Article Online - Genomics, Proteomics & Bioinformatics

In ‘‘Omics’’ era of the life sciences, data is presented in many forms, which represent the information at various levels of biological systems, including data about genome, transcriptome, epigenome, proteome, metabolome, molecular imaging, molecular pathways, different population of people and clinical/medical records. The biological data is big, and its scale has already been well beyond petabyte (PB) even exabyte (EB). Nobody doubts that the biological data will create huge amount of values, if scientists can overcome many challenges, e.g., how to handle the complexity of information, how to integrate the data from very heterogeneous resources, what kind of principles or standards to be adopted when facing with the big data. Tools and techniques for analyzing big biological data enable us to translate massive amount of information into a better understanding of the basic biomedical mechanisms, which can be further applied to translational or personalized medicine.

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Next-generation sequencing (NGS) technology, with its high-throughput capacity and low cost, has developed rapidly in recent years and become an important analytical tool for many genomics researchers. New opportunities in the research domain of the forensic studies emerge by harnessing the power of NGS technology, which can be applied to simultaneously analyzing multiple loci of forensic interest in different genetic contexts, such as autosomes, mitochondrial and sex chromosomes. Furthermore, NGS technology can also have potential applications in many other aspects of research. These include DNA database construction, ancestry and phenotypic inference, monozygotic twin studies, body fluid and species identification, and forensic animal, plant and microbiological analyses. Here we review the application of NGS technology in the field of forensic science with the aim of providing a reference for future forensics studies and practice.

由高通量、低成本的新一代测序技术引领的基因组科学正在以空前的速度迅猛发展。法医科学家也正在不断努力将该技术与法医工作的实际应用相结合，不断开发基于新一代测序技术的包括同时能检测多种遗传标记、个体来源和表型特征推断、双生子鉴别、体液斑鉴定以及法医微生物、动植物数据库建立等法医学应用新方法。本文围绕这一领域的最新研究进展和应用进行评述和展望，希望能对法医学研究和实践提供参考及借鉴。

Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC) as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomarkers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.

顺铂作为一种铂金类抗癌药物，已有30余年的应用历史。该药广泛用于治疗多种癌症，但疗效在不同患者个体中表现不同。在晚期非小细胞肺癌的治疗中，顺铂是基础化疗药物之一，但病人对该药物的反应存在很大的个体差异。为了更好地治疗非小细胞肺癌，目前有大量的研究工作致力于生物标记物的发现以期预测非小细胞肺癌患者对顺铂的药物敏感性。在这篇综述里，我们全面总结了已有文献报导的存在于非小细胞肺癌治疗中的顺铂药物敏感性生物标记物。由于核苷酸切除修复、药物转运和药物代谢通路在铂金药物功能中的重要性，这篇综述重点总结了这些通路中的基因表达和非癌细胞DNA变异与铂金疗效的关系。数据显示，应用生物标记物指导顺铂应用可以改善这种药物的治疗效果。

Genetic studies are traditionally based on single-gene analysis. The use of these analyses can pose tremendous challenges for elucidating complicated genetic interplays involved in complex human diseases. Modern pathway-based analysis provides a technique, which allows a comprehensive understanding of the molecular mechanisms underlying complex diseases. Extensive studies utilizing the methods and applications for pathway-based analysis have significantly advanced our capacity to explore large-scale omics data, which has rapidly accumulated in biomedical fields. This article is a comprehensive review of the pathway-based analysis methods—the powerful methods with the potential to uncover the biological depths of the complex diseases. The general concepts and procedures for the pathway-based analysis methods are introduced and then, a comprehensive review of the major approaches for this analysis is presented. In addition, a list of available pathway-based analysis software and databases is provided. Finally, future directions and challenges for the methodological development and applications of pathway-based analysis techniques are discussed. This review will provide a useful guide to dissect complex diseases.

传统的遗传学研究主要采用的是基于单基因的分析方法,这类分析方法在阐明人类复杂疾病所涉及的复杂的基因相互作用机制方面面临着巨大的挑战。最新的基于通路的分析方法为全面解析复杂疾病的分子机制提供了一种新技术。通路分析方法的广泛研究和应用显著提高了我们分析在生物医学领域迅速积累的组学大数据的能力。本文系统地介绍了这类功能强大并能揭示复杂疾病深层生物学背景的方法，包括通路分析的一般概念和分析步骤，对主要通路分析方法全面的回顾，并给出了现有的通路分析软件和数据库清单，最后，针对通路分析方法的发展以及该分析技术应用的前景和面临的挑战进行了讨论。本文可为分析复杂疾病提供一个有效的方法学指引。

Charcot–Marie–Tooth disease type 4B2 with early-onset glaucoma (CMT4B2, OMIM 604563) is a genetically-heterogeneous childhood-onset neuromuscular disorder. Here, we report the case of a 15-year-old male adolescent with lower extremity weakness, gait abnormalities, foot deformities and early-onset glaucoma. Since clinical diagnosis alone was insufficient for providing pathogenetic evidence to indicate that the condition belonged to a consanguineous family, we applied whole-exome sequencing to samples from the patient, his parents and his younger brother, assuming that the patient’s condition is transmitted in an autosomal recessive pattern. A frame-shift mutation, c.4571delG (P.Gly1524Glufs∗42), was revealed in the CMT4B2-related gene SBF2 (also known as MTMR13, MIM 607697), and this mutation was found to be homozygous in the proband and heterozygous in his parents and younger brother. Together with the results of clinical diagnosis, this case was diagnosed as CMT4B2. Our finding further demonstrates the use of whole-exome sequencing in the diagnosis and treatment of rare diseases.

