Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs

PLoS Genetics
August Yue HuangLiping Wei

Abstract

Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter- and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs). Compared to clonal expansion pSNMs, embryonic pSNMs had higher proportion of C>T mutations with elevated mutation rate at CpG sites. We observed differences in replication timing between these two types of pSNMs, with embryonic and clonal expansion pSNMs enriched in early- and late-replicating regions, respectively. An increased number of embryonic pSNMs were located in open chromatin states and topologically associating domains that transcribed embryonically. Our findings provide new insight...Continue Reading

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Citations

Nov 20, 2019·Environmental and Molecular Mutagenesis·Roger W L GodschalkFrancesco Marchetti
Nov 9, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Qingping ZhangXinhua Bao
Jan 8, 2020·Nature Biotechnology·Yanmei DouPeter J Park
Mar 21, 2019·Clinical Genetics·Xiaoling YangYuehua Zhang
Dec 25, 2019·Nature Medicine·Martin W BreussJoseph G Gleeson
Jun 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·August Yue HuangChristopher A Walsh
Jun 1, 2019·Science Advances·Ewart KuijkEdwin Cuppen
Apr 6, 2021·Movement Disorders Clinical Practice·Francesca MagrinelliKailash P Bhatia
Jun 24, 2021·Trends in Genetics : TIG·Martin W BreussJoseph G Gleeson
Aug 14, 2021·Cell·Xiaoxu YangJoseph G Gleeson

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Datasets Mentioned

BETA
GSM958733

Methods Mentioned

BETA
single-cell sequencing
deamination
single-clone sequencing
PCR
ChIP-seq
Hi-C
Amplicon Sequencing

Software Mentioned

BWA
CNVnator
PASM
UCSC Genome Browser
MosaicHunter
CNVkit
GATK
Picard

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