Articles Online (Volume 15, Issue 1)


A Piece of History that Cannot Be Missed for Precision Medicine

Jun Yu

Page 1-2

Historical Note

A Behind-the-Scenes Story of Precision Medicine

Maynard V. Olson

Page 3-10


GSA and BIGD: Filling the Gap of Bioinformatics Resource and Service in China

Jingchu Luo

Page 11-13


GSA: Genome Sequence Archive

Yanqing Wang, Fuhai Song, Junwei Zhu, Sisi Zhang, Yadong Yang, Tingting Chen, Bixia Tang, Lili Dong, Nan Ding, Qian Zhang, Zhouxian Bai, Xunong Dong, Huanxin Chen, Mingyuan Sun, Shuang Zhai, Yubin Sun, Lei Yu, Li Lan, Jingfa Xiao, Xiangdong Fang, Hongxing Lei, Zhang Zhang, Wenming Zhao

With the rapid development of sequencing technologies towards higher throughput and lower cost, sequence data are generated at an unprecedentedly explosive rate. To provide an efficient and easy-to-use platform for managing huge sequence data, here we present Genome Sequence Archive (GSA; or, a data repository for archiving raw sequence data. In compliance with data standards and structures of the International Nucleotide Sequence Database Collaboration (INSDC), GSA adopts four data objects (BioProject, BioSample, Experiment, and Run) for data organization, accepts raw sequence reads produced by a variety of sequencing platforms, stores both sequence reads and metadata submitted from all over the world, and makes all these data publicly available to worldwide scientific communities. In the era of big data, GSA is not only an important complement to existing INSDC members by alleviating the increasing burdens of handling sequence data deluge, but also takes the significant responsibility for global big data archive and provides free unrestricted access to all publicly available data in support of research activities throughout the world.
随着测序技术和测序产业的高速发展,生命科学研究过程中产出的海量组学数据已成为重要的数据资源,国际上NCBI、EBI、DDBJ已建立起相应的数据管理体系,但中国至今尚未形成统一的组学大数据管理。中国科学院北京基因组研究所自主开发的组学原始数据汇交、存储、管理与共享系统——组学原始数据归档库(Genome Sequence Archive, GSA),立足中国,面向全球接收不同测序平台产生的组学原始数据并提供数据长期存储、管理与共享服务。GSA遵循国际核酸数据库联盟(INSDC)的数据库建设标准,为用户提供便捷、安全的预审稿链接和超大规模数据的个性化递交服务。自2015年11月上线以来,GSA系统已相继获得PNAS、Genome Research、AJHG等多个国际期刊认可,并获得领域内同行广泛支持与好评。未来,GSA系统将着眼国家精准医学和重要战略生物资源,为国家重大科研部署提供数据与平台支持。

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Lysine Acetylation and Deacetylation in Brain Development and Neuropathies

