Ionizing Radiation Alters the Transition/Transversion Ratio in the Exome of Human Gingiva Fibroblasts. Issue 1 (July 2020)

• Record Type: Journal Article
• Authors: Nath, Neetika; Hagenau, Lisa; Weiss, Stefan; Tzvetkova, Ana; Jensen, Lars R.; Kaderali, Lars; Port, Matthias; Scherthan, Harry; Kuss, Andreas W.
• Is Part Of: Health physics. Volume 119:Issue 1(2020)
• Publication Date: 2020-07
• Subjects: analysis, statistical -- dose -- exposure, radiation -- genetic effects; Biophysics -- Periodicals; Health Physics -- periodicals; Radiation Protection -- periodicals; Radiotherapy -- periodicals; Medische fysica; Electronic journals; 612.01448
• DOI: 10.1097/HP.0000000000001251
• Languages: English
• ISSNs: 0017-9078

Abstract

Abstract : Abstract: Little is known about the mutational impact of ionizing radiation (IR) exposure on a genome-wide level in mammalian tissues. Recent advancements in sequencing technology have provided powerful tools to perform exome-wide analyses of genetic variation. This also opened up new avenues for studying and characterizing global genomic IR-induced effects. However, genotypes generated by next generation sequencing (NGS) studies can contain errors, which may significantly impact the power to detect signals in common and rare variant analyses. These genotyping errors are not explicitly detected by the standard Genotype Analysis ToolKit (GATK) and Variant Quality Score Recalibration (VQSR) tool and thus remain a potential source of false-positive variants in whole exome sequencing (WES) datasets. In this context, the transition-transversion ratio (Ti/Tv) is commonly used as an additional quality check. In case of IR experiments, this is problematic when Ti/Tv itself might be influenced by IR treatment. It was the aim of this study to determine a suitable threshold for variant filters for NGS datasets from irradiated cells in order to achieve high data quality using Ti/Tv, while at the same time being able to investigate radiation-specific effects on the Ti/Tv ratio for different radiation doses. By testing a variety of filter settings and comparing the obtained results with publicly available datasets, we observe that a coverage filter setting of depth (DP) 3 and genotype quality (GQ) 20 is sufficient for high quality single nucleotide variants (SNVs) calling in an analysis combining GATK and VSQR and that Ti/Tv values are a consistent and useful indicator for data quality assessment for all tested NGS platforms. Furthermore, we report a reduction in Ti/Tv in IR-induced mutations in primary human gingiva fibroblasts (HGFs), which points to an elevated proportion of transversions among IR-induced SNVs and thus might imply that mismatch repair (MMR) plays a role in the cellular damage response to IR-induced DNA lesions. Abstract : Supplemental digital content is available in the text.