来自杂志 Nature genetics 的文献。
当前共找到 16 篇文献分享。
1.
徐炳祥
(2024-06-30 14:57):
#paper doi:10.1038/s41588-021-00784-4 Nature genetics, 2021, Liquid chromatin Hi-C characterizes compartment-dependent chromatin interaction dynamics。对染色质区室结构(chromatin compartments)的识别是三维基因组学研究的重要课题。本研究中作者基于Flory–Huggins聚合物理论预言了在染色质构象捕获实验中,检测到不同位于不同区室的染色质片段聚合倾向与片段长度和相同/不同区室片段聚合能差异之乘积成正比。在此理论指导下,作者指出实验前预先对基因组施以不同时间的酶解,进而控制片段化后染色质长度,便可在不同水平和维度检查染色质区室结构。作者发现过度预酶解可导致实验无法检测区室和染色质环结构,与核纤层关联的结构域对预酶解是稳定的,而与核斑或多数蛋白有关的结构与对预酶解是敏感的。本研究为染色质构象捕获实验的动力学提供了一个新架构,也为解释一些实验现象提供了新思路。
Abstract:
Nuclear compartmentalization of active and inactive chromatin is thought to occur through microphase separation mediated by interactions between loci of similar type. The nature and dynamics of these interactions are …
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Nuclear compartmentalization of active and inactive chromatin is thought to occur through microphase separation mediated by interactions between loci of similar type. The nature and dynamics of these interactions are not known. We developed liquid chromatin Hi-C to map the stability of associations between loci. Before fixation and Hi-C, chromosomes are fragmented, which removes strong polymeric constraint, enabling detection of intrinsic locus-locus interaction stabilities. Compartmentalization is stable when fragments are larger than 10-25 kb. Fragmentation of chromatin into pieces smaller than 6 kb leads to gradual loss of genome organization. Lamin-associated domains are most stable, whereas interactions for speckle- and polycomb-associated loci are more dynamic. Cohesin-mediated loops dissolve after fragmentation. Liquid chromatin Hi-C provides a genome-wide view of chromosome interaction dynamics.
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2.
哪有情可长
(2024-04-30 22:30):
#paper doi:https://doi.org/10.1038/s41588-024-01715-9,Nature genetics, 11 April 2024. A pan-genome of 69 Arabidopsis thaliana accessions reveals a conserved genome structure throughout the global species range. 通过对来自全球不同地理起源的 72 个拟南芥种质进行SNP分析,确定了四个主要遗传群体:“欧洲”、“非洲”、“马德拉”和“亚洲”,以及三个“混合”种质。使用了长读取(PacBio HiFi,平均深度为 45×,和牛津纳米孔,平均深度为 67×)和短读取测序,结合参考导向的拼接和手动修正,为每个 72 个种质生成了基因组组装。69 个种质经确认为纯合子品系,为了解释基因组大小变异的潜在基因组特征,选择了最完整的 46 个组装,并分析了组装与基因组大小估计的比值以及着丝粒重复长度与着丝粒大小估计的比值。这些种质的组装大小范围从 130 到 148 Mb。着丝粒重复序列平均长度为 14 Mb,与组装大小高度相关。通过从个体组装的初始 TE 注释生成的 pan-TE 库注释了转座元件。TE 空间大小在基因组之间非常相似,长末端重复序列和 Helitrons 占据了最大的 TE 分数。拟南芥基因组大小变异主要由着丝粒重复长度主导,而 TE 只是次要贡献者。单个染色体的大小独立于彼此地演化。后续作者利用共线性分析,发现拟南芥的染色体臂存在高度的同源性,而在着丝粒附近存在大型的重排现象。后续对泛基因组进行基因家族分析,发现一些核心、软核心、可选和私有家族基因。
Abstract:
Although originally primarily a system for functional biology, Arabidopsis thaliana has, owing to its broad geographical distribution and adaptation to diverse environments, developed into a powerful model in population genomics. …
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Although originally primarily a system for functional biology, Arabidopsis thaliana has, owing to its broad geographical distribution and adaptation to diverse environments, developed into a powerful model in population genomics. Here we present chromosome-level genome assemblies of 69 accessions from a global species range. We found that genomic colinearity is very conserved, even among geographically and genetically distant accessions. Along chromosome arms, megabase-scale rearrangements are rare and typically present only in a single accession. This indicates that the karyotype is quasi-fixed and that rearrangements in chromosome arms are counter-selected. Centromeric regions display higher structural dynamics, and divergences in core centromeres account for most of the genome size variations. Pan-genome analyses uncovered 32,986 distinct gene families, 60% being present in all accessions and 40% appearing to be dispensable, including 18% private to a single accession, indicating unexplored genic diversity. These 69 new Arabidopsis thaliana genome assemblies will empower future genetic research.
