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Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs

Chen, Jenny and Shishkin, Alexander A. and Zhu, Xiaopeng and Kadri, Sabah and Maza, Itay (2016) Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs. Genome Biology, 17 . Art. No. 19. ISSN 1474-760X. http://resolver.caltech.edu/CaltechAUTHORS:20160211-121026093

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Abstract

Background: Recent advances in transcriptome sequencing have enabled the discovery of thousands of long non-coding RNAs (lncRNAs) across many species. Though several lncRNAs have been shown to play important roles in diverse biological processes, the functions and mechanisms of most lncRNAs remain unknown. Two significant obstacles lie between transcriptome sequencing and functional characterization of lncRNAs: identifying truly non-coding genes from de novo reconstructed transcriptomes, and prioritizing the hundreds of resulting putative lncRNAs for downstream experimental interrogation. Results: We present slncky, a lncRNA discovery tool that produces a high-quality set of lncRNAs from RNA-sequencing data and further uses evolutionary constraint to prioritize lncRNAs that are likely to be functionally important. Our automated filtering pipeline is comparable to manual curation efforts and more sensitive than previously published computational approaches. Furthermore, we developed a sensitive alignment pipeline for aligning lncRNA loci and propose new evolutionary metrics relevant for analyzing sequence and transcript evolution. Our analysis reveals that evolutionary selection acts in several distinct patterns, and uncovers two notable classes of intergenic lncRNAs: one showing strong purifying selection on RNA sequence and another where constraint is restricted to the regulation but not the sequence of the transcript. Conclusion: Our results highlight that lncRNAs are not a homogenous class of molecules but rather a mixture of multiple functional classes with distinct biological mechanism and/or roles. Our novel comparative methods for lncRNAs reveals 233 constrained lncRNAs out of tens of thousands of currently annotated transcripts, which we make available through the slncky Evolution Browser.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1186/s13059-016-0880-9DOIArticle
http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0880-9PubMed CentralArticle
Additional Information:© Chen et al. 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Received: 26 October 2015. Accepted: 14 January 2016. Published: 2 February 2016. We thank Leslie Gaffney for artwork and advise on figures. JC was supported by an NHGRI training grant and by the Jan and Ruby Krouwer Fellowship Fund. MG was supported by DARPA grants D12AP00004 and D13AP00074. AR and MG were also supported by the CEGS 1P50HG006193. AR is supported by the Howard Hughes Medical Institute. JHH is supported by Ilana and Pascal Mantoux; the New York Stem Cell Foundation and is a New York Stem Cell Foundation - Robertson Investigator. We thank the Garber, Lander, and Regev laboratory members for helpful discussions. Authors’ contributions: JC participated in the design and coordination of the study, carried out all computational analysis and software development of slncky and slncky Evolutionary Browser, and wrote the manuscript. AS carried out RNA-Sequencing. XZ and SK participated in development of supporting software. IM and JH participated in deriving cell lines. M Guttman and AR participated in writing the manuscript. MG conceived of the study, participated in its design and coordination, and wrote the manuscript. All authors read and approved the final manuscript. The authors declare that they have no competing interests.
Funders:
Funding AgencyGrant Number
National Human Genome Research InstituteUNSPECIFIED
Jan and Ruby Krouwer Fellowship FundUNSPECIFIED
Defense Advanced Research Projects Agency (DARPA)D12AP00004
Defense Advanced Research Projects Agency (DARPA)D13AP00074
CEGS1P50HG006193
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Ilana and Pascal MantouxUNSPECIFIED
New York Stem Cell FoundationUNSPECIFIED
Subject Keywords:Long non-coding RNAs, Evolution, Comparative genomics, Molecular evolution, Annotation, LincRNA, RNA-seq, Transcriptome
Record Number:CaltechAUTHORS:20160211-121026093
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160211-121026093
Official Citation:Evolutionary analysis across mammals reveals distinct classes of long non-coding RNAs Jenny Chen, Alexander A. Shishkin, Xiaopeng Zhu, Sabah Kadri, Itay Maza, Mitchell Guttman, Jacob H. Hanna, Aviv Regev and Manuel Garber Genome Biology 2016 17:19 Published on: 2 February 2016
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64423
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:16 Feb 2016 10:12
Last Modified:16 Feb 2016 10:12

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