Inherent mosaicism and extensive mutation of human placentas
Placentas can exhibit chromosomal aberrations that are absent from the fetus 1 . 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-ge...
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| Veröffentlicht in: | Nature (London) 2021-04, Vol.592 (7852), p.80-85 |
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| creator | Coorens, Tim H. H. Oliver, Thomas R. W. Sanghvi, Rashesh Sovio, Ulla Cook, Emma Vento-Tormo, Roser Haniffa, Muzlifah Young, Matthew D. Rahbari, Raheleh Sebire, Neil Campbell, Peter J. Charnock-Jones, D. Stephen Smith, Gordon C. S. Behjati, Sam |
| description | Placentas can exhibit chromosomal aberrations that are absent from the fetus
1
. 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.
Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development. |
| doi_str_mv | 10.1038/s41586-021-03345-1 |
| format | Article |
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1
. 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.
Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03345-1</identifier><identifier>PMID: 33692543</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45/23 ; 631/136/2086/1986 ; 631/208/135 ; 631/208/212 ; 631/443/494 ; 692/308/2056 ; Aneuploidy ; Biopsy ; Blastocyst Inner Cell Mass - cytology ; Bulk sampling ; Children ; Chromosome aberrations ; Cloning ; Copy number