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3.
小年
(2024-03-31 17:31):
#paper Fehlings, D.L., Zarrei, M., Engchuan, W. et al. Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy. Nat Genet (2024). https://doi-org-443.webvpn.las.ac.cn/10.1038/s41588-024-01686-x
本文对超过320名患有脑瘩(CP)的儿童及其生物学父母进行了全基因组测序(WGS)数据分享。研究发现,11.3%的儿童存在致病/可能致病(P/LP)变异,17.7%的儿童存在不确定意义的变异。这些变异类型包括单核苷酸变异/缺失、拷贝数变异以及线粒体变异,其中COL4A1基因发现了最多的P/LP单核苷酸变异(SNVs)。此外,本项研究还将脑瘫患者与儿科对照组进行了比较,以确立新生突变率和遗传负荷分析的基准,发现新生有害变异与与神经系统相关的基因之间存在关联。本篇文章强调,脑瘫是最常见的儿童起始期身体残疾,经常伴随认知和行为障碍等额外发展影响。研究突显了遗传因素对脑瘫的重要影响,尤其是在没有明显产前、产时或产后病理因素、足月出生以及脑部影像学正常的情况下。研究强调了脑瘫的多因素本质,涉及遗传变异与环境因素的复杂交互作用。该研究的结果支持在脑瘫的诊断流程中引入全基因组测序,以识别包括罕见变异和线粒体变异在内的广泛遗传变异。同时表明,遗传测试有助于深入了解脑瘫的病因,改善家庭咨询,并指导针对性治疗。
Abstract:
We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and …
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We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.
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4.
哪有情可长
(2024-02-29 21:01):
#paper A quantitative genomics map of rice provides genetic insights and guides breeding, Nature genetics,01 February 2021, doi.org/10.1038/s41588-020-00769-9. 这篇文章先收集水稻中各种性状前人已经定位的QTL,对QTL区间内的关键功能变异位点锚定到水稻基因组精确的位置上,获取了一个包含348个变异位点和562个等位基因的分子图谱(QTN)。然后对另外收集的404份种质材料,构建包含前面鉴定的等位基因的数据库,方便后人进行遗传改良过程亲本的选择。作者有对基因变异的遗传效应进行评估,来鉴定变异位点的效应方向和量化变化的强弱关系。利用水稻QTN图谱和遗传图,论文作者系统分析了水稻基因组中存在的遗传累赘,并针对杂交-回交-自交、群体样本量、导入位点数等各类情形进行了大数据仿真模拟,获得了育种设计路线的优化参数。这篇文章对我与现在处理大量的小麦GWAS得到的显著的SNP位点,如何进行量化管理,形成对育种家有用的数据很有启发。
Abstract:
Extensive allelic variation in agronomically important genes serves as the basis of rice breeding. Here, we present a comprehensive map of rice quantitative trait nucleotides (QTNs) and inferred QTN effects …
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Extensive allelic variation in agronomically important genes serves as the basis of rice breeding. Here, we present a comprehensive map of rice quantitative trait nucleotides (QTNs) and inferred QTN effects based on eight genome-wide association study cohorts. Population genetic analyses revealed that domestication, local adaptation and heterosis are all associated with QTN allele frequency changes. A genome navigation system, RiceNavi, was developed for QTN pyramiding and breeding route optimization, and implemented in the improvement of a widely cultivated indica variety. This work presents an efficient platform that bridges ever-increasing genomic knowledge and diverse improvement needs in rice.
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5.