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MicroRNAs (miRNAs) were discovered two decades ago, yet there is still a great need for further studies elucidating their genesis and targeting in different phyla. Since experimental discovery and validation of miRNAs is difficult, computational predictions are indispensable and today most computational approaches employ machine learning. Toxoplasma gondii, a parasite residing within the cells of its hosts like human, uses miRNAs for its post-transcriptional gene regulation. It may also regulate its hosts’ gene expression, which has been shown in brain cancer. Since previous studies have shown that overexpressed miRNAs within the host are causal for disease onset, we hypothesized that T. gondii could export miRNAs into its host cell. We computationally predicted all hairpins from the genome of T. gondii and used mouse and human models to filter possible candidates. These were then further compared to known miRNAs in human and rodents and their expression was examined for T. gondii grown in mouse and human hosts, respectively. We found that among the millions of potential hairpins in T. gondii, only a few thousand pass filtering using a human or mouse model and that even fewer of those are expressed. Since they are expressed and differentially expressed in rodents and human, we suggest that there is a chance that T. gondii may export miRNAs into its hosts for direct regulation.

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Ovary development is a complex process involving numerous genes. A well-developed ovary is essential for females to keep fertility and reproduce offspring. In order to gain a better insight into the molecular mechanisms related to the process of mammalian ovary development, we performed a comparative transcriptomic analysis on ovaries isolated from infant and adult mice by using next-generation sequencing technology (SOLiD). We identified 15,454 and 16,646 transcriptionally active genes at the infant and adult stage, respectively. Among these genes, we also identified 7021 differentially expressed genes. Our analysis suggests that, in general, the adult ovary has a higher level of transcriptomic activity. However, it appears that genes related to primordial follicle development, such as those encoding Figla and Nobox, are more active in the infant ovary, whereas expression of genes vital for follicle development, such as Gdf9, Bmp4 and Bmp15, is upregulated in the adult. These data suggest a dynamic shift in gene expression during ovary development and it is apparent that these changes function to facilitate follicle maturation, when additional functional gene studies are considered. Furthermore, our investigation has also revealed several important functional pathways, such as apoptosis, MAPK and steroid biosynthesis, that appear to be much more active in the adult ovary compared to those of the infant. These findings will provide a solid foundation for future studies on ovary development in mice and other mammals and help to expand our understanding of the complex molecular and cellular events that occur during postnatal ovary development.

卵巢是雌性哺乳动物的生殖器官，卵巢发育是一个多基因调控的复杂生理过程。为了深入研究卵巢发育过程中所涉及的分子调控机理，我们采用新一代测序技术（SOLiD）对幼年期小鼠和成年期小鼠卵巢进行了比较转录组学分析。在幼年期小鼠和成年期小鼠卵巢中分别鉴定出15454和16646个转录活跃的基因，其中7021个基因呈现差异表达。我们的分析结果表明：总体而言，成年小鼠卵巢的基因表达比幼年期小鼠卵巢活跃。然而，与原始卵泡启动生长相关的基因（Figla、Nobox）在幼年期小鼠卵巢中表达水平更高。与之相对的，与卵泡后期成熟相关的基因（Gdf9、Bmp4、Bmp15）在成年期小鼠卵巢中的表达水平更高。数据显示：在卵巢发育的不同阶段，基因表达情况发生了比较大的变化，且这些变化都有助于卵泡成熟。另外，我们的研究也表明几个重要的生物通路（细胞凋亡、MAPK、激素合成）也在成年小鼠卵巢中被激活。

Nucleosome positioning is critical for gene expression and of major biological interest. The high cost of experimentally mapping nucleosomal arrangement signifies the need for computational approaches to predict nucleosome positions at high resolution. Here, we present a web-based application to fulfill this need by implementing two models, YR and W/S schemes, for the translational and rotational positioning of nucleosomes, respectively. Our methods are based on sequence-dependent anisotropic bending that dictates how DNA is wrapped around a histone octamer. This application allows users to specify a number of options such as schemes and parameters for threading calculation and provides multiple layout formats. The nuMap is implemented in Java/Perl/MySQL and is freely available for public use at http://numap.rit.edu. The user manual, implementation notes, description of the methodology and examples are available at the site.

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