Alicia Tapias, Zhao-Qi Wang

Embryonic development is critical for the final functionality and maintenance of the adult brain. Brain development is tightly regulated by intracellular and extracellular signaling. Lysine acetylation and deacetylation are posttranslational modifications that are able to link extracellular signals to intracellular responses. A wealth of evidence indicates that lysine acetylation and deacetylation are critical for brain development and functionality. Indeed, mutations of the enzymes and cofactors responsible for these processes are often associated with neurodevelopmental and psychiatric disorders. Lysine acetylation and deacetylation are involved in all levels of brain development, starting from neuroprogenitor survival and proliferation, cell fate decisions, neuronal maturation, migration, and synaptogenesis, as well as differentiation and maturation of astrocytes and oligodendrocytes, to the establishment of neuronal circuits. Hence, fluctuations in the balance between lysine acetylation and deacetylation contribute to the final shape and performance of the brain. In this review, we summarize the current basic knowledge on the specific roles of lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) complexes in brain development and the different neurodevelopmental disorders that are associated with dysfunctional lysine (de)acetylation machineries.
胚胎期大脑的发育过程对于成体大脑的维持和功能有着至关重要的影响。大脑的发育受到细胞外和细胞内信号传导通路紧密调节。蛋白赖氨酸乙酰化是一种常见翻译后修饰,其作用可连接细胞外信号与细胞内应答通路。大量的实验数据显示,催化赖氨酸乙酰化/脱乙酰化过程的主要酶或其辅因子的突变,通常与神经发育障碍和神经性疾病关联,表明赖氨酸乙酰化/脱乙酰化在调控大脑发育和功能方面起着非常重要作用。赖氨酸乙酰化/脱乙酰化参与了大脑发育的各个过程,包括神经母细胞(neuroprogenitors)的存活,增殖, 及其命运的决定,神经元迁移和成熟,以及星形胶质细胞和少突胶质细胞的分化和成熟,突触和神经元回路的建立等。由此,调节赖氨酸乙酰化和脱乙酰化之间的平衡,将影响大脑的最终形态和性能。本综述着重介绍当前有关蛋白赖氨酸乙酰转移酶(KAT)和脱乙酰酶(KDAC)复合物在大脑发育中的特异作用,并总结与赖氨酸(脱)乙酰化功能失调相关的各种神经发育障碍疾病。
Die embryonale Entwicklung ist essentiell für die spätere Funktionalität und Erhaltung des Gehirns im Erwachsenenalter. Dabei ist die Entwicklung des Gehirns durch intra- und extrazelluläre Signalwege streng kontrolliert. Lysinacetylierungen und -deacetylierungen sind posttranslationale Modifikationen die in der Lage sind, extrazelluläre Signale mit intrazellulären Antworten zu verknüpfen. Zahlreiche Hinweise legen nahe, dass Lysinacetylierungen und -deacetylierungen von großer Bedeutung für die Gehirnentwicklung und -funktionalität sind. Mutationen dieser Enzyme und der beteiligten Kofaktoren die diese Modifikationen vermitteln, sind häufig mit Störungen der neuronalen Entwicklung und psychischen Erkrankungen assoziiert. Lysinacetylierungen und -deacetylierungen sind an allen Ebenen der Gehirnentwicklung, beginnend mit dem Überleben und Wachstum von Neuroprogenitorzellen, der Entscheidung über das Schicksal der Zellen, über die neuronale Reifung und Migration, der Differenzierung und Reifung von Astrozyten und Oligodendrozyten, hin zur Etablierung von Synapsen und neuronalen Schaltkreisen, beteiligt. Daher tragen Veränderungen des Gleichgewichts zwischen Lysinacetylierungen und -deacetylierungen zum endgültigen Gesamtzustand und Leistung des Gehirns bei. Dieser Review konzentriert sich auf das gegenwärtige Wissen über die speziellen Funktionen von Lysinacetyltransferase (KAT) und Lysindeacetylase (KDAC) Komplexen während der Gehirnentwicklung und darüber hinaus auf unterschiedliche Störungen während der neuronalen Entwicklung, die mit Fehlfunktionen der Lysin(de)acetylierungsmaschinerie in Zusammenhang stehen.

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Original Research

Transcriptome Analysis of Monozygotic Twin Brothers with Childhood Primary Myelofibrosis

Nan Ding, Zhaojun Zhang, Wenyu Yang, Lan Ren, Yingchi Zhang, Jingliao Zhang, Zhanqi Li, Peihong Zhang, Xiaofan Zhu, Xiaojuan Chen, Xiangdong Fang

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following the same treatment regimen. The transcriptomic profiles of patient samples after drug treatment (E2 and Y2) were significantly different between the twin pair, which is consistent with the observation that the drug treatment was effective only in the younger brother, despite the twin being genetically identical. Bioinformatics analysis of the drug-responsive genes showed that the JAK-STAT pathway was activated in the cured younger brother, which is opposite to the pathway inhibition observed in adult PMF cases following treatment. Moreover, apoptosis and cell cycle processes were both significantly influenced by drug treatment in the sample of younger brother (Y2), implying their potential association with the pathogenesis of childhood PMF. Gene mutations in JAK2, MPL, or CALR were not observed; however, mutations in genes including SRSF2 and SF3B1 occurred in this twin pair with childhood PMF. Gene fusion events were extensively screened in the twin pair samples and the occurrence of IGLV2-14-IGLL5 gene fusion was confirmed. The current study reported at transcriptomic level the different responses of monozygotic twin brothers with childhood PMF to the same androgen/prednisone treatment regimen providing new insights into the potential pathogenesis of childhood PMF for further research and clinical applications.
原发性骨髓纤维化(Primary Myelofibrosis, PMF),是一种慢性骨髓增生性疾病,也是BCR-ABL1阴性骨髓增殖性肿瘤(Myeloproliferative Neoplasm, MPN)最严重的一种亚型。临床上主要表现为骨髓中巨核细胞和粒细胞显著增生,反应性纤维结缔组织沉积,伴髓外造血,大多数患者出现贫血、脾脏肿大或者发热、乏力、盗汗、消瘦、骨痛等全身症状,随着疾病进展出现髓外造血,最终发展为骨髓衰竭或转化为急性髓系白血病而死亡。 PMF在MPNs中预后最差,中位生存期约5年。有超过50%的成人PMF患者在JAK2,MPL或CALR基因中产生突变,这些基因的突变被认为可直接或间接激活JAK-STAT通路。然而,这些基因突变很少在儿童中检测到,表明儿童PMF发病机理与成人存在差异。 本文是关于一对同卵双胞胎儿童PMF患者治疗前后骨髓样本的转录组学研究。其中,经司坦唑醇和泼尼松药物治疗后,弟弟临床表现明显好转(29个月已痊愈),但该药物对哥哥却几乎不起作用,双胞胎患儿的临床指征与转录组图谱特征截然不同。通过转录组分析发现,治愈PMF患儿的药物响应基因主要涉及细胞凋亡、细胞周期以及红系造血等生物过程,表明这些过程可能与儿童PMF发病机理有关。同时,结果显示治愈患儿的JAK-STAT通路被激活,这与以往治愈成人PMF病例中报导的JAK-STAT途径被抑制明显不同。本研究还从转录组数据中鉴定了新的融合基因(如IGLV2-14-IGLL5),以及SRSF2和SF3B1的基因突变,并已在临床样本中进行了验证。这些致病因素与儿童PMF发病的关系,以及如何导致PMF发病等的分子机制还有待于研究。 总之,本研究提供了一对罕见儿童PMF同卵双胞胎病例分析结果与转录组数据信息,为后续进一步探讨儿童PMF发病机制、药物治疗反应等提供了重要的研究模型与参考信息。

