Abstract

In the last decade, one of the biggest challenges in genomics research has been to distinguish definitive pathogenic variants from all likely pathogenic variants identified by next-generation sequencing. This task is particularly complex because of our lack of knowledge regarding overall genome variation and pathogenicity of the variants. Therefore, obtaining sufficient information about genome variants in the general population is necessary as such data could be used for the interpretation of de novo mutations (DNMs) in the context of patient’s phenotype in cases of sporadic genetic disease. In this study, data from whole-exome sequencing of the general population in Lithuania were directly examined. In total, 84 (VarScan) and 95 (VarSeqTM) DNMs were identified and validated using different algorithms. Thirty-nine of these mutations were considered likely to be pathogenic based on gene function, evolutionary conservation, and mutation impact. The mutation rate estimated per position pair per generation was 2.74 × 10-8 [95% CI: 2.24 × 10-8–3.35 × 10-8] (VarScan) and 2.4 × 10-8 [95% CI: 1.96 × 10-8–2.99 × 10-8] (VarSeqTM), with 1.77 × 10-8 [95% CI: 6.03 × 10-9–5.2 × 10-8] de novo indels per position per generation. The rate of germline DNMs in the Lithuanian population and the effects of the genomic and epigenetic context on DNM formation were calculated for the first time in this study, providing a basis for further analysis of DNMs in individuals with genetic diseases. Considering these findings, additional studies in patient groups with genetic diseases with unclear etiology may facilitate our ability to distinguish certain pathogenic or adaptive DNMs from tolerated background DNMs and to reliably identify disease-causing DNMs by their properties through direct observation.

Highlights

  • Germline de novo mutations (DNMs) are genetic changes in the individual caused by mutagenesis occurring in parental gametes during oogenesis and spermatogenesis

  • In humans with genetic non-Mendelian diseases that occur sporadically, DNMs are usually novel, more reliable, and more harmful than inherited variants because they are not subjected to strong natural selection (Crow, 2000; Front Line Genomics, 2017)

  • After DNM analysis, an exceptionally high number of DNMs were identified for two trios: 113 and 123 and 16 (VarScan)

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Summary

Introduction

Germline de novo mutations (DNMs) are genetic changes in the individual caused by mutagenesis occurring in parental gametes during oogenesis and spermatogenesis. Even upon detection of candidate de novo variants, there is still insufficient information about the common and rare variants, which precludes a clear conclusion about the pathogenicity of the identified de novo variant and its role in disease (Acuna-Hidalgo et al, 2016). This limitation may be explained by the fact that de novo variants are usually heterozygous and may be either extremely rare or common. Irrespective of the rate of de novo variants, both types of variants may be scaled on the basis of relative fitness and natural selection

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