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Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.


ABSTRACT: MOTIVATION: Long expansions of short tandem repeats (STRs), i.e. DNA repeats of 2-6 nt, are associated with some genetic diseases. Cost-efficient high-throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads. RESULTS: We propose ab initio procedures for sensing and locating long STRs promptly by using the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in 11 SCA31 samples using SMRT(TM) sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads. AVAILABILITY AND IMPLEMENTATION: Our TRhist software is available at http://trhist.gi.k.u-tokyo.ac.jp/. CONTACT: moris@cb.k.u-tokyo.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUBMITTER: Doi K 

PROVIDER: S-EPMC3957077 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.

Doi Koichiro K   Monjo Taku T   Hoang Pham H PH   Yoshimura Jun J   Yurino Hideaki H   Mitsui Jun J   Ishiura Hiroyuki H   Takahashi Yuji Y   Ichikawa Yaeko Y   Goto Jun J   Tsuji Shoji S   Morishita Shinichi S  

Bioinformatics (Oxford, England) 20131108 6


<h4>Motivation</h4>Long expansions of short tandem repeats (STRs), i.e. DNA repeats of 2-6 nt, are associated with some genetic diseases. Cost-efficient high-throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads.<h4>Results</h4>We propose ab initio proce  ...[more]

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