小年
(2024-02-29 10:51):
Choo, ZN., Behr, J.M., Deshpande, A. et al. Most large structural variants in cancer genomes can be detected without long reads. Nat Genet 55, 2139–2148 (2023). https://doi-org-443.webvpn.las.ac.cn/10.1038/s41588-023-01540-6
短读测序(SRS)普遍应用于癌症基因组学研究,但SRS对于检测癌症结构变异(SVs,包括拷贝数改变和重排)的灵敏度有限,特别是大型染色体结构改变,这是因为人类基因组中有许多同源序列。本研究分析了短读全基因组中的“松散末端”——相邻DNA片段之间质量平衡的局部违反,用于检测短读测序遗漏的SVs。作者在1,330个高纯度癌症全基因组的松散末端景观中,发现大多数大于10kb的克隆SVs在人类基因组87%的区域内可以被短读测序完全解析,并且可以准确检测拷贝数。值得注意的是,一些松散末端代表新端粒,可将其作为替代性端粒延长表型的标志,以上发现通过还38例乳腺癌和黑色素瘤病例的长读长测序得到验证。本项研究的结果表明,异常同源重组不太可能驱动大多数大型癌症SVs,总得来说,全基因组SRS数据中的质量平衡分析提供了癌症染色体结构的一个出人意料的完整景象。("松散末端"是指那些在短读测序数据中没有找到匹配的断点末端。这些末端可能是因为基因组重排事件而产生的,这些事件将本不相连的DNA片段的末端连接在一起,形成了新的结合点)
Abstract:
Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we …
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Short-read sequencing is the workhorse of cancer genomics yet is thought to miss many structural variants (SVs), particularly large chromosomal alterations. To characterize missing SVs in short-read whole genomes, we analyzed 'loose ends'-local violations of mass balance between adjacent DNA segments. In the landscape of loose ends across 1,330 high-purity cancer whole genomes, most large (>10-kb) clonal SVs were fully resolved by short reads in the 87% of the human genome where copy number could be reliably measured. Some loose ends represent neotelomeres, which we propose as a hallmark of the alternative lengthening of telomeres phenotype. These pan-cancer findings were confirmed by long-molecule profiles of 38 breast cancer and melanoma cases. Our results indicate that aberrant homologous recombination is unlikely to drive the majority of large cancer SVs. Furthermore, analysis of mass balance in short-read whole genome data provides a surprisingly complete picture of cancer chromosomal structure.
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6.
小年
(2024-01-31 19:56):
#paper Feng, Y., Xie, N., Inoue, F. et al. Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans. Nat Genet (2024). https://doi.org/10.1038/s41588-023-01626-1.
肤色是人类群体间一个显著的差异性状,具有高度遗传性的复杂性状,受到数百个基因位点的影响,其遗传基础尚未完全阐明。本篇文章作者采用了综合的功能基因组学分析方法,揭示了影响非洲人群肤色的遗传变异。该研究团队通过全基因组关联分析(GWAS)和自然选择扫描,鉴定了与肤色相关的单核苷酸多态性(SNP),利用大规模平行报告基因检测技术(MPRA),他们测试了这些SNP的调控活性。作者进一步使用 Hi-C 和 H3K27ac HiChIP 技术,构建了高分辨率的染色质相互作用图谱,以确定这些SNP的潜在靶基因。该研究通过荧光素酶报告基因检测、CRISPR基因编辑、转录组分析和黑色素丰度检测等技术,发现MITF 附近的 rs111969762、LEF1 附近的 rs17038630 和 TRPS1 附近的 rs11985280,这三个Di-SNP均能显著影响增强子活性及其靶基因的表达,可能对桑人皮肤色素的适应性进化发挥了作用。总得来说,本项研究发现了多个新的影响黑色素细胞中黑色素水平的新基因,这些发现有助于深入理解人类肤色的遗传机制,并为研究其他复杂性状的遗传因素提供了有价值的方法论。
IF:31.700Q1
Nature genetics,
2024-Feb.
DOI: 10.1038/s41588-023-01626-1
PMID: 38200130
PMCID:PMC11005318
Abstract:
Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin …
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Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. Here we applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin pigmentation in Africans and identified 165 single-nucleotide polymorphisms showing differential regulatory activities between alleles. We combine Hi-C, genome editing and melanin assays to identify regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6 and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1, which may contribute to the light skin color of Khoesan-speaking populations from Southern Africa. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.
