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      Hyperlipidemia-associated gene variations and expression patterns revealed by whole-genome and transcriptome sequencing of rabbit models

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          Abstract

          The rabbit ( Oryctolagus cuniculus) is an important experimental animal for studying human diseases, such as hypercholesterolemia and atherosclerosis. Despite this, genetic information and RNA expression profiling of laboratory rabbits are lacking. Here, we characterized the whole-genome variants of three breeds of the most popular experimental rabbits, New Zealand White (NZW), Japanese White (JW) and Watanabe heritable hyperlipidemic (WHHL) rabbits. Although the genetic diversity of WHHL rabbits was relatively low, they accumulated a large proportion of high-frequency deleterious mutations due to the small population size. Some of the deleterious mutations were associated with the pathophysiology of WHHL rabbits in addition to the LDLR deficiency. Furthermore, we conducted transcriptome sequencing of different organs of both WHHL and cholesterol-rich diet (Chol)-fed NZW rabbits. We found that gene expression profiles of the two rabbit models were essentially similar in the aorta, even though they exhibited different types of hypercholesterolemia. In contrast, Chol-fed rabbits, but not WHHL rabbits, exhibited pronounced inflammatory responses and abnormal lipid metabolism in the liver. These results provide valuable insights into identifying therapeutic targets of hypercholesterolemia and atherosclerosis with rabbit models.

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          Most cited references 22

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          Integration of biological networks and gene expression data using Cytoscape.

          Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.
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            The Bioperl toolkit: Perl modules for the life sciences.

            The Bioperl project is an international open-source collaboration of biologists, bioinformaticians, and computer scientists that has evolved over the past 7 yr into the most comprehensive library of Perl modules available for managing and manipulating life-science information. Bioperl provides an easy-to-use, stable, and consistent programming interface for bioinformatics application programmers. The Bioperl modules have been successfully and repeatedly used to reduce otherwise complex tasks to only a few lines of code. The Bioperl object model has been proven to be flexible enough to support enterprise-level applications such as EnsEMBL, while maintaining an easy learning curve for novice Perl programmers. Bioperl is capable of executing analyses and processing results from programs such as BLAST, ClustalW, or the EMBOSS suite. Interoperation with modules written in Python and Java is supported through the evolving BioCORBA bridge. Bioperl provides access to data stores such as GenBank and SwissProt via a flexible series of sequence input/output modules, and to the emerging common sequence data storage format of the Open Bioinformatics Database Access project. This study describes the overall architecture of the toolkit, the problem domains that it addresses, and gives specific examples of how the toolkit can be used to solve common life-sciences problems. We conclude with a discussion of how the open-source nature of the project has contributed to the development effort.
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              PopGenome: An Efficient Swiss Army Knife for Population Genomic Analyses in R

              Although many computer programs can perform population genetics calculations, they are typically limited in the analyses and data input formats they offer; few applications can process the large data sets produced by whole-genome resequencing projects. Furthermore, there is no coherent framework for the easy integration of new statistics into existing pipelines, hindering the development and application of new population genetics and genomics approaches. Here, we present PopGenome, a population genomics package for the R software environment (a de facto standard for statistical analyses). PopGenome can efficiently process genome-scale data as well as large sets of individual loci. It reads DNA alignments and single-nucleotide polymorphism (SNP) data sets in most common formats, including those used by the HapMap, 1000 human genomes, and 1001 Arabidopsis genomes projects. PopGenome also reads associated annotation files in GFF format, enabling users to easily define regions or classify SNPs based on their annotation; all analyses can also be applied to sliding windows. PopGenome offers a wide range of diverse population genetics analyses, including neutrality tests as well as statistics for population differentiation, linkage disequilibrium, and recombination. PopGenome is linked to Hudson’s MS and Ewing’s MSMS programs to assess statistical significance based on coalescent simulations. PopGenome’s integration in R facilitates effortless and reproducible downstream analyses as well as the production of publication-quality graphics. Developers can easily incorporate new analyses methods into the PopGenome framework. PopGenome and R are freely available from CRAN (http://cran.r-project.org/) for all major operating systems under the GNU General Public License.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                01 June 2016
                2016
                : 6
                Affiliations
                [1 ]Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China
                [2 ]Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center , Ann Arbor, MI, USA
                [3 ]Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi , Yamanashi, Japan
                [4 ]Shanghai Center for Bioinformation Technology, Shanghai Industrial Technology Institute , Shanghai, China
                [5 ]School of Life Science and Biotechnology, Shanghai Jiaotong University , Shanghai, China
                [6 ]Department of Computational Medicine and Bioinformatics, University of Michigan , Ann Arbor, MI, USA
                [7 ]EG Information Technology Enterprise (EGI), BasePair Biotechnology Co., Ltd. , Shanghai, China
                [8 ]Key Lab of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai, China
                [9 ]University of Chinese Academy of Sciences , Beijing, China
                [10 ]School of Biotechnology, East China University of Science and Technology , Shanghai, China
                [11 ]School of Life Science and Technology, Shanghai Tongji University , Shanghai, China
                [12 ]Institute for Experimental Animals, Kobe University School of Medicine , Kobe, Japan
                [13 ]Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi’an Jiaotong University School of Medicine , Xi’an, China
                [14 ]Department of Pathology, Xi’an Medical University , Xi’an, China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep26942
                10.1038/srep26942
                4887883
                27245873
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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