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

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 techni...

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Autores principales: Huang, August Y, Xu, Xiaojing, Ye, Adam Y, Wu, Qixi, Yan, Linlin, Zhao, Boxun, Yang, Xiaoxu, He, Yao, Wang, Sheng, Zhang, Zheng, Gu, Bowen, Zhao, Han-Qing, Wang, Meng, Gao, Hua, Gao, Ge, Zhang, Zhichao, Yang, Xiaoling, Wu, Xiru, Zhang, Yuehua, Wei, Liping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220156/
https://www.ncbi.nlm.nih.gov/pubmed/25312340
http://dx.doi.org/10.1038/cr.2014.131
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author Huang, August Y
Xu, Xiaojing
Ye, Adam Y
Wu, Qixi
Yan, Linlin
Zhao, Boxun
Yang, Xiaoxu
He, Yao
Wang, Sheng
Zhang, Zheng
Gu, Bowen
Zhao, Han-Qing
Wang, Meng
Gao, Hua
Gao, Ge
Zhang, Zhichao
Yang, Xiaoling
Wu, Xiru
Zhang, Yuehua
Wei, Liping
author_facet Huang, August Y
Xu, Xiaojing
Ye, Adam Y
Wu, Qixi
Yan, Linlin
Zhao, Boxun
Yang, Xiaoxu
He, Yao
Wang, Sheng
Zhang, Zheng
Gu, Bowen
Zhao, Han-Qing
Wang, Meng
Gao, Hua
Gao, Ge
Zhang, Zhichao
Yang, Xiaoling
Wu, Xiru
Zhang, Yuehua
Wei, Liping
author_sort Huang, August Y
collection PubMed
description 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.
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spelling pubmed-42201562014-11-07 Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals Huang, August Y Xu, Xiaojing Ye, Adam Y Wu, Qixi Yan, Linlin Zhao, Boxun Yang, Xiaoxu He, Yao Wang, Sheng Zhang, Zheng Gu, Bowen Zhao, Han-Qing Wang, Meng Gao, Hua Gao, Ge Zhang, Zhichao Yang, Xiaoling Wu, Xiru Zhang, Yuehua Wei, Liping Cell Res Original Article 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. Nature Publishing Group 2014-11 2014-10-14 /pmc/articles/PMC4220156/ /pubmed/25312340 http://dx.doi.org/10.1038/cr.2014.131 Text en Copyright © 2014 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences http://creativecommons.org/licenses/by-nc-nd/3.0 This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0
spellingShingle Original Article
Huang, August Y
Xu, Xiaojing
Ye, Adam Y
Wu, Qixi
Yan, Linlin
Zhao, Boxun
Yang, Xiaoxu
He, Yao
Wang, Sheng
Zhang, Zheng
Gu, Bowen
Zhao, Han-Qing
Wang, Meng
Gao, Hua
Gao, Ge
Zhang, Zhichao
Yang, Xiaoling
Wu, Xiru
Zhang, Yuehua
Wei, Liping
Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title_full Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title_fullStr Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title_full_unstemmed Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title_short Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
title_sort postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220156/
https://www.ncbi.nlm.nih.gov/pubmed/25312340
http://dx.doi.org/10.1038/cr.2014.131
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