Discovering human germ cell mutagens with whole genome sequencing: insights from power calculations reveal the importance of controlling for between family variability

Publication date: Available online 20 April 2018 Source:Mutation Research/Genetic Toxicology and Environmental Mutagenesis Author(s): R.J. Webster, A. Williams, F. Marchetti, C.L. Yauk Mutations in germ cells pose potential genetic risks to offspring. However, de novo mutations are rare events that are spread across the genome and are difficult to detect. Thus, studies in this area have generally been under-powered, and no human germ cell mutagen has been identified. Whole Genome Sequencing (WGS) of human pedigrees has been proposed as an approach to overcome these technical and statistical challenges. WGS enables analysis of a much wider breadth of the genome than traditional approaches. Here, we performed power analyses to determine the feasibility of using WGS in human families to identify germ cell mutagens. Different statistical models were compared in the power analyses (ANOVA and multiple regression for one-child families, and mixed effect model sampling between two and four siblings per family). Assumptions were made based on parameters from the existing literature, such as the mutation-by-paternal age effect. We explored two scenarios: a constant effect due to an exposure that occurred in the past, and an accumulating effect where the exposure is continuing. Our analysis revealed the importance of modeling inter-family variability of the mutation-by-paternal age effect. Statistical power was improved by models accounting for the family-to-family variability. Ou...
Source: Mutation Research Genetic Toxicology and Environmental Mutagenesis - Category: Genetics & Stem Cells Source Type: research