Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair

Background Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70x10(-8) mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31x10(-8) and 1.01x10(-8) for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34x10(-8) for twin I and 0.04x10(-8) for twin II. Conclusions Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.