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Strategic targeting of Cas9 nickase induces large segmental duplications. Cas9缺口酶的策略性靶向诱导大片段重复。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-08-14 Epub Date: 2024-07-24 DOI: 10.1016/j.xgen.2024.100610
Yuki Sugiyama, Satoshi Okada, Yasukazu Daigaku, Emiko Kusumoto, Takashi Ito

Gene/segmental duplications play crucial roles in genome evolution and variation. Here, we introduce paired nicking-induced amplification (PNAmp) for their experimental induction. PNAmp strategically places two Cas9 nickases upstream and downstream of a replication origin on opposite strands. This configuration directs the sister replication forks initiated from the origin to break at the nicks, generating a pair of one-ended double-strand breaks. If homologous sequences flank the two break sites, then end resection converts them to single-stranded DNAs that readily anneal to drive duplication of the region bounded by the homologous sequences. PNAmp induces duplication of segments as large as ∼1 Mb with efficiencies exceeding 10% in the budding yeast Saccharomyces cerevisiae. Furthermore, appropriate splint DNAs allow PNAmp to duplicate/multiplicate even segments not bounded by homologous sequences. We also provide evidence for PNAmp in mammalian cells. Therefore, PNAmp provides a prototype method to induce structural variations by manipulating replication fork progression.

基因/片段重复在基因组进化和变异中起着至关重要的作用。在这里,我们引入了配对缺口诱导扩增(PNAmp)技术,用于实验诱导。PNAmp 策略性地将两个 Cas9 挑刺酶分别置于复制原点的上游和下游的相对链上。这种配置会引导从原点开始的姐妹复制叉在缺口处断裂,产生一对单端双链断裂。如果同源序列位于两个断裂点的两侧,那么末端切除就会将它们转化为单链 DNA,这些单链 DNA 很容易退火,从而驱动同源序列所包围区域的复制。在芽殖酵母(Saccharomyces cerevisiae)中,PNAmp 能诱导大至 1 Mb 的区段复制,效率超过 10%。此外,适当的拼接 DNA 甚至可以让 PNAmp 复制/增殖没有同源序列限制的片段。我们还提供了哺乳动物细胞中存在 PNAmp 的证据。因此,PNAmp 提供了一种通过操纵复制叉进程诱导结构变异的原型方法。
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引用次数: 0
ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer. ERCC2突变改变了体细胞突变的基因组分布模式,并对膀胱癌的预后具有独立影响。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-08-14 Epub Date: 2024-08-02 DOI: 10.1016/j.xgen.2024.100627
Jayne A Barbour, Tong Ou, Haocheng Yang, Hu Fang, Noel C Yue, Xiaoqiang Zhu, Michelle W Wong-Brown, Yuen T Wong, Nikola A Bowden, Song Wu, Jason W H Wong

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

切除修复交叉互补组 2(ERCC2)编码 DNA 螺旋酶色素沉着病 D 组,它在转录和核苷酸切除修复中发挥作用。ERCC2的点突变是约10%的膀胱癌(BLCA)的潜在诱因,也是顺铂治疗反应的潜在阳性生物标志物。然而,人们对ERCC2突变直接导致的预后意义及其在基因组不稳定性中的致病作用仍然知之甚少。我们首先证明了突变的ERCC2是BLCA预后的独立预测因子。然后,我们利用一组ERCC2野生型(n = 343)和突变型(n = 39)的BLCA全基因组研究了它对体细胞突变景观的影响。在ERCC2突变体中,体细胞突变的全基因组分布发生了显著改变,包括T[C>T]N富集、复制时间相关性改变以及CTCF-粘连素结合位点突变热点。我们利用这些改变开发了一种预测致病性 ERCC2 突变的机器学习模型,这可能有助于为 BLCA 患者的治疗提供信息。
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引用次数: 0
Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk. 具有进化特征的非编码区的罕见变异导致自闭症谱系障碍风险。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-08-14 Epub Date: 2024-07-16 DOI: 10.1016/j.xgen.2024.100609
Taehwan Shin, Janet H T Song, Michael Kosicki, Connor Kenny, Samantha G Beck, Lily Kelley, Irene Antony, Xuyu Qian, Julieta Bonacina, Frances Papandile, Dilenny Gonzalez, Julia Scotellaro, Evan M Bushinsky, Rebecca E Andersen, Eduardo Maury, Len A Pennacchio, Ryan N Doan, Christopher A Walsh

Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.

人们对非编码区在自闭症谱系障碍(ASD)病因学中的作用知之甚少。我们研究了三类非编码区:人类加速区(HARs),它在人类中显示出正选择的特征;实验验证的神经VISTA增强子(VEs);以及预测为神经增强子的保守区(CNEs)。对超过 16,600 份样本和超过 4,900 名 ASD 感测者进行的靶向和全基因组分析表明,HARs、VEs 和 CNEs 中可能存在的隐性、罕见、遗传变异对父母共享祖先的感测者的 ASD 风险有很大的影响,这富集了隐性贡献,但在单系家族结构中,即使有贡献,也是微不足道的。我们在 IL1RAPL1 附近的 HARs 以及 OTX1 和 SIM1 附近的 VEs 中发现了多个患者变异,并证明它们改变了增强子的活性。我们的研究结果表明,人类进化和进化保守的非编码区都与 ASD 风险有关,并提出了调控变化如何调节社会行为的潜在机制。
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引用次数: 0
Implications of noncoding regulatory functions in the development of insulinomas. 非编码调控功能对胰岛素瘤发展的影响。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-08-14 Epub Date: 2024-07-02 DOI: 10.1016/j.xgen.2024.100604
Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali

Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.

胰岛素瘤是由胰腺β细胞引起的罕见神经内分泌肿瘤,其特点是异常增殖和胰岛素分泌改变,导致葡萄糖稳态失调。为了揭示非编码调控区及其畸变在这些肿瘤发生中的作用,我们将表观遗传学和转录组分析与全基因组测序结合起来。结果,我们发现了与调控功能变化相关的体细胞突变。至关重要的是,这些区域会影响胰岛素分泌、肿瘤发生和表观遗传修饰基因,包括多聚酶复合体成分。染色质重塑在患者共有的胰岛素瘤选择性区域中非常明显,这些区域包含一组以 SOX17 结合基序为主的特定调控序列。此外,这些区域中有许多在β细胞中受到H3K27me3抑制,这表明肿瘤的转变涉及多聚酶靶向结构域的去抑制。我们的研究汇编了影响β细胞功能和转归的异常顺式调控元件,这些元件会影响β细胞向胰岛素瘤的发展,我们的研究还提供了一个框架来识别编码和非编码驱动突变。
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引用次数: 0
Neotelomeres and telomere-spanning chromosomal arm fusions in cancer genomes revealed by long-read sequencing. 长线程测序揭示癌症基因组中的新端粒和跨端粒染色体臂融合。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-24 DOI: 10.1016/j.xgen.2024.100588
Kar-Tong Tan, Michael K Slevin, Mitchell L Leibowitz, Max Garrity-Janger, Jidong Shan, Heng Li, Matthew Meyerson

Alterations in the structure and location of telomeres are pivotal in cancer genome evolution. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeats, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. These results provide a framework for the systematic study of telomeric repeats in cancer genomes, which could serve as a model for understanding the somatic evolution of other repetitive genomic elements.

端粒结构和位置的改变是癌症基因组进化的关键。在这里,我们应用长读程和短读程基因组测序技术来评估癌症和癌细胞系中含有端粒重复序列的结构。利用跨越端粒重复序列的长读数基因组序列,我们定义了癌细胞中端粒重复变异的四种类型:端粒添加可修复染色体断裂的新端粒、跨越端粒重复序列的染色体臂融合、新端粒融合以及端粒和中心粒重复序列相邻的近中心粒融合。这些结果为系统研究癌症基因组中的端粒重复序列提供了一个框架,可作为了解其他重复基因组元素体细胞进化的模型。
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引用次数: 0
Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank. 英国生物库中常见表型的复合杂合效应的全外显子证据。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-28 DOI: 10.1016/j.xgen.2024.100602
Frederik H Lassen, Samvida S Venkatesh, Nikolas Baya, Barney Hill, Wei Zhou, Alex Bloemendal, Benjamin M Neale, Benedikt M Kessler, Nicola Whiffin, Cecilia M Lindgren, Duncan S Palmer

The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10-7) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10-8). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.

复合杂合子(CH)变异的表型影响尚未在人群范围内进行调查。我们对英国生物库(UKBB)外显子组测序数据中的罕见变异(MAF ∼0.001%)进行了分阶段分析,以确定311种常见疾病中175,587人的隐性效应特征。共有6.5%的个体携带有可能造成损害的CH变异,其中90%的变异只有在考虑了亲缘关系、多基因性、附近的常见变异和罕见变异负担后,通过分期罕见变异(MAF -7)才能确定。如果只考虑同源性,其中只有一个变异被发现。利用纵向健康记录,我们还发现并复制了 ATP2C2 双等位基因变异与慢性阻塞性肺病(COPD)发病年龄提前之间的新型关联(p -8)。遗传阶段对基因-性状对的疾病风险有影响:ATP2C2-COPD (p = 0.000238)、FLG-哮喘 (p = 0.00205) 和 USH2A-视力障碍 (p = 0.0084)。我们展示了大规模遗传队列分期发现复合杂合子全表型后果的能力。
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引用次数: 0
Rhesus macaque as a model for sex-biased neurological diseases. 将猕猴作为研究性神经疾病的模型。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-27 DOI: 10.1016/j.xgen.2024.100585
Leticia Rodríguez-Montes, Henrik Kaessmann

Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.1 explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain.

