title: 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.
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: August Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Peking University First Hospital, Peking University, Beijing 100034, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Xu
authors.affiliation: 1] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [2] Peking-Tsinghua Center for Life Sciences, Beijing 100871, China [3] Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
authors.forename: Adam Y
authors.initials: AY
authors.lastname: Ye
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Qixi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Yan
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] Graduate School of Peking Union Medical College, Beijing 100730, China.
authors.forename: Boxun
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [3] Peking-Tsinghua Center for Life Sciences, Beijing 100871, China [4] Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: He
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China [3] Peking-Tsinghua Center for Life Sciences, Beijing 100871, China [4] Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Gu
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Han-Qing
authors.initials: HQ
authors.lastname: Zhao
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.affiliation: Peking University First Hospital, Peking University, Beijing 100034, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Peking University First Hospital, Peking University, Beijing 100034, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Peking University First Hospital, Peking University, Beijing 100034, China.
authors.forename: Xiru
authors.initials: X
authors.lastname: Wu
authors.affiliation: Peking University First Hospital, Peking University, Beijing 100034, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] National Institute of Biological Sciences, Beijing 102206, China [2] Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wei
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000328:Adult; D000483:Alleles; D001499:Bayes Theorem; D002675:Child, Preschool; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000473:pathology; D005260:Female; D005817:Genetic Counseling; D015894:Genome, Human; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009030:Mosaicism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D015053:Zygote / Q000378:metabolism*
chemical_list: C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase