Detection of long repeat expansions from PCR-free whole-genome sequence data
Name
Genome Res.-2017-Dolzhenko-1895-903.pdf
Size
831.91 KB
Format
Adobe PDF
Checksum (MD5)
e7d946355042e6992e0e01bae2dfdbf3
Author(s)
Dolzhenko, Egor
van Vugt, Joke J.F.A.
Shaw, Richard J.
Bekritsky, Mitchell A.
van Blitterswijk, Marka
Narzisi, Giuseppe
Ajay, Subramanian S.
Rajan, Vani
Lajoie, Bryan R.
Johnson, Nathan H.
Date Issued
September 2017
Journal
Genome Research
Publisher
Cold Spring Harbor Laboratory
Citation
Dolzhenko, Egor et al. “Detection of Long Repeat Expansions from PCR-Free Whole-Genome Sequence Data.” Genome Research 27, 11 (September 2017): 1895–1903 © 2017 Dolzhenko et al
Version
Final published version
Abstract
Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI [0.997, 1.00] ) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich’s ataxia, and Huntington’s disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1101/GR.225672.117
