Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair
Date
2014Source Title
Journal of Medical Genetics
Print ISSN
0022-2593
Publisher
B M J Group
Volume
51
Issue
7
Pages
455 - 459
Language
English
Type
ArticleItem Usage Stats
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Abstract
Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 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 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 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.
Keywords
DNAAdult
Controlled study
DNA isolation
Female
Gene frequency
Gene mapping
Gene sequence
Genetic procedures
Genetic variability
Genome analysis
Genotype
Human
Human experiment
Indel mutation
Male
Middle aged
Mitosis
Monozygotic twins
Mutagenesis
Mutation rate
Normal human
Parent
Priority journal
Reference allele frequency
Sanger sequencing
Single nucleotide polymorphism
Single nucleotide variation
Young adult
DNA sequence
Twins