RT Journal Article
SR Electronic
T1 STRling: a k-mer counting approach that detects short tandem repeat expansions at known and novel loci
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.18.469113
DO 10.1101/2021.11.18.469113
A1 Harriet Dashnow
A1 Brent S. Pedersen
A1 Laurel Hiatt
A1 Joe Brown
A1 Sarah J. Beecroft
A1 Gianina Ravenscroft
A1 Amy J. LaCroix
A1 Phillipa Lamont
A1 Richard H. Roxburgh
A1 Miriam J. Rodrigues
A1 Mark Davis
A1 Heather C. Mefford
A1 Nigel G. Laing
A1 Aaron R. Quinlan
YR 2021
UL http://biorxiv.org/content/early/2021/11/20/2021.11.18.469113.abstract
AB Expansions of short tandem repeats (STRs) cause dozens of rare Mendelian diseases. However, STR expansions, especially those arising from repeats not present in the reference genome, are challenging to detect from short-read sequencing data. Such “novel” STRs include new repeat units occurring at known STR loci, or entirely new STR loci where the sequence is absent from the reference genome. A primary cause of difficulty detecting STR expansions is that reads arising from STR expansions are frequently mismapped or unmapped. To address this challenge, we have developed STRling, a new STR detection algorithm that counts k-mers (short DNA sequences of length k) in DNA sequencing reads, to efficiently recover reads that inform the presence and size of STR expansions. As a result, STRling can call expansions at both known and novel STR loci. STRling has a sensitivity of 83% for 14 known STR disease loci, including the novel STRs that cause CANVAS and DBQD2. It is the first method to resolve the position of novel STR expansions to base pair accuracy. Such accuracy is essential to interpreting the consequence of each expansion. STRling has an estimated 0.078 false discovery rate for known pathogenic loci in unaffected individuals and a 0.20 false discovery rate for genome-wide loci in unaffected individuals when using variants called from long-read data as truth. STRling is fast, scalable on cloud computing, open-source, and freely available at https://github.com/quinlan-lab/STRling.Competing Interest StatementThe authors have declared no competing interest.