢性阻塞性肺病遗传流行病学研究)的非裔美国人样本中,研究了预处理和 GWAS 模型中 PCs 数量的影响。在所有三个样本中,我们发现第一个 PC 与全基因组祖先高度相关,而后面的 PC 通常捕捉局部基因组特征。哪些基因变异以及有多少基因变异与单个 PC 高度相关,这种模式与之前针对欧洲人群的研究中观察到的模式不同,并导致了不同的下游后果:由于对撞机偏差现象,调整这些 PC 会产生有偏差的效应大小估计值和较高的虚假关联率。排除以往研究中发现的高 LD 区域并不能解决这些问题。低密度修剪证明更为有效,但不同数据集的最佳阈值选择各不相同。总之,我们的研究突出了使用 PCA 控制混血人群祖先异质性时出现的独特问题,并证明了仔细预处理和诊断的重要性,以确保捕获多个局部基因组特征的 PC 不被纳入 GWAS 模型。
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引用次数: 0
Estimating and visualising multivariable Mendelian randomization analyses within a radial framework. 在径向框架内估计和可视化多变量孟德尔随机化分析。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-16 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011506
Wes Spiller, Jack Bowden, Eleanor Sanderson

Background: Mendelian randomization (MR) is a statistical approach using genetic variants as instrumental variables to estimate causal effects of a single exposure on an outcome. Multivariable MR (MVMR) extends this to estimate the direct effect of multiple exposures simulatiously. MR and MVMR can be biased by the presence of pleiotropic genetic variants in the set used as instrumental variables, violating one of the core IV assumptions. Genetic variants that give outlying estimates are often considered to be potentially pleiotropic variants. Radial plots can be used in MR to help identify these variants. Analogous plots for MVMR have so far been unavailable due to the multidimensional nature of the analysis.

Methods: We propose a radial formulation of MVMR, and an adapted Galbraith radial plot, which allows for the estimated effect of each exposure within an MVMR analysis to be visualised. Radial MVMR additionally includes an option for removal of outlying SNPs which may violate one or more assumptions of MVMR. A RMVMR R package is presented as accompanying software for implementing the methods described.

Results: We demonstrate the effectiveness of the radial MVMR approach through simulations and applied analyses. We highlight how outliers with respect to all exposures can be visualised and removed through Radial MVMR. We present simulations that illustrate how outlier removal decreases the bias in estimated effects under various forms of pleiotropy. We apply Radial MVMR to estimate the effect of lipid fractions on coronary heart disease (CHD). In combination with simulated examples, we highlight how important features of MVMR analyses can be explored using a range of tools incorporated within the RMVMR R package.

Conclusions: Radial MVMR effectively visualises causal effect estimates, and provides valuable diagnostic information with respect to the underlying assumptions of MVMR.

背景:孟德尔随机化(Mendelian randomization,MR)是一种统计方法,利用遗传变异作为工具变量来估计单一暴露对结果的因果效应。多变量随机对照法(MVMR)将其扩展到模拟估计多种暴露的直接效应。MR 和 MVMR 可能会因作为工具变量的多向遗传变异的存在而产生偏差,从而违反 IV 的核心假设之一。给出离散估计值的遗传变异通常被认为是潜在的多向变异。在 MR 中可以使用径向图来帮助识别这些变异体。由于分析的多维性,MVMR 至今还没有类似的曲线图:方法:我们提出了 MVMR 的径向表述,并改编了 Galbraith 径向图,使 MVMR 分析中每次暴露的估计效应可视化。径向 MVMR 还包括一个选项,用于剔除可能违反 MVMR 一个或多个假设的离群 SNP。RMVMR R 软件包是实施所述方法的配套软件:我们通过模拟和应用分析证明了径向 MVMR 方法的有效性。我们重点介绍了如何通过径向 MVMR 可视化并移除所有暴露的异常值。我们通过模拟说明了在各种形式的多重效应下,异常值的去除如何减少估计效应的偏差。我们应用 Radial MVMR 估算脂质组分对冠心病(CHD)的影响。结合模拟示例,我们强调了如何使用 RMVMR R 软件包中的一系列工具来探索 MVMR 分析的重要特征:结论:径向 MVMR 有效地直观显示了因果效应估计值,并就 MVMR 的基本假设提供了有价值的诊断信息。
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引用次数: 0
The cells are all-right: Regulation of the Lefty genes by separate enhancers in mouse embryonic stem cells. 细胞是正常的:在小鼠胚胎干细胞中,由不同的增强子调控左基因。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-13 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011513
Tiegh Taylor, Hongyu Vicky Zhu, Sakthi D Moorthy, Nawrah Khader, Jennifer A Mitchell

