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Computational methods for translation regulation analysis from Ribo-seq data
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Computational methods for translation regulation analysis from Ribo-seq data
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Abstract (if available)
Abstract
Since its inception, Ribo-seq, a technique for deep sequencing the ribosome protected fragments (RPFs) of mRNA, has greatly expanded our knowledge of translation. With Ribo-seq, the coding potentials of the transcripts are re-evaluated, thousands of novel open reading frames (ORFs) are found translating, especially within those previously presumed non-coding regions. With matched RNA-seq data, Ribo-seq has been widely used for translation regulation studies, and numerous key insights have been unveiled. Among the various applications of Ribo-seq, two fundamental aims attract broad interest, the identification of differential translation across conditions and the detection of actively translating ORFs. Here we present two computational methods, Riborex and RiboCop, for those two tasks, respectively. ❧ Global analysis of translation regulation has recently been enabled by the development of the Ribo-seq technology. This approach provides maps of ribosome activity for each expressed gene in a given biological sample. Measurements of translation efficiency are generated when Ribo-seq data is analyzed in combination with matched RNA-seq gene expression profiles. Existing computational methods for identifying genes with differential translation across samples are based on sound principles, but require users to choose between accuracy and speed. We present Riborex, a computational tool for mapping genome-wide differences in translation efficiency. Riborex shares a similar mathematical structure with existing methods, but has a simplified implementation. Riborex directly leverages established RNA-seq analysis frameworks for all parameter estimation, providing users with a choice among robust engines for these computations. The result is a method that is dramatically faster than available methods without sacrificing accuracy. ❧ In addition, Ribo-seq provides single nucleotide resolution of the positions of translating ribosomes which can be leveraged for annotating translation beyond those canonical coding regions. As the characteristic feature of Ribo-seq profile, the truly translating ORFs show a three-nucleotide periodicity for its RPF profile which can be used to distinguish between translation signals and noise. As one of the most surprising discoveries, thousands of translating ORFs are detected from 5' untranslated regions and other previously annotated non-coding regions. However, due to the high heterogeneity and noise of Ribo-seq data, the interpretation of those discoveries needs extra care. Especially, the short lengths of those novel ORFs render further challenges for periodicity based methods because fewer profiles of codons can be observed to assess the periodicity of the entire ORF. Here we also present RiboCop which directly leverages the three-nucleotide periodicity of the RPF profile with a 3D to 2D transformation. We compared the performance of RiboCop with other methods on multiple published datasets in human and mouse. RiboCop demonstrates unprecedented accuracy and robustness compared with other existing methods.
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University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Li, Wenzheng
(author)
Core Title
Computational methods for translation regulation analysis from Ribo-seq data
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Computational Biology and Bioinformatics
Publication Date
04/23/2019
Defense Date
03/20/2019
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
OAI-PMH Harvest,ORFs,Ribo-seq,ribosome,translation,translation-regulation
Format
application/pdf
(imt)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Smith, Andrew David (
committee chair
), Chaisson, Mark (
committee member
), Rohs, Remo (
committee member
), Thomas, Paul D. (
committee member
)
Creator Email
liyukuang@gmail.com,wenzhenl@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c89-141599
Unique identifier
UC11676759
Identifier
etd-LiWenzheng-7218.pdf (filename),usctheses-c89-141599 (legacy record id)
Legacy Identifier
etd-LiWenzheng-7218.pdf
Dmrecord
141599
Document Type
Dissertation
Format
application/pdf (imt)
Rights
Li, Wenzheng
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA
Tags
ORFs
Ribo-seq
ribosome
translation-regulation