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7.
徐炳祥
(2024-01-31 09:45):
#paper doi: 10.1038/s41588-020-00712-y Nature Genetics, 2020, CHESS enables quantitative comparison of chromatin contact data and automatic feature extraction。本文介绍了一种基于计算机视觉中结构相似度(SSIM)的Hi-C数据相似度度量和结构变化区域的搜索算法,通过在基因组上进行滑窗计算,该算法不仅能基于Hi-C数据计算出两个样品在全基因组水平下染色质空间构象的相似程度,更能通过局部计算寻找出存在显著染色质空间构象变异的区域。该算法不仅可以进行同一物种内的比较,也可以进行跨物种比较。且对测序深度不敏感。本文将计算机视觉中的很多降噪/特征提取/形态学处理技术引入到了Hi-C相互作用图谱的处理中,对计算机上视觉技术在染色质空间构象数据的分析中的应用有重要参考价值。
Abstract:
Dynamic changes in the three-dimensional (3D) organization of chromatin are associated with central biological processes, such as transcription, replication and development. Therefore, the comprehensive identification and quantification of these changes …
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Dynamic changes in the three-dimensional (3D) organization of chromatin are associated with central biological processes, such as transcription, replication and development. Therefore, the comprehensive identification and quantification of these changes is fundamental to understanding of evolutionary and regulatory mechanisms. Here, we present Comparison of Hi-C Experiments using Structural Similarity (CHESS), an algorithm for the comparison of chromatin contact maps and automatic differential feature extraction. We demonstrate the robustness of CHESS to experimental variability and showcase its biological applications on (1) interspecies comparisons of syntenic regions in human and mouse models; (2) intraspecies identification of conformational changes in Zelda-depleted Drosophila embryos; (3) patient-specific aberrant chromatin conformation in a diffuse large B-cell lymphoma sample; and (4) the systematic identification of chromatin contact differences in high-resolution Capture-C data. In summary, CHESS is a computationally efficient method for the comparison and classification of changes in chromatin contact data.
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8.
颜林林
(2023-07-25 00:17):
#paper doi:10.1038/s41588-023-01452-5. Nature Genetics, 2023, Crosstalk between RNA m6A and DNA methylation regulates transposable element chromatin activation and cell fate in human pluripotent stem cells. 这篇文章开发了一种名为CARGO-BioID的方法,基于CRISPR技术 和 蛋白质邻位连接技术(Proximity Ligation Assay,PLA),能够抓取与基因组上特定转座元件(Transposable elements,TEs)区域序列相结合的蛋白,并通过质谱和ChIP-seq等实验,对这些蛋白进行鉴定和定量检测。文章以LTR7/HRV-H为目标,这是个灵长目特有的TE序列,通过上述技术方法,识别出与之结合的蛋白,其中包括 YTHDC2 和 TET1 这两个蛋白,前者是RNA m6A甲基化的读取器(reader),后者则是DNA 5mC甲基化的去甲基酶。随后,文章又利用一系列细胞实验,证实了这两个蛋白在该基因组区域上的生物学作用,包括相应的RNA甲基化与DNA甲基化之间的相互作用(crosstalk)、它们对TE活性的调控、以及对hPSC(人多能干细胞)分化命运的影响等。
Abstract:
Transposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, …
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Transposable elements (TEs) are parasitic DNA sequences accounting for over half of the human genome. Tight control of the repression and activation states of TEs is critical for genome integrity, development, immunity and diseases, including cancer. However, precisely how this regulation is achieved remains unclear. Here we develop a targeted proteomic proximity labeling approach to capture TE-associated proteins in human embryonic stem cells (hESCs). We find that the RNA N-methyladenosine (mA) reader, YTHDC2, occupies genomic loci of the primate-specific TE, LTR7/HERV-H, specifically through its interaction with mA-modified HERV-H RNAs. Unexpectedly, YTHDC2 recruits the DNA 5-methylcytosine (5mC)-demethylase, TET1, to remove 5mC from LTR7/HERV-H and prevent epigenetic silencing. Functionally, the YTHDC2/LTR7 axis inhibits neural differentiation of hESCs. Our results reveal both an underappreciated crosstalk between RNA mA and DNA 5mC, the most abundant regulatory modifications of RNA and DNA in eukaryotes, and the fact that in hESCs this interplay controls TE activity and cell fate.
