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Title: Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

Journal Article · · Nature (London)
DOI:https://doi.org/10.1038/nature21703· OSTI ID:1356130
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  1. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Korea Advanced Institute of Science and Technology, Daejeon (Republic of Korea)
  2. Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
  3. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); European Bioinformatics Institute, Hinxton (United Kingdom)
  4. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Wellcome Trust Centre for Human Genetics, Oxford (United Kingdom)
  6. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  7. Univ. of Oslo, Lorenskog (Norway)
  8. King's College London School of Medicine, London (United Kindgom)
  9. Ninewells Hospital and Medicine School, Dundee (United Kingdom)
  10. BioCare, Lund (Sweden); CREATE Health, Lund (Sweden); Lund Univ., Lund (Sweden)
  11. Radboud Univ. Medical Center, Nijmegen (The Netherlands)
  12. Academic Medical Center, Amsterdam (The Netherlands)
  13. Singapore General Hospital (Singapore)
  14. Univ. of Cambridge, Cambridge (United Kingdom)
  15. King's College London, London (United Kingdom); Institute of Cancer Research, London (United Kingdom)
  16. The Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
  17. Univ. of California, San Francisco, CA (United States)
  18. Erasmus Univ. Medical Center, Rotterdam (Netherlands)
  19. Institut Jules Bordet, Brussels (Belgium)
  20. Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
  21. Radboud Univ. Medical Center, Nijmegen (Netherlands)
  22. Univ. of Queensland, Brisbane (Australia); Royal Brisbane and Women's Hospital, Brisbane (Australia)
  23. Univ. of Iceland, Reykjavik (Iceland)
  24. Oslo Univ. Hospital, The Norwegian Radium Hospital, Oslo (Norway); Univ. of Oslo, Oslo (Norway)
  25. Johns Hopkins Medicine, Washington, D.C. (United States)
  26. Centre Leon Berard, Lyon Cedex (France)
+ Show Author Affiliations

Somatic cells acquire mutations throughout the course of an individual’s life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. As a result, this study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Laboratory Directed Research and Development (LDRD) Program
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1356130
Report Number(s):
LA-UR-16-20126
Journal Information:
Nature (London), Vol. 543, Issue 7647; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 164 works
Citation information provided by
Web of Science

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Cited By (79)

Entanglement of Genetics and Epigenetics in Parkinson’s Disease journal March 2019
Somatic mutagenesis in satellite cells associates with human skeletal muscle aging journal February 2018
Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development journal February 2019
Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing posted_content August 2018
Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo. text January 2018
Overlooked roles of DNA damage and maternal age in generating human germline mutations posted_content October 2018
Population dynamics of normal human blood inferred from somatic mutations journal September 2018
Detection and genomic characterization of a mammary-like adenocarcinoma journal September 2017
A probabilistic framework for cellular lineage reconstruction using single-cell 5-hydroxymethylcytosine sequencing posted_content August 2019
Aging and the rise of somatic cancer-associated mutations in normal tissues journal January 2018
The genome-wide landscape of C:G > T:A polymorphism at the CpG contexts in the human population journal March 2020
Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel journal June 2014
Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease journal February 2018
The Origins and Vulnerabilities of Two Transmissible Cancers in Tasmanian Devils. journalarticle January 2018
Cell competition: the winners and losers of fitness selection journal July 2019
Mapping human development at single-cell resolution journal February 2018
Human glioblastoma arises from subventricular zone cells with low-level driver mutations journal August 2018
Single-cell lineage tracing by integrating CRISPR-Cas9 mutations with transcriptomic data journal June 2020
Replicative cellular age distributions in compartmentalized tissues journal August 2018
Concordance for clonal hematopoiesis is limited in elderly twins. text January 2020
Novel Insights Into the NLRP3 Inflammasome in Atherosclerosis journal June 2019
Frequency and signature of somatic variants in 1461 human brain exomes. journalarticle January 2019
A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing journal July 2019
Robust identification of mosaic variants in congenital heart disease journal February 2018
Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations journal December 2018
Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations posted_content May 2018
Early divergence of mutational processes in human fetal tissues journal May 2019
Development of the variant calling algorithm, ADIScan, and its use to estimate discordant sequences between monozygotic twins journal June 2018
Systematic comparative analysis of single-nucleotide variant detection methods from single-cell RNA sequencing data text January 2019
Systematic comparative analysis of single-nucleotide variant detection methods from single-cell RNA sequencing data text January 2019
Signatures of replication timing, recombination and sex in the spectrum of rare variants on the human X chromosome and autosomes posted_content May 2019
Genomic mosaicism in paternal sperm and multiple parental tissues in a Dravet syndrome cohort journal November 2017
Tracing the origin of heterogeneity and symmetry breaking in the early mammalian embryo journal May 2018
Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes journal August 2019
Mutations beget more mutations – The baseline mutation rate and runaway accumulation posted_content July 2019
Mutations Beget More Mutations—Rapid Evolution of Mutation Rate in Response to the Risk of Runaway Accumulation journal December 2019
Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs journal May 2018
Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates journal June 2018
Embryonal precursors of Wilms tumor journal December 2019
APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa journal August 2018
The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation journal October 2017
Concordance for clonal hematopoiesis is limited in elderly twins journal January 2020
Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis journal December 2017
Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing journal April 2019
Immune Cell Dynamics Unfolded by Single-Cell Technologies journal June 2018
Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis journal November 2018
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Variation of mutational burden in healthy human tissues suggests non-random strand segregation and allows measuring somatic mutation rates posted_content May 2018
Frequency of mosaicism points towards mutation-prone early cleavage cell divisions in cattle posted_content June 2017
Identification of somatic mutations in monozygotic twins discordant for psychiatric disorders journal April 2018
The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues journal May 2020
A characterization of postzygotic mutations identified in monozygotic twins journal July 2018
An analysis of intrinsic base substitution patterns in diverse species reveals connections to cancer and metabolism posted_content March 2020
Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability posted_content November 2019
Population dynamics of normal human blood inferred from somatic mutations. text January 2018
Age-related clonal hematopoiesis journal February 2018
The rate and spectrum of mosaic mutations during embryogenesis revealed by RNA sequencing of 49 tissues posted_content October 2019
Mapping human development at single-cell resolution. text January 2018
Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer journal April 2019
Systematic comparative analysis of single-nucleotide variant detection methods from single-cell RNA sequencing data journal November 2019
Somatic mutations in the human brain: implications for psychiatric research journal August 2018
Single-cell Lineage Tracing by Integrating CRISPR-Cas9 Mutations with Transcriptomic Data posted_content May 2019
Paternal age in rhesus macaques is positively associated with germline mutation accumulation but not with measures of offspring sociability journal May 2020
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Delayed Laparoscopic Cholecystectomy in a Case of Acute Cholecystitis and Intestinal Malrotation Type I journal February 2019
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Mosaic abnormalities of the skin: review and guidelines from the European Reference Network for rare skin diseases journal July 2019
Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders journal September 2017
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Networks of enhancers and microRNAs drive variation in cell states posted_content June 2019
Quantification of somatic mutation flow across individual cell division events by lineage sequencing journal November 2018
Accurate detection of mosaic variants in sequencing data without matched controls journal January 2020

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