哺乳动物普遍存在性二型现象,即同一物种的雌性和雄性之间存在差异。然而,目前还缺乏研究人类性二态表型的良好动物模型。在本期杂志中,DeCasien 等人1 探讨了猕猴作为研究人脑性双态特征模型的潜力。
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引用次数: 0
Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci. 迭代模板切换形成的反向三联体在基因组紊乱位点产生结构变异多样性。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-06-21 DOI: 10.1016/j.xgen.2024.100590
Christopher M Grochowski, Jesse D Bengtsson, Haowei Du, Mira Gandhi, Ming Yin Lun, Michele G Mehaffey, KyungHee Park, Wolfram Höps, Eva Benito, Patrick Hasenfeld, Jan O Korbel, Medhat Mahmoud, Luis F Paulin, Shalini N Jhangiani, James Paul Hwang, Sravya V Bhamidipati, Donna M Muzny, Jawid M Fatih, Richard A Gibbs, Matthew Pendleton, Eoghan Harrington, Sissel Juul, Anna Lindstrand, Fritz J Sedlazeck, Davut Pehlivan, James R Lupski, Claudia M B Carvalho

The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.

重复-三重/倒置-重复(DUP-TRP/INV-DUP)结构是一种复杂的基因组重排(CGR)。虽然它已被确定为基因组疾病和癌症基因组中重要的致病 DNA 突变特征,但其结构仍未得到解决。在这里,我们研究了 DUP-TRP/INV-DUP 的基因组结构,调查了通过阵列比较基因组杂交(aCGH)确定的 24 名患者的 DNA,在这些患者身上,我们发现了 4 个预测的结构变异(SV)单倍型中存在 4 个结构变异单倍型的证据。通过结合使用短线程基因组测序(GS)、长线程基因组测序、光学基因组图谱和单细胞 DNA 模板链测序(strand-seq),我们确定了 18 个样本的单倍型结构。结果表明,4 个样本的模板切换点是倒置重复对中核苷酸相似度为 100% 的 2.2 至 5.5 kb 的片段。这些数据提供了倒位低拷贝重复序列作为重组底物的实验证据。这种类型的 CGR 可导致多种构象在易感剂量敏感基因座中产生不同的 SV 单倍型。
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引用次数: 0
Sepsis research: Heterogeneity as a foundation rather than an afterthought. 败血症研究:异质性是基础而非事后考虑。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.xgen.2024.100608
Timothy H Ciesielski

Our understanding of sepsis has been hampered by the implicit assumption that sepsis is a homogeneous disease. In this issue of Cell Genomics, Burnham et al.1 have started to characterize the genetic variants and regulatory networks that underlie variations in the individual response to sepsis; this may eventually enable targeted intervention development.

脓毒症是一种同质性疾病,这一隐含假设阻碍了我们对脓毒症的了解。在本期的《细胞基因组学》(Cell Genomics)杂志上,Burnham 等人1 已开始描述脓毒症个体反应变异的基因变异和调控网络的特征;这可能最终有助于开发有针对性的干预措施。
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引用次数: 0
Mudskipper detects combinatorial RNA binding protein interactions in multiplexed CLIP data. Mudskipper 在多重 CLIP 数据中检测组合 RNA 结合蛋白的相互作用。
IF 11.1 Q1 CELL BIOLOGY Pub Date : 2024-07-10 Epub Date: 2024-07-01 DOI: 10.1016/j.xgen.2024.100603
Hsuanlin Her, Katherine L Rothamel, Grady G Nguyen, Evan A Boyle, Gene W Yeo

The uncovering of protein-RNA interactions enables a deeper understanding of RNA processing. Recent multiplexed crosslinking and immunoprecipitation (CLIP) technologies such as antibody-barcoded eCLIP (ABC) dramatically increase the throughput of mapping RNA binding protein (RBP) binding sites. However, multiplex CLIP datasets are multivariate, and each RBP suffers non-uniform signal-to-noise ratio. To address this, we developed Mudskipper, a versatile computational suite comprising two components: a Dirichlet multinomial mixture model to account for the multivariate nature of ABC datasets and a softmasking approach that identifies and removes non-specific protein-RNA interactions in RBPs with low signal-to-noise ratio. Mudskipper demonstrates superior precision and recall over existing tools on multiplex datasets and supports analysis of repetitive elements and small non-coding RNAs. Our findings unravel splicing outcomes and variant-associated disruptions, enabling higher-throughput investigations into diseases and regulation mediated by RBPs.

揭示蛋白质与 RNA 的相互作用有助于加深对 RNA 加工的理解。最近的多重交联和免疫沉淀(CLIP)技术,如抗体条形码 eCLIP(ABC),极大地提高了绘制 RNA 结合蛋白(RBP)结合位点的通量。然而,多重 CLIP 数据集是多变量的,每个 RBP 的信噪比不均匀。为了解决这个问题,我们开发了 Mudskipper,这是一个多功能计算套件,由两个部分组成:一个是 Dirichlet 多叉混合物模型,用于解释 ABC 数据集的多变量性质;另一个是软掩蔽方法,用于识别和去除信噪比低的 RBP 中的非特异性蛋白质-RNA 相互作用。在多重数据集上,Mudskipper 的精确度和召回率均优于现有工具,并支持对重复元素和小型非编码 RNA 的分析。我们的研究结果揭示了剪接结果和变异相关的破坏,从而能够对由 RBPs 介导的疾病和调控进行更高通量的研究。
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引用次数: 0
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Cell genomics
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