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9.
惊鸿
(2023-03-27 11:42):
#paper doi:https://ma.x-mol.com/paperRedirect/1639426668090503168 Thymidine nucleotide metabolism controls human telomere length
人类的端粒长度与寿命和严重疾病有关,但端粒长度的遗传决定因素仍未完全确定。在这里,我们进行了全基因组 CRISPR-Cas9 功能性端粒长度筛选,并将胸苷 (dT) 核苷酸代谢确定为人类端粒维持的限制因素。使用 CRISPR-Cas9 的靶向基因破坏揭示了胸苷核苷酸代谢途径中的多个端粒长度控制点:通过删除编码核胸苷激酶 ( TK1 ) 的基因减少 dT 核苷酸回收或通过敲除胸苷酸合酶基因 (TYMS )从头产生端粒长度减少,而脱氧核苷三磷酸水解酶编码基因SAMHD1失活延长的端粒。值得注意的是,单独补充 dT 可通过细胞中的端粒酶驱动端粒的稳健延伸,并且三磷酸胸苷在体外以底物非依赖性方式刺激端粒酶活性。在源自遗传性端粒生物学障碍患者的诱导多能干细胞中,补充 dT 或抑制SAMHD1可促进端粒恢复。我们的结果表明胸苷代谢在控制人端粒酶和端粒长度方面的关键作用,这可能对致命的退行性疾病患者具有治疗作用。
Abstract:
Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR-Cas9 functional telomere length screening …
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Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR-Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR-Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.
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10.
哪有情可长
(2023-01-31 19:16):
#paper # De novo genome assembly and analyses of 12 founder inbred lines provide insights into maize heterosis, Nature Genetics,16 January 2023,doi.org/10.1038/s41588-022-01283-w.玉米是三大粮食作物中杂种优势研究最多的物种,只是证明玉米存在杂种优势,但是关于对不同的育种目标对父母本的选择还没有文章说明,所以作者想对现在的骨干亲本组装想鉴定发现前人杂种优势形成的缘由。作者首先通过进化树分析对现在玉米常用的350自交系进行分析,对进化树每个分支上选取目前世界范围内广泛使用的12个骨干自交系,通过三代测序组装高质量基因组,同时结合玉米中之前已经发表的B73和Mo17基因组,构建了温带玉米核心育种种质泛基因组。作者对14个材料之间进行基因组比较分析发现存在广泛的遗传变异,通过对对玉米中现在 常用的自交系350份对花期、穗行数、穗粒数等表型进行鉴定和关键基因的单倍型分析,发现结构变异对杂种有事的形成和表型分化具有重要的贡献。通过对131份自交系雌穗的转录组数据分析,鉴定到306,868个调控基因表达的顺式eQTL,并挖掘到了一批调控玉米雄穗分枝数、穗位高及穗腐病抗性相关的候选基因及其关键结构变异;进一步结合14 个自交系的双列杂交群体 (91个F1)及3个环境的表型数据分析发现,玉米杂种优势与双亲基因组间结构变异的数量呈显著正相关,而与双亲基因组间共线性程度呈显著负相关,说明玉米杂种优势与双亲在全基因组水平的遗传互补性密切相关,为杂种优势的遗传互补模型提供了强有力的支持。同时结合遗传和分子生物学证据,挖掘到了ZmACO2 (编码一个乙烯合成酶)和ARGOS1 (ZAR1, 编码一个乙烯信号传导相关蛋白) 2个关键产量杂种优势位点,证明了其以超显性效应发挥作用。
Abstract:
Hybrid maize displays superior heterosis and contributes over 30% of total worldwide cereal production. However, the molecular mechanisms of heterosis remain obscure. Here we show that structural variants (SVs) between …
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Hybrid maize displays superior heterosis and contributes over 30% of total worldwide cereal production. However, the molecular mechanisms of heterosis remain obscure. Here we show that structural variants (SVs) between the parental lines have a predominant role underpinning maize heterosis. De novo assembly and analyses of 12 maize founder inbred lines (FILs) reveal abundant genetic variations among these FILs and, through expression quantitative trait loci and association analyses, we identify several SVs contributing to genomic and phenotypic differentiations of various heterotic groups. Using a set of 91 diallel-cross F hybrids, we found strong positive correlations between better-parent heterosis of the F hybrids and the numbers of SVs between the parental lines, providing concrete genomic support for a prevalent role of genetic complementation underlying heterosis. Further, we document evidence that SVs in both ZAR1 and ZmACO2 contribute to yield heterosis in an overdominance fashion. Our results should promote genomics-based breeding of hybrid maize.
