Identification of Off-Target Regions for C9orf72 Repeat Expansions
Paired IRRs originating from expanded STRs may align to other genomic locations, especially if the STR is short in the reference genome at the target location. We refer to the loci where IRRs may misalign as off-target regions. Identifying off-target regions enables us to reduce the search for IRRs to a few regions instead of the whole genome. In order to obtain off-target regions for the C9orf72 repeat, we searched through the 182 samples in cohort one that had an expanded repeat according to the original RP-PCR results to identify all the GGGGCC IRRs. The search was performed through the whole genome for read pairs with a low mapping quality (MAPQ = 0) and a weighted purity score of at least 0.9. The mapping positions of all identified IRRs were merged if they were closer than 500 bp, and the resulting 29 loci that were present in five or more samples were designated as off-target regions (Supplemental Fig. 4) and were used to find additional reads from the C9orf72 repeat expansion.
Dolzhenko E., van Vugt J.J., Shaw R.J., Bekritsky M.A., van Blitterswijk M., Narzisi G., Ajay S.S., Rajan V., Lajoie B.R., Johnson N.H., Kingsbury Z., Humphray S.J., Schellevis R.D., Brands W.J., Baker M., Rademakers R., Kooyman M., Tazelaar G.H., van Es M.A., McLaughlin R., Sproviero W., Shatunov A., Jones A., Al Khleifat A., Pittman A., Morgan S., Hardiman O., Al-Chalabi A., Shaw C., Smith B., Neo E.J., Morrison K., Shaw P.J., Reeves C., Winterkorn L., Wexler N.S., Housman D.E., Ng C.W., Li A.L., Taft R.J., van den Berg L.H., Bentley D.R., Veldink J.H, & Eberle M.A. (2017). Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Research, 27(11), 1895-1903.
Other organizations :
Illumina (United States), University Medical Center Utrecht, Utrecht University, Illumina (United Kingdom), Mayo Clinic in Florida, New York Genome Center, SURFsara (Netherlands), Trinity College Dublin, Beaumont Hospital, King's College London, University College London, University of Southampton, University of Sheffield, Columbia University, Hereditary Disease Foundation, Massachusetts Institute of Technology
Identification of off-target regions where GGGGCC IRRs may misalign
control variables
Distance between merged mapping positions of identified IRRs (less than 500 bp)
Presence of the identified off-target regions in five or more samples
positive controls
None specified
negative controls
None specified
Annotations
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