Article Online

Articles Online (Volume 14, Issue 5)

News and Views

Precision Medicine: What Challenges Are We Facing?

Yu Xue, Eric-Wubbo Lameijer, Kai Ye, Kunlin Zhang, Suhua Chang, Xiaoyue Wang, Jianmin Wu, Ge Gao, Fangqing Zhao, Jian Li, Chunsheng Han, Shuhua Xu, Jingfa Xiao, Xuerui Yang, Xiaomin Ying, Xuegong Zhang, Wei-Hua Chen, Yun Liu, Zhang Zhang, Kun Huang, Jun Yu

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Research Highlight

Broad H3K4me3 as A Novel Epigenetic Signature for Normal Development and Disease

Jie Lv, Kaifu Chen

染色体上H3K4me3富集区域的宽度变化正逐渐成为表观遗传学研究的一个新热点。H3K4me3是染色体上可能出现的几百种组蛋白修饰中的一种。 过去通常认为H3K4me3出现在基因启动子内一个较窄的、约为一千个碱基对的区域，相关的研究主要关注H3K4me3的富集强度。然而，近期发表于Cell、Nature Genetics、Nature等杂志的多篇论文陆续揭示， 染色体上相当数量的 H3K4me3富集区域可以变得异常宽广、每个区域覆盖数十万个碱基对 。 尤为特别的是， 在受精卵及胚胎极早期发育过程中，异常宽广的H3K4me3富集区域在基因组中大量而广泛地出现与消失。 这些宽域H3K4me3的宽度与丰度没有明显的关联。 基因启动子上的窄域H3K4me3可能在转录启动过程中发挥功能，沿基因转录方向拓展的宽域H3K4me3则与转录延伸过程相关，而在基因间区大量出现的宽域H3K4me3的具体功能目前还不清楚。因此，针对不同物种、不同细胞类型的研究一致表明，H3K4me3 富集区域的宽度变化具有重要的分子生物学功能，可能编码一些尚未知晓的表观调控机制。

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Review Article

Oxford Nanopore MinION Sequencing and Genome Assembly

Hengyun Lu, Francesca Giordano, Zemin Ning

The revolution of genome sequencing is continuing after the successful second-generation sequencing (SGS) technology. The third-generation sequencing (TGS) technology, led by Pacific Biosciences (PacBio), is progressing rapidly, moving from a technology once only capable of providing data for small genome analysis, or for performing targeted screening, to one that promises high quality de novo assembly and structural variation detection for human-sized genomes. In 2014, the MinION, the first commercial sequencer using nanopore technology, was released by Oxford Nanopore Technologies (ONT). MinION identifies DNA bases by measuring the changes in electrical conductivity generated as DNA strands pass through a biological pore. Its portability, affordability, and speed in data production makes it suitable for real-time applications, the release of the long read sequencer MinION has thus generated much excitement and interest in the genomics community. While de novo genome assemblies can be cheaply produced from SGS data, assembly continuity is often relatively poor, due to the limited ability of short reads to handle long repeats. Assembly quality can be greatly improved by using TGS long reads, since repetitive regions can be easily expanded into using longer sequencing lengths, despite having higher error rates at the base level. The potential of nanopore sequencing has been demonstrated by various studies in genome surveillance at locations where rapid and reliable sequencing is needed, but where resources are limited.
PacBio 首开三代测序的先河，其应用已从小微生物或局部基因组测序，发展到人类基因组全基因组组装和基因组结构变化检测。2014年，位于英国的牛津纳米孔技术公司（Oxford Nanopore Technologies) 推出了世界上最小的测序仪-MinION。当DNA片段引导通过纳米孔时，测序仪根据电流变化确定DNA序列。其仪器具有便携性、经济性和数据的快速产生性，一经推出，即获广泛关注。本文首先介绍纳米孔测序仪MinION的基本结构、工作原理和数据特征。重点分析长片段、高误差数据的组装，并与PacBio 组装进行比较。文章最后介绍目前的应用状况和展望未来的发展。

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Review Article

Long Non-coding RNAs and Their Roles in Non-small-cell Lung Cancer

Ming-Ming Wei, Guang-Biao Zhou

As a leading cause of cancer deaths worldwide, lung cancer is a collection of diseases with diverse etiologies which can be broadly classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Lung cancer is characterized by genomic and epigenomic alterations; however, mechanisms underlying lung tumorigenesis remain to be elucidated. Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs that consist of ⩾200 nucleotides but possess low or no protein-coding potential. Accumulating evidence indicates that abnormal expression of lncRNAs is associated with tumorigenesis of various cancers, including lung cancer, through multiple biological mechanisms involving epigenetic, transcriptional, and post-transcriptional alterations. In this review, we highlight the expression and roles of lncRNAs in NSCLC and discuss their potential clinical applications as diagnostic or prognostic biomarkers, as well as therapeutic targets.
作为全球肿瘤死亡因素的罪魁祸首，肺癌是一种由多因素综合诱发的恶性肿瘤，如基因组和表观遗传等方面的变化。根据细胞生物学特性和治疗方案，肺癌可以分为小细胞肺癌（small cell lung cancer, SCLC）和非小细胞肺癌（non-small cell lung cancer, NSCLC），其中非小细胞肺癌病人约占肺癌患者的 85%。因此，非小细胞肺癌发病的分子机制研究是非常重要的。长链非编码 RNA（long non-coding RNA，lncRNA）是一类长度大于 200bp， 且不具有或少有蛋白编码能力的 RNA，它们能够在转录水平、转录后水平和表观遗传修饰水平参与多种生物学过程。lncRNA的异常表达与非小细胞肺癌的发生发展有着密切的关系，这篇综述主要是对lncRNA的发现史、特性、功能以及它们在非小细胞肺癌早期诊断、分期或者预后和药物治疗中的作用等方面进行总结。

