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Gene co-expression analysis for functional classification and gene–disease predictions

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      Gene co-expression networks can be used to associate genes of unknown function with biological processes, to prioritize candidate disease genes or to discern transcriptional regulatory programmes. With recent advances in transcriptomics and next-generation sequencing, co-expression networks constructed from RNA sequencing data also enable the inference of functions and disease associations for non-coding genes and splice variants. Although gene co-expression networks typically do not provide information about causality, emerging methods for differential co-expression analysis are enabling the identification of regulatory genes underlying various phenotypes. Here, we introduce and guide researchers through a (differential) co-expression analysis. We provide an overview of methods and tools used to create and analyse co-expression networks constructed from gene expression data, and we explain how these can be used to identify genes with a regulatory role in disease. Furthermore, we discuss the integration of other data types with co-expression networks and offer future perspectives of co-expression analysis.

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      Most cited references 182

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      Fast and accurate short read alignment with Burrows–Wheeler transform

      Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: Contact:
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        Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

        DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
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          Cytoscape: a software environment for integrated models of biomolecular interaction networks.

          Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.

            Author and article information

            [1 ]Department of Genetics, UMCG HPC CB50, RB Groningen, Netherlands
            [2 ]Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
            Author notes
            Corresponding authors: Sipko van Dam, Systems Genetics, Department of Genetics, UMCG HPC CB50, P.O. Box: 30001, 9700 RB Groningen, The Netherlands, Tel.: +31 50 361 72 29; Fax: +31 50 361 72 31; E-mail: sipkovandam@
            João Pedro de Magalhães, Institute of Ageing and Chronic Disease, University of Liverpool, William Duncan Building, Room 281, 6 West Derby Street, Liverpool L7 8TX, United Kingdom, Tel.: +44 151 7954517; Fax: +44 151 795 8420; E-mail: jp@
            Brief Bioinform
            Brief. Bioinformatics
            Briefings in Bioinformatics
            Oxford University Press
            July 2018
            10 January 2017
            10 January 2017
            : 19
            : 4
            : 575-592
            28077403 6054162 10.1093/bib/bbw139 bbw139
            © The Author 2017. Published by Oxford University Press.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

            Pages: 18
            Funded by: UK Biotechnology and Biological Sciences Research Council 10.13039/501100000268
            Award ID: BB/K016741/1
            Funded by: European Research Council 10.13039/100010663
            Award ID: 637640
            Funded by: Organization for Scientific Research
            Award ID: 917.14.374


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