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Inherent mosaicism and extensive mutation of human placentas

Abstract

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.

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Fig. 1: The genomes of bulk placental biopsies.
Fig. 2: Clonal architecture of microdissected trophoblast clusters and mesenchymal cores.
Fig. 3: Early embryonic genetic bottlenecks and their relationship to trisomic rescue.
Fig. 4: The genomes of microdissected trophoblast clusters.

Data availability

DNA sequencing data are deposited in the European Genome-phenome Archive (EGA) with accession code EGAD00001006337. Sample information and data on mutation burdens and signatures can be found in Supplementary Table 1. Further clinical information can be found in Supplementary Tables 2 and 3. Somatic mutations and embryonic mutations (bulk samples) can be found in Supplementary Tables 4 and 6, respectively. Calls of structural variants with associated copy number changes can be found in Supplementary Table 5.

Code availability

Bespoke R scripts used for analysis and visualization in this study are available online at https://github.com/TimCoorens/Placenta.

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Acknowledgements

We thank M. Zernicka-Goetz, M. Stratton and I. Martincorena for insightful discussions. This experiment was primarily funded by Wellcome (core funding to the Wellcome Sanger Institute, and personal fellowships to T.H.H.C., T.R.W.O. and S.B.). All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The Pregnancy Outcome Prediction study was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Women’s Health theme). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Author information

Affiliations

Authors

Contributions

S.B. designed the experiment. T.H.H.C. performed phylogenetic analyses. T.H.H.C. and T.R.W.O. analysed somatic mutations. T.R.W.O. performed microdissections. R.S., U.S., E.C., R.V.-T., M.H., M.D.Y. and R.R. contributed to experiments or analyses. N.S. provided histopathological expertise. P.J.C. contributed to discussions. S.B., T.H.H.C. and T.R.W.O. wrote the manuscript, aided by D.S.C.-J. and G.C.S.S. D.S.C.-J., G.C.S.S. and S.B. co-directed this study.

Corresponding authors

Correspondence to D. Stephen Charnock-Jones, Gordon C. S. Smith or Sam Behjati.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Daniel Ariad, Marshall Horwitz, Rajiv McCoy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Differences in substitutions between clinical groups.

a, Analysis per clinical group of the substitution burden of each bulk placental sample, adjusted for coverage and median VAF (n = 84, samples from trisomic rescue case not included). The centre values represent the cohort median whilst the lines denote the interquartile range. The difference in substitution burden between the clinical groups is not significant (Kruskal–Wallis rank-sum test, P = 0.7438). b, Mutational signature profiles of each bulk placental sample by their clinical group. Each bar represents a single bulk placental sample. Clinical groups are defined in Supplementary Tables 2, 3.

Extended Data Fig. 2 Unique variants in placental biopsies.

Proportion of variants that are unique to each bulk placental sample (blue), and are therefore absent from matched umbilical cord as well as any other bulk placental sample taken from the same case.

Extended Data Fig. 3 Asymmetry across trophectoderm and umbilical cord.

Heat maps of VAFs of early embryonic mutations, with the two earliest lineages contributing both to the placenta and umbilical cord. Putative earliest mutations are highlighted in red. P, placenta; M, maternal.

Extended Data Fig. 4 Unexplained placental lineages.

Heat maps of VAFs of early embryonic mutations, with the two earliest lineages contributing to the umbilical cord. Putative earliest mutations are highlighted in red. An asterisk indicates that the placental lineage is not fully explained by the umbilical cord (Methods).

Extended Data Fig. 5 Full segregation of placental and umbilical cord lineages.

Heat maps of VAFs of early embryonic mutations, with the umbilical cord being derived from one clonal lineage. In all cases, one or more placental lineages do not share any genetic ancestry with the umbilical cord and are largely unexplained (indicated by an asterisk) (Methods).

Extended Data Fig. 6 Substitution burden per individual trophoblast cluster.

Adjusted for coverage and median VAF.

Extended Data Fig. 7 Indels versus substitutions.

Indel burden versus substitution burden per trophoblast cluster. Both are corrected for median VAF and coverage.

Extended Data Fig. 8 Effects of mutations.

a, b, Overview of functional consequences of the unique SNVs (a) and indels (b) seen in the placental biopsies and trophoblast clusters.

Extended Data Fig. 9 Sensitivity of variant calling.

a, Histogram of the estimated sensitivity for SNV calling in microdissected trophoblast clusters and bulk placenta samples. b, The observed sensitivity of germline variants across placental samples plotted against the coverage of the sample. The red dashed line indicates the predicted sensitivity using the correction that we applied to our cohort.

Extended Data Fig. 10 Signature extraction and deconvolution.

ac, Signature extraction by hierarchical Dirichlet process yielded a noise component (a) and one genuine mutational signature (b), which we convoluted and reconstructed using three reference mutational signatures (SBS1, SBS5 and SBS18) (c).

Supplementary information

Supplementary Results

Exclusion of maternal contamination. Boxplots of B-allele frequency (BAF) of rare SNPs called in mother, but absent from umbilical cord, as an indicator of possible maternal contamination across placental samples.

Reporting Summary

Supplementary Tables

This file contains Supplementary Tables 1-6.

Peer Review File

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Coorens, T.H.H., Oliver, T.R.W., Sanghvi, R. et al. Inherent mosaicism and extensive mutation of human placentas. Nature 592, 80–85 (2021). https://doi.org/10.1038/s41586-021-03345-1

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