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11.
徐炳祥
(2023-01-06 22:21):
#paper doi: 10.1038/s41588-022-01223-8 Nature, 2022, Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1。染色质空间构象对基因表达的调控模式目前依然是表观遗传学中一个有争议的话题,在本文中,作者快速降解了几个维持与调控染色质空间构象的重要因子(CTCF,cohesin,YY1)并测量了他们对染色质空间构象和基因表达谱的冲击。结果显示降解这些因子主要影响结构性染色质环,对启动子-启动子环或启动子-增强子环的影响有限,降解也不大范围改变基因表达谱。进一步,作者通过活细胞成像技术对YY1的结合动态进行了追踪,论证了YY1与DNA的结合是动态的且大部分YY1处于游离状态。进一步,作者论证了cohesin的敲除影响YY1的结合位点识别效率。本文中以下两个观点是值得注意的:1. 启动子-启动子环/启动子-增强子环与连接TAD边界的结构性染色质环的形成机理/对基因表达谱的影响是不同的;2. Cohesin敲除不仅直接破坏染色质构象,且可通过影响YY1的结合效率发挥间接作用,类似多效性机制也可能出现在其他因子上。
Abstract:
It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression of most genes despite substantially perturbing three-dimensional (3D) genome folding at the level of …
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It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression of most genes despite substantially perturbing three-dimensional (3D) genome folding at the level of domains and structural loops. To address this conundrum, we used high-resolution Micro-C and nascent transcript profiling in mouse embryonic stem cells. We find that enhancer-promoter (E-P) interactions are largely insensitive to acute (3-h) depletion of CTCF, cohesin or WAPL. YY1 has been proposed as a structural regulator of E-P loops, but acute YY1 depletion also had minimal effects on E-P loops, transcription and 3D genome folding. Strikingly, live-cell, single-molecule imaging revealed that cohesin depletion reduced transcription factor (TF) binding to chromatin. Thus, although CTCF, cohesin, WAPL or YY1 is not required for the short-term maintenance of most E-P interactions and gene expression, our results suggest that cohesin may facilitate TFs to search for and bind their targets more efficiently.
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12.
哪有情可长
(2022-10-26 20:33):
#paper doi:#paper doi:doi:10.1038/ng.592, OsSPL14 promotes panicle branching and higher grainproductivity in rice.作物产量三要素主要是亩穗数、穗粒数和千粒重。提高产量主要是提高三要素之间的协同作用。水稻的第二次“绿色革命”是通过降低株高来增加了水稻的产量。而现在有人认为在水稻中IPA这个基因是新型的"绿色革命"基因。该基因能够能够在水稻的生殖期通过在水稻幼穗内高表达促进水稻穗分枝和籽粒产量。小麦中关于SBP蛋白的研究有很多,通过同源blast,在小麦中也鉴定到了IPA的同源基因。文章在2017年发表在《Plant Physiology》“Functional conservation and divergence among homoeologs of TaSPL20 and TaSPL21, two SBP-box genes governing yield-related traits in hexaploid wheat”,作者发现普通小麦部分同源基因TaSPL20和TaSPL21在小麦长期的驯化和遗传改良过程中产生功能分化,其优异的自然变异在我国小麦育种进程中受到了定向选择并被广泛应用,但是这个文中中验证基因由于当初小麦转基因比较难,文中中验证是在水稻中进行的,证明该基因增加了籽粒大小,从而增加了产量。如果是在小麦中验证会更好。
Abstract:
Identification of alleles that improve crop production and lead to higher-yielding varieties are needed for food security. Here we show that the quantitative trait locus WFP (WEALTHY FARMER'S PANICLE) encodes …
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Identification of alleles that improve crop production and lead to higher-yielding varieties are needed for food security. Here we show that the quantitative trait locus WFP (WEALTHY FARMER'S PANICLE) encodes OsSPL14 (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 14, also known as IPA1). Higher expression of OsSPL14 in the reproductive stage promotes panicle branching and higher grain yield in rice. OsSPL14 controls shoot branching in the vegetative stage and is affected by microRNA excision. We also demonstrate the feasibility of using the OsSLP14(WFP) allele to increase rice crop yield. Introduction of the high-yielding OsSPL14(WFP) allele into the standard rice variety Nipponbare resulted in increased rice production.