Enhancers play a critical role in regulating precise gene expression patterns essential for development and cellular identity; however, how gene-enhancer specificity is encoded within the genome is not clearly defined. To investigate how this specificity arises within topologically associated domains (TAD), we performed allele-specific genome editing of sequences surrounding the Lefty1 and Lefty2 paralogs in mouse embryonic stem cells. The Lefty genes arose from a tandem duplication event and these genes interact with each other in chromosome conformation capture assays which place these genes within the same TAD. Despite their physical proximity, we demonstrate that these genes are primarily regulated by separate enhancer elements. Through CRISPR-Cas9 mediated deletions to remove the intervening chromatin between the Lefty genes, we reveal a distance-dependent dosage effect of the Lefty2 enhancer on Lefty1 expression. These findings indicate a role for chromatin distance in insulating gene expression domains in the Lefty locus in the absence of architectural insulation.

增强子在调控对发育和细胞特性至关重要的精确基因表达模式方面发挥着关键作用;然而,基因组内如何编码基因增强子特异性还没有明确定义。为了研究这种特异性是如何在拓扑相关域(TAD)中产生的,我们在小鼠胚胎干细胞中对围绕Lefty1和Lefty2旁系基因的序列进行了等位基因特异性基因组编辑。Lefty基因由串联复制事件产生,这些基因在染色体构象捕获试验中相互影响,从而将这些基因置于同一TAD中。尽管它们的物理位置很近,但我们证明这些基因主要受不同的增强子元件调控。通过 CRISPR-Cas9 介导的删除来移除左侧基因之间的染色质,我们揭示了 Lefty2 增强子对 Lefty1 表达的距离依赖性剂量效应。这些研究结果表明,在缺乏结构隔离的情况下,染色质距离在隔离左侧基因位点的基因表达域方面发挥了作用。
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引用次数: 0
TransferGWAS of T1-weighted brain MRI data from UK Biobank. 来自UK Biobank的t1加权脑MRI数据的TransferGWAS。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-13 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011332
Alexander Rakowski, Remo Monti, Christoph Lippert

Genome-wide association studies (GWAS) traditionally analyze single traits, e.g., disease diagnoses or biomarkers. Nowadays, large-scale cohorts such as UK Biobank (UKB) collect imaging data with sample sizes large enough to perform genetic association testing. Typical approaches to GWAS on high-dimensional modalities extract predefined features from the data, e.g., volumes of regions of interest. This limits the scope of such studies to predefined traits and can ignore novel patterns present in the data. TransferGWAS employs deep neural networks (DNNs) to extract low-dimensional representations of imaging data for GWAS, eliminating the need for predefined biomarkers. Here, we apply transferGWAS on brain MRI data from UKB. We encoded 36, 311 T1-weighted brain magnetic resonance imaging (MRI) scans using DNN models trained on MRI scans from the Alzheimer's Disease Neuroimaging Initiative, and on natural images from the ImageNet dataset, and performed a multivariate GWAS on the resulting features. We identified 289 independent loci, associated among others with bone density, brain, or cardiovascular traits, and 11 regions having no previously reported associations. We fitted polygenic scores (PGS) of the deep features, which improved predictions of bone mineral density and several other traits in a multi-PGS setting, and computed genetic correlations with selected phenotypes, which pointed to novel links between diffusion MRI traits and type 2 diabetes. Overall, our findings provided evidence that features learned with DNN models can uncover additional heritable variability in the human brain beyond the predefined measures, and link them to a range of non-brain phenotypes.

