Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals

Abstract

Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ∼80× whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5%-31%. We found that C→T and C→A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non-synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling.

Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation

“…[10][11][12] Similarly, there is increasing evidence of a high prevalence of mosaicism for single-nucleotide variants (SNVs) as a result of mutations appearing from early embryogenesis onward 13,14 and throughout adult life. 15,16 Currently, post-zygotic de novo mutations receive growing attention in developmental diseases.…”

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

“…Candidate somatic mutations were identified using the single-sample (when only AVM DNA was available) and paired-sample (when AVM and blood/saliva DNA were available) modes of MosaicHunter. 5 Somatic mutations with at least 2% mutant allele fraction and at least five reads supporting the variant allele were considered in subsequent analyses. We excluded common variants that were annotated in the Single Nucleotide Polymorphism, 6 1000 Genomes Project, 7 Exome Sequencing Project, 8 or Exome Aggregation Consortium 9 databases.…”

Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2

“…An unknown proportion of mutations categorized as de novo may in fact result from unrecognized parental mosaicism 20. Asymptomatic parental somatic mosaicism has recently been identified by NGS and reported for a number of rare diseases such as Alport syndrome, tuberous sclerosis, and Dravet syndrome 22, 23, 24, 25.…”