Genome-wide detection of somatic mosaicism at short tandem repeats.

Motivation: Somatic mosaicism, in which a mutation occurs post-zygotically, has been implicated in several developmental disorders, cancers, and other diseases. Short tandem repeats (STRs) consist of repeated sequences of 1-6bp and comprise more than 1 million loci in the human genome. Somatic mosaicism at STRs is known to play a key role in the pathogenicity of loci implicated in repeat expansion disorders and is highly prevalent in cancers exhibiting microsatellite instability. While a variety of tools have been developed to genotype germline variation at STRs, a method for systematically identifying mosaic STRs (mSTRs) is lacking.

Results: We introduce prancSTR, a novel method for detecting mSTRs from individual high-throughput sequencing datasets. Unlike many existing mosaicism detection methods for other variant types, prancSTR does not require a matched control sample as input. We show that prancSTR accurately identifies mSTRs in simulated data and demonstrate its feasibility by identifying candidate mSTRs in whole genome sequencing (WGS) data derived from lymphoblastoid cell lines for individuals sequenced by the 1000 Genomes Project. Our analysis identified an average of 76 and 577 non-homopolymer and homopolymer mSTRs respectively per cell line as well as multiple cell lines with outlier mSTR counts more than 6 times the population average, suggesting a subset of cell lines have particularly high STR instability rates.

Availability: prancSTR is freely available at https://github.com/gymrek-lab/trtools.

Documentation: Detailed documentation is available at https://trtools.readthedocs.io/.