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bioRxiv · 10.1101/2020.02.03.933002

Accuracy of short tandem repeats genotyping tools in whole exome sequencing data

Halman, A.·Oshlack, A.
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Abstract

BackgroundShort tandem repeats are important source of genetic variation, they are highly mutable and repeat expansions are associated dozens of human disorders, such as Huntingtons disease and spinocerebellar ataxias. Technical advantages in sequencing technology have made it possible to analyse these repeats at large scale, however, accurate genotyping is still a challenging task. We compared four different short tandem repeats genotyping tools on whole exome sequencing data to determine their genotyping performance and limits which will aid other researchers to choose a suitable tool and parameters for analysis. MethodsThe analysis was performed on the Simons Simplex Collection dataset where we used a novel method of evaluation with accuracy determined by the rate of homozygous calls on the X chromosome of male samples. In total we analysed 433 samples and around a million genotypes for evaluating tools on whole exome sequencing data. ResultsWe determined a relatively good performance of all tools when genotyping repeats of 3-6 bp in length which could be improved with coverage and quality score filtering. However, genotyping homopolymers was challenging for all tools and a high error rate was present across different thresholds of coverage and quality scores. Interestingly, dinucleotide repeats displayed a high error rate as well, which was found to be mainly caused by the AC/TG repeats. Overall, LobSTR was able to make the most calls and was also the fastest tool while RepeatSeq and HipSTR exhibited the lowest heterozygous error rate at low coverage. ConclusionsAll tools have different strengths and weaknesses and the choice may depend on the type of analysis. In this analysis we demonstrated the effect of using different filtering parameters and offered recommendations based on the trade-off between the best accuracy of genotyping and the highest number of calls.

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Halman, A., Oshlack, A.. 2020-02-04. Accuracy of short tandem repeats genotyping tools in whole exome sequencing data. https://doi.org/10.1101/2020.02.03.933002

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