AbstractMotivationLow-copy repeats (LCRs) or segmental duplications are long segments of duplicated DNA that cover>5% of the human genome. Existing tools for variant calling using short reads exhibit low accuracy in LCRs due to ambiguity in read mapping and extensive copy number variation. Variants in more than 150 genes overlapping LCRs are associated with risk for human diseases.MethodsWe describe a short-read variant calling method, ParascopyVC, that performs variant calling jointly across all repeat copies and utilizes reads independent of mapping quality in LCRs. To identify candidate variants, ParascopyVC aggregates reads mapped to different repeat copies and performs polyploid variant calling. Subsequently, paralogous sequence variants that can differentiate repeat copies are identified using population data and used for estimating the genotype of variants for each repeat copy.ResultsOn simulated whole-genome sequence data, ParascopyVC achieved higher precision (0.997) and recall (0.807) than three state-of-the-art variant callers (best precision = 0.956 for DeepVariant and best recall = 0.738 for GATK) in 167 LCR regions. Benchmarking of ParascopyVC using the genome-in-a-bottle high-confidence variant calls for HG002 genome showed that it achieved a very high precision of 0.991 and a high recall of 0.909 across LCR regions, significantly better than FreeBayes (precision = 0.954 and recall = 0.822), GATK (precision = 0.888 and recall = 0.873) and DeepVariant (precision = 0.983 and recall = 0.861). ParascopyVC demonstrated a consistently higher accuracy (meanF1= 0.947) than other callers (bestF1= 0.908) across seven human genomes.Availability and implementationParascopyVC is implemented in Python and is freely available athttps://github.com/tprodanov/ParascopyVC.