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13.
小年
(2022-07-31 16:40):
#paper doi:10.1038/ng.3972
The draft genome of tropical fruit durian (Durio zibethinus)
这是一篇癌症研究所,发表在2017年的Nature Genetics上的关于榴莲(品种是猫山王)基因组组装草图的文章。(不务正业)文章介绍了拼接方法和组装完整性与正确性验证的思路,有一定的参考意义。
文章还用转录组测序,将猫山王、金枕和小猫山王三个品种,与其他水果做了RNA测序,通过富集分析差异比较,发现了榴莲与其他水果气味差异的途径,同时也分析了不同榴莲品种之间味道和气味差异的控制途径,以及连个基因组与转录组分析表明榴莲气味与果实成熟之间存在潜在关联。
看完这个我就在想还有哪些贵的水果还没测基因组的
Abstract:
Durian (Durio zibethinus) is a Southeast Asian tropical plant known for its hefty, spine-covered fruit and sulfury and onion-like odor. Here we present a draft genome assembly of D. zibethinus, …
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Durian (Durio zibethinus) is a Southeast Asian tropical plant known for its hefty, spine-covered fruit and sulfury and onion-like odor. Here we present a draft genome assembly of D. zibethinus, representing the third plant genus in the Malvales order and first in the Helicteroideae subfamily to be sequenced. Single-molecule sequencing and chromosome contact maps enabled assembly of the highly heterozygous durian genome at chromosome-scale resolution. Transcriptomic analysis showed upregulation of sulfur-, ethylene-, and lipid-related pathways in durian fruits. We observed paleopolyploidization events shared by durian and cotton and durian-specific gene expansions in MGL (methionine γ-lyase), associated with production of volatile sulfur compounds (VSCs). MGL and the ethylene-related gene ACS (aminocyclopropane-1-carboxylic acid synthase) were upregulated in fruits concomitantly with their downstream metabolites (VSCs and ethylene), suggesting a potential association between ethylene biosynthesis and methionine regeneration via the Yang cycle. The durian genome provides a resource for tropical fruit biology and agronomy.
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14.
翁凯
(2022-06-30 22:15):
#paper 10.1038/s41588-018-0129-5。Nature Genetics。2018。Genetic identification of brain cell types underlying schizophrenia。貌似是第一批利用单细胞转录组来定位遗传学研究积累的候选致病基因富集在哪些细胞类型。这有利于进行更细致的机制研究。
IF:31.700Q1
Nature genetics,
2018-06.
DOI: 10.1038/s41588-018-0129-5
PMID: 29785013
PMCID:PMC6477180
Abstract:
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying …
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With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.
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除了少数例外,关于精神分裂症遗传基础的知识的显着进展并没有集中在可以自信地用于精确实验建模的发现上。通过应用来自单细胞RNA测序的大脑细胞分类学知识,我们评估了与精神分裂症有关的基因组位点是否映射到特定的脑细胞类型。我们发现,常见变异的基因组结果一致地映射到锥体细胞、中棘神经元(MSN)和某些中间神经元,但对胚胎细胞、祖细胞或神经胶质细胞的一致性要低得多。这些富集是由于在这些细胞类型中的每一种中特异性表达的基因集造成的。我们还发现,许多以前与精神分裂症相关的不同基因集(参与突触功能的基因,编码与FMRP相互作用的mRNA,抗精神病靶点等)通常与相同的脑细胞类型有关。我们的研究结果提出了一个简洁的解释:精神分裂症的常见变异遗传结果指向有限的神经元集,而基因集指向相同的细胞。与MSNs相关的遗传风险与谷氨酸能锥体细胞和中间神经元的遗传风险没有重叠,这表明不同的细胞类型在精神分裂症中具有生物学上不同的作用。
15.