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Review Article

Towards Personalized Intervention for Alzheimer’s Disease

Xing Peng, Peiqi Xing, Xiuhui Li, Ying Qian, Fuhai Song, Zhouxian Bai, Guangchun Han, Hongxing Lei

Alzheimer’s disease (AD) remains to be a grand challenge for the international community despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells (iPSCs). Comprehensive information collection, better understanding of the disease mechanisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.
阿尔兹海默症（Alzheimer’s Disease, AD）是一种慢性神经退行性疾病，早期症状表现为短时记忆丧失，随着病情发展，病人症状主要表现为语言障碍、迷失方向感、情绪波动、生活不能自理等。尽管科学家对AD的研究已经超过一个世纪，但是具体的致病机理尚不明确，更不用说治愈。这归咎于AD病理学的异质性，涉及到各种复杂的生物通路。针对AD病人不同的亚群，应采用相对应的干预策略。因此，对AD病人进行详细地分类极为重要。这种分类基于患者的一些常规信息，包括APOE基因型、年龄、性别、受教育程度、生活方式、医疗史等，同时基于一些深层次的信息，包括基因组、脑成像、外周血标志物、患者特异性神经元功能实验等。只有全方位收集患者的信息，才能更好地对AD病人进行精确细分，从而更深层次认识AD的发病机制，最终针对每种AD病人亚型进行有效的精准治疗。

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Review Article

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine

Shabbir Ahmed, Zhan Zhou, Jie Zhou, Shu-Qing Chen

The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
人类基因组计划成功地在全基因组层面定位了近1400万个单核酸多态性（SNP）位点。这些基因组上的个体差异被注意到是造成药物在不同个体间药物代谢动力学差异的重要原因，尤其是编码药物代谢酶、药物核受体蛋白质和药物转运体蛋白质的基因上的核酸多态性。药物基因组学正是研究和评估特定药物反应相对应的特定基因变异，是精准医学的重要组成部分。本文讨论了多个造成个体药物反应差异的重要基因多态性位点，如编码I相药物代谢酶CYP家族中的CYP2D6、CYP2C9、CYP2C19、CYP3A4和CYP3A5的基因，编码药物转运体蛋白质ABC和SLC家族的基因。本文不仅综述了以上位点可能产生的功能影响以及不同地区群体分布的频率差异，更探讨了在药物相互作用时药物代谢酶与转运蛋白间的协同效应。随着对药物基因组学的深入研究，特定药物造成不同种族间不同个体间的药物反应差异的遗传变异应该是药物开发、伴随诊断试剂开发和临床用药指导等可依靠的重要标志物。

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Original Research

Construction and Analysis of Functional Networks in the Gut Microbiome of Type 2 Diabetes Patients

Lianshuo Li, Zicheng Wang, Peng He, Shining Ma, Jie Du, Rui Jiang

Although networks of microbial species have been widely used in the analysis of 16S rRNA sequencing data of a microbiome, the construction and analysis of a complete microbial gene network are in general problematic because of the large number of microbial genes in metagenomics studies. To overcome this limitation, we propose to map microbial genes to functional units, including KEGG orthologous groups and the evolutionary genealogy of genes: Non-supervised Orthologous Groups (eggNOG) orthologous groups, to enable the construction and analysis of a microbial functional network. We devised two statistical methods to infer pairwise relationships between microbial functional units based on a deep sequencing dataset of gut microbiome from type 2 diabetes (T2D) patients as well as healthy controls. Networks containing such functional units and their significant interactions were constructed subsequently. We conducted a variety of analyses of global properties, local properties, and functional modules in the resulting functional networks. Our data indicate that besides the observations consistent with the current knowledge, this study provides novel biological insights into the gut microbiome associated with T2D.

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Meeting Report

Cancer Precision Medicine in China

Hui Li

“第一届中美肿瘤精准医学高峰论坛”于9月22至24日在天津召开，此次高峰论坛由国家肿瘤临床医学研究中心(天津)、中国抗癌协会、中国医药生物技术协会、中国工程院医药卫生学部、天津医科大学肿瘤医院、美国西奈山医学院肿瘤中心、美国癌症研究基金会联合主办。来自中美两国的5位院士及全球肿瘤学领域专家、学者肿瘤学领域最受关注的精准医学这个话题进行了深入研讨，通过充分交流、加强合作，将共同促进肿瘤精准医学领域的发展。本次高峰论坛中，参会人员包括中国工程院院士、中国抗癌协会理事长郝希山，中科院院士、北京医院曾益新，中国工程院院士、北京大学医学部詹启敏，美国科学院院士、哈佛大学医学院Raju Kucherlapati教授，美国科学院院士、Ludwig研究所Webster Cavanee教授在内的5位院士及全球肿瘤学领域专家、学者，临床机构、国家管理机构、公司等多个领域相关人士，大会充分聚焦肿瘤精准医学，就肿瘤精准医疗的政策和管理、投资、研究平台建设、肿瘤基因组学研究、生物大数据、精准免疫治疗、肿瘤精准医疗的临床应用等多个当下全球肿瘤防治前沿热点话题，通过大会报告的形式进行了探讨。此外，大会还就新技术、大数据及分析在肿瘤精准医学中的作用；靶向治疗与药物研发；肿瘤基因检测；精准医学领域的投资；中国精准医学领域的发展和未来等话题通过Panel Discussion的形式开展了深入讨论。会议期间还举办了高通量测序和生物大数据及生物信息学分析培训班。通过讲座的形式针对性地就二代测序技术，生物信息分析等进行了系统培训。

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