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Characterization of Leaf Transcriptome in Banksia hookeriana

Sim Lin Lim, Haylee M. D'Agui, Neal J. Enright, Tianhua He

Banksia is a significant element in vegetation of southwestern Australia, a biodiversity hotspot with global significance. In particular, Banksia hookeriana represents a species with significant economic and ecological importance in the region. For better conservation and management, we reported an overview of transcriptome of B. hookeriana using RNA-seq and de novo assembly. We have generated a total of 202.7 million reads (18.91 billion of nucleotides) from four leaf samples in four plants of B. hookeriana, and assembled 59,063 unigenes (average size = 1098 bp) through de novotranscriptome assembly. Among them, 39,686 unigenes were annotated against the Swiss-Prot, Clusters of Orthologous Groups (COG), and NCBI non-redundant (NR) protein databases. We showed that there was approximately one single nucleotide polymorphism (SNP) per 5.6–7.1 kb in the transcriptome, and the ratio of transitional to transversional polymorphisms was approximately 1.82. We compared unigenes of B. hookeriana to those of Arabidopsis thaliana and Nelumbo nucifera through sequence homology, Gene Ontology (GO) annotation, and KEGG pathway analyses. The comparative analysis revealed that unigenes of B. hookeriana were closely related to those of N. nucifera. B. hookeriana, N. nucifera, and A. thaliana shared similar GO annotations but different distributions in KEGG pathways, indicating that B. hookeriana has adapted to dry-Mediterranean type shrublands via regulating expression of specific genes. In total 1927 potential simple sequence repeat (SSR) markers were discovered, which could be used in the genotype and genetic diversity studies of the Banksia genus. Our results provide valuable sequence resource for further study in Banksia.
山龙眼科班克木属(Banksia)植物是澳大利亚西南部植被的重要组成之一。其中,胡克班克木(Banksia hookeriana)是生长在该地区易燃植被中的一种灌木, 也是多年来澳洲野花产业一个最重要的物种,具有重要的生态和经济价值。为了更好地保护和管理,我们报道了使用RNA-seq和de novo组装的胡克班克木转录组概况。在四个叶子样本中,一共产生了202.7M的读段(18.91 billion核苷酸),通过do novo转录组组装,组装拼接了59,063个基因(平均长度为1098bp)。其中 39,686个基因通过Swiss-Prot、COG、NR蛋白质数据库进行注释。结果显示,在转录组中大约每5.6-7.1 kb有一个单核苷酸多态(SNP),过渡多态性和易位多态性的比率大约1.82。序列同源性、GO注释和KEGG通路分析比较胡克班克木, 荷花, 和 拟南芥的基因表明胡克班克木的基因与荷花最相近,三种植物的GO注释相似,但KEGG通路不同。 说明胡克班克木通过调控特异的基因表达已经适应了干燥的地中海型灌木带。此外,我们一共发现了1927个潜在的简单重复序列(ssr),这个可以用在班克木属的基因型和遗传多样性研究。我们的结果为班克木植物的进一步研究提供了宝贵的序列资源。

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