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A novel statistical method for the accurate identification of RNA-edits with application to human cancers Giuliany, Ryan S.
Abstract
RNA-editing is the post-transcriptional, enzymatic modification of RNA molecules resulting in an altered nucleotide sequence. These modifications play a critical role in mammalian tissues and are essential for proper function of liver and neuronal development, among other processes. The advent of high-throughput sequencing (HTS) technologies (e.g. Illumina HiSeq) has renewed interest in RNA-editing discovery due to unprecedented opportunities for simultaneous interrogation of whole genome and transcriptome sequences. In the past several months a number of studies have been published describing methods and results of RNA-editing discovery in HTS data. These methods have been ad hoc approaches based on repurposing SNP calling tools designed for genome-based variant detection. However, the statistical properties of RNA-editing warrant specialized analytical strategies that leverage the non-uniform substitution distributions inherent in RNA-editing processes. A novel statistical framework, called Auditor, that simultaneously analyzes the genomic and transcriptomic base-counts and infers the likelihood of an RNA-edit at each position in the transcriptome is reported. This model leverages the inherent correlation present in the RNA and DNA sequence while encoding the non-uniform substitution distributions induced by RNA-editing, conferring increased sensitivity. Further, a Random-Forest based technical artifact removal tool that accurately identifies sequencing and alignment errors has been implemented, greatly increasing the specificity of the method. The combination of these approaches leads to a robust, principled method that accurately detects RNA-edits in the presence of both biological and technical noise. It is systematically shown, in both a simulation study and on real matched whole genome and transcriptome data generated from 11 lymphoma samples, that Auditor significantly outperforms similar, but simpler statistical frameworks, including a Samtools/bcftools based approach that is similar to a recently published study. Finally by profiling 11 diffuse large B-cell lymphomas and 16 triple negative breast cancers with Auditor, it is shown that RNA-editing is an active process in human malignancies. Surprisingly, consistent patterns of nucleotide substitutions and regional enrichment of RNA-edits in 3 UTRs suggests that RNA-editing processes are invariant between cell lineages and between tumours of similar histological subtypes and even cancers from distinct tissues of origin. ii
Item Metadata
Title |
A novel statistical method for the accurate identification of RNA-edits with application to human cancers
|
Creator | |
Publisher |
University of British Columbia
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Date Issued |
2012
|
Description |
RNA-editing is the post-transcriptional, enzymatic modification of RNA molecules resulting in an
altered nucleotide sequence. These modifications play a critical role in mammalian tissues and are
essential for proper function of liver and neuronal development, among other processes. The advent
of high-throughput sequencing (HTS) technologies (e.g. Illumina HiSeq) has renewed interest in
RNA-editing discovery due to unprecedented opportunities for simultaneous interrogation of whole
genome and transcriptome sequences. In the past several months a number of studies have been published
describing methods and results of RNA-editing discovery in HTS data. These methods have
been ad hoc approaches based on repurposing SNP calling tools designed for genome-based variant
detection. However, the statistical properties of RNA-editing warrant specialized analytical strategies
that leverage the non-uniform substitution distributions inherent in RNA-editing processes.
A novel statistical framework, called Auditor, that simultaneously analyzes the genomic and
transcriptomic base-counts and infers the likelihood of an RNA-edit at each position in the transcriptome
is reported. This model leverages the inherent correlation present in the RNA and DNA
sequence while encoding the non-uniform substitution distributions induced by RNA-editing, conferring
increased sensitivity. Further, a Random-Forest based technical artifact removal tool that
accurately identifies sequencing and alignment errors has been implemented, greatly increasing the
specificity of the method. The combination of these approaches leads to a robust, principled method
that accurately detects RNA-edits in the presence of both biological and technical noise.
It is systematically shown, in both a simulation study and on real matched whole genome and
transcriptome data generated from 11 lymphoma samples, that Auditor significantly outperforms
similar, but simpler statistical frameworks, including a Samtools/bcftools based approach that is
similar to a recently published study. Finally by profiling 11 diffuse large B-cell lymphomas and
16 triple negative breast cancers with Auditor, it is shown that RNA-editing is an active process
in human malignancies. Surprisingly, consistent patterns of nucleotide substitutions and regional
enrichment of RNA-edits in 3 UTRs suggests that RNA-editing processes are invariant between
cell lineages and between tumours of similar histological subtypes and even cancers from distinct
tissues of origin.
ii
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Genre | |
Type | |
Language |
eng
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Date Available |
2013-01-31
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0072919
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2012-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International