Early post-zygotic mutations contribute to de novo variation in a healthy monozygotic twin pair. Postzygotic Mutations

Background Human de novo single nucleotide variation (SNV) rate is estimated to range between 0.84 – 3 × 10-8 mutations per base per generation. However, contribution of early post-zygotic 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 a healthy monozygotic twin pair and their parents. We examined the genotypes of the 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 characterized 22 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. We found twin specific rate to be 0.04 and 0.29 × 10-8 among the overall de novo SNV rate of 0.85 and 1.10 × 10-8. Conclusion Early post-zygotic mutations constitute an important proportion of human overall de novo mutations. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of genetic diseases.