全基因组关联研究(GWAS)传统上分析单一性状,如疾病诊断或生物标记物。如今,英国生物库(UKB)等大规模队列收集的成像数据样本量大到足以进行遗传关联测试。对高维模式进行 GWAS 的典型方法是从数据中提取预定义的特征,如感兴趣区域的体积。这就将此类研究的范围限制在预定义的性状上,并可能忽略数据中存在的新模式。TransferGWAS利用深度神经网络(DNN)提取成像数据的低维表示,用于GWAS,从而消除了对预定义生物标志物的需求。在此,我们将 transferGWAS 应用于 UKB 的脑 MRI 数据。我们使用在阿尔茨海默病神经成像倡议的核磁共振扫描数据和 ImageNet 数据集的自然图像上训练的 DNN 模型对 36,311 个 T1 加权脑磁共振成像(MRI)扫描数据进行了编码,并对得到的特征进行了多变量 GWAS 分析。我们发现了 289 个与骨密度、大脑或心血管特征等相关的独立基因位点,以及 11 个以前未报道过相关性的区域。我们拟合了深度特征的多基因评分(PGS),在多基因评分设置中提高了对骨矿密度和其他几种特征的预测,并计算了与选定表型的遗传相关性,发现了弥散核磁共振成像特征与 2 型糖尿病之间的新联系。总之,我们的研究结果提供了证据,证明利用 DNN 模型学习到的特征可以发现人脑中除预定义测量之外的其他遗传变异,并将它们与一系列非脑表型联系起来。
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引用次数: 0
Integrin adhesome axis inhibits the RPM-1 ubiquitin ligase signaling hub to regulate growth cone and axon development. 整合素粘附体轴抑制 RPM-1 泛素连接酶信号枢纽,以调控生长锥和轴突的发育。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-13 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011496
Jonathan Amezquita, Muriel Desbois, Karla J Opperman, Joseph S Pak, Elyse L Christensen, Nikki T Nguyen, Karen Diaz-Garcia, Melissa A Borgen, Brock Grill

Integrin signaling plays important roles in development and disease. An adhesion signaling network called the integrin adhesome has been principally defined using bioinformatics and cell-based proteomics. To date, the adhesome has not been studied using integrated proteomic and genetic approaches. Here, proteomic studies in C. elegans identified physical associations between the RPM-1 ubiquitin ligase signaling hub and numerous adhesome components including Talin (TLN-1), Kindlin (UNC-112) and β-integrin (PAT-3). C. elegans RPM-1 is orthologous to human MYCBP2, a prominent player in nervous system development recently associated with a neurodevelopmental disorder. After curating and updating the conserved C. elegans adhesome, we identified an adhesome subnetwork physically associated with RPM-1 that has extensive links to human neurobehavioral abnormalities. Using neuron-specific, CRISPR loss-of-function strategies, we demonstrate that a PAT-3/UNC-112/TLN-1 adhesome axis regulates axon termination in mechanosensory neurons by inhibiting RPM-1. Developmental time-course studies and pharmacological results suggest TLN-1 inhibition of RPM-1 affects growth cone collapse and microtubule dynamics during axon outgrowth. These results indicate the PAT-3/UNC-112/TLN-1 adhesome axis restricts RPM-1 signaling to ensure axon outgrowth is terminated in a spatially and temporally accurate manner. Thus, our findings orthogonally validate the adhesome using an organismal setting, identify an adhesome axis that inhibits RPM-1 (MYCBP2), and highlight important new links between the adhesome and brain disorders.