颜林林
(2022-06-16 00:40):
#paper doi:10.1038/s41588-022-01075-2 Nature Genetics, 2022, Allelic imbalance of chromatin accessibility in cancer identifies candidate causal risk variants and their mechanisms. 这又是一篇只有两位作者署名的论文。如今,司空见惯了一篇文章动辄好几十位甚至成百上千位作者的情况,见到这类一两位作者“单打独斗”的作品,还是挺佩服的。从这篇文章,我学到个新词“调节组(regulome)”;相应地,其关联分析方法,被称为“regulome-wide associations study (RWAS)”。这篇文章还有个特点,它并未通过湿实验产出新数据,而是完全使用公开数据进行分析,包括结果验证,也是在公共数据库中进行。从概念到方法上进行创新,而成果发表到Nature子刊上,挺值得学习的。作者使用了来自TCGA的406例ATAC-seq数据,涵盖23个不同癌种,识别出7262个胚系allele-specific accessibility QTLs (as-aQTLs),即把染色质开放程度当做一种数量性状来研究,这个aQTL也是仿照eQTL提出的概念,的确很有意思。而通过RWAS,在各个癌种中鉴别出与癌症发生风险相关的as-aQTL位点,且发现它们在癌症风险遗传力方面的富集度甚至优于其他功能注释。这不仅实现了对非编码的“垃圾DNA(junk DNA)”区间的功能研究和解释,也开辟了肿瘤治疗的新思路,即针对这些调控区间及其相关机制来开展治疗。
Abstract:
While many germline cancer risk variants have been identified through genome-wide association studies (GWAS), the mechanisms by which these variants operate remain largely unknown. Here we used 406 cancer ATAC-Seq …
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While many germline cancer risk variants have been identified through genome-wide association studies (GWAS), the mechanisms by which these variants operate remain largely unknown. Here we used 406 cancer ATAC-Seq samples across 23 cancer types to identify 7,262 germline allele-specific accessibility QTLs (as-aQTLs). Cancer as-aQTLs had stronger enrichment for cancer risk heritability (up to 145 fold) than any other functional annotation across seven cancer GWAS. Most cancer as-aQTLs directly altered transcription factor (TF) motifs and exhibited differential TF binding and gene expression in functional screens. To connect as-aQTLs to putative risk mechanisms, we introduced the regulome-wide associations study (RWAS). RWAS identified genetically associated accessible peaks at >70% of known breast and prostate loci and discovered new risk loci in all examined cancer types. Integrating as-aQTL discovery, motif analysis and RWAS identified candidate causal regulatory elements and their probable upstream regulators. Our work establishes cancer as-aQTLs and RWAS analysis as powerful tools to study the genetic architecture of cancer risk.
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16.
颜林林
(2022-06-13 05:47):
#paper doi:10.1038/s41588-022-01082-3 Nature Genetics, 2022, Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer. 本文研究导管原位癌(DCIS)。该疾病常见于乳腺癌筛查,即使经过治疗,也仍然有小部分患者会恶化复发成为浸润性乳腺癌。本文试图研究,恶化的这些患者,是否都来自原发性DCIS的复发克隆,亦或仅是新发的无关疾病。为此,本研究纳入了129对DCIS复发病例样本(即原位DCIS样本和复发样本;同时也包含匹配的癌旁对照组织),通过开展全外显子组测序、SNP芯片检测或靶向基因组panel测序(这里技术平台方法存在差别,是因为样本及其实验,分别来自和开展于荷兰、英国和美国的三家不同单位),进行基因组突变分析和拷贝数变异分析。同时也从中选取了4例病例,将其原发与复发组织,分别进行解离并开展单细胞基因组测序。针对这两种策略,都分别进行了克隆演化分析,最终确认并非所有同侧浸润性乳腺癌都与先前的 DCIS 有克隆相关性,其中有约五分之一其实为新发原发性癌症。此结果也在更大范围且更详细的程度上,验证了前人的研究结果。
Abstract:
Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental …
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Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.
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