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


METHODS
Our TRhist software is available at http://trhist.gi.k.u-tokyo.ac.jp/.


BACKGROUND
moris@cb.k.u-tokyo.ac.jp


BACKGROUND
Supplementary data are available at Bioinformatics online.
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.
Koichiro
K
Doi
Taku
T
Monjo
Pham H
PH
Hoang
Jun
J
Yoshimura
Hideaki
H
Yurino
Jun
J
Mitsui
Hiroyuki
H
Ishiura
Yuji
Y
Takahashi
Yaeko
Y
Ichikawa
Jun
J
Goto
Shoji
S
Tsuji
Shinichi
S
Morishita
D001483:Base Sequence; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D015203:Reproducibility of Results; D012984:Software