整合素信号在发育和疾病中发挥着重要作用。一种名为整合素粘附体的粘附信号网络主要是通过生物信息学和基于细胞的蛋白质组学来定义的。迄今为止,还没有利用蛋白质组学和遗传学综合方法对粘附体进行研究。在这里,对 elegans 进行的蛋白质组学研究发现了 RPM-1 泛素连接酶信号枢纽与包括 Talin (TLN-1)、Kindlin (UNC-112) 和 β 整合素 (PAT-3) 在内的众多粘附体成分之间的物理关联。elegans RPM-1 与人类的 MYCBP2 同源,MYCBP2 是神经系统发育过程中的一个重要角色,最近与一种神经发育障碍有关。在对保守的 elegans 粘着体进行整理和更新后,我们发现了一个与 RPM-1 有物理关联的粘着体亚网,它与人类神经行为异常有广泛的联系。利用神经元特异性 CRISPR 功能缺失策略,我们证明了 PAT-3/UNC-112/TLN-1 黏附体轴通过抑制 RPM-1 来调节机械感觉神经元的轴突终止。发育时程研究和药理学结果表明,TLN-1抑制RPM-1会影响轴突生长过程中的生长锥塌陷和微管动力学。这些结果表明,PAT-3/UNC-112/TLN-1粘附体轴限制了RPM-1信号传导,以确保轴突生长在空间和时间上准确终止。因此,我们的研究结果利用生物环境正交验证了粘附体,确定了抑制 RPM-1 的粘附体轴(MYCBP2),并强调了粘附体与脑部疾病之间的重要新联系。
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引用次数: 0
The Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) oncogene is upregulated in cystic epithelial cells revealing a potential new target for polycystic kidney disease. 肿瘤相关钙信号转导子 2 (TACSTD2) 癌基因在囊性上皮细胞中上调,揭示了治疗多囊肾的潜在新靶点。
IF 4 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2024-12-12 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pgen.1011510
Abigail O Smith, William Tyler Frantz, Kenley M Preval, Yvonne J K Edwards, Craig J Ceol, Julie A Jonassen, Gregory J Pazour

Polycystic kidney disease (PKD) is an important cause of kidney failure, but treatment options are limited. While later stages of the disease have been extensively studied, mechanisms driving the initial conversion of kidney tubules into cysts are not understood. To identify genes with the potential to promote cyst initiation, we deleted polycystin-2 (Pkd2) in mice and surveyed transcriptional changes before and immediately after cysts developed. We identified 74 genes which we term cyst initiation candidates (CICs). To identify conserved changes with relevance to human disease we compared these murine CICs to single cell transcriptomic data derived from patients with PKD and from healthy controls. Tumor-associated calcium signal transducer 2 (Tacstd2) stood out as an epithelial-expressed gene with elevated levels early in cystic transformation that further increased with disease progression. Human tissue biopsies and organoids show that TACSTD2 protein is low in normal kidney cells but is elevated in cyst lining cells, making it an excellent candidate for mechanistic exploration of its role in cyst initiation. While TACSTD2 has not been studied in PKD, it has been studied in cancer where it is highly expressed in solid tumors while showing minimal expression in normal tissue. This property is being exploited by antibody drug conjugates that target TACSTD2 for the delivery of cytotoxic drugs. Our finding that Tacstd2/TACSTD2 is prevalent in cysts, but not normal tissue, suggests that it should be explored as a candidate for drug development in PKD. More immediately, our work suggests that PKD patients undergoing TACSTD2-directed treatment for breast and urothelial cancer should be monitored for kidney effects.

多囊肾病(PKD)是肾衰竭的重要原因,但治疗选择有限。虽然该疾病的晚期已被广泛研究,但驱动肾小管最初转化为囊肿的机制尚不清楚。为了鉴定可能促进囊肿形成的基因,我们在小鼠中删除了多囊蛋白-2 (Pkd2),并调查了囊肿形成前后的转录变化。我们鉴定了74个被称为囊肿起始候选基因(CICs)的基因。为了确定与人类疾病相关的保守变化,我们将这些小鼠CICs与来自PKD患者和健康对照的单细胞转录组学数据进行了比较。肿瘤相关钙信号传感器2 (Tacstd2)作为上皮表达基因在囊性转化早期水平升高,随着疾病进展进一步升高。人体组织活检和类器官显示,TACSTD2蛋白在正常肾细胞中含量较低,但在囊肿内膜细胞中含量升高,这使其成为探索其在囊肿形成过程中作用的机制的极好候选蛋白。虽然TACSTD2尚未在PKD中进行研究,但它已在癌症中进行了研究,在实体瘤中高表达,而在正常组织中表达很少。靶向TACSTD2的抗体药物偶联物正利用这一特性递送细胞毒性药物。我们发现Tacstd2/ Tacstd2在囊肿中普遍存在,但在正常组织中不存在,这表明它应该作为PKD药物开发的候选物进行探索。更直接的是,我们的研究表明,接受tacstd2定向治疗乳腺癌和尿路上皮癌的PKD患者应该监测其肾脏影响。
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