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Bioinformatics. 2014 Mar 15;30(6):815-22. doi: 10.1093/bioinformatics/btt647. Epub 2013 Nov 8.

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

Author information

1
Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Department of Information and Communication Engineering, Faculty of Engineering and Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

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.

PMID:
24215022
PMCID:
PMC3957077
DOI:
10.1093/bioinformatics/btt647
[Indexed for MEDLINE]
Free PMC Article

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