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Inherent mosaicism and extensive mutation of human placentas.

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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.



Biopsy, Blastocyst Inner Cell Mass, Female, Genome, Human, Humans, Mesoderm, Mosaicism, Mutagenesis, Mutation, Mutation Rate, Placenta, Pregnancy, Trisomy, Trophoblasts, Zygote

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Springer Science and Business Media LLC


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Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Biotechnology and Biological Sciences Research Council (BB/R008590/1)
This experiment was primarily funded by Wellcome (core funding to Wellcome Sanger Institute; personal fellowships to T.H.H.C, T.R.W.O., 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 POP study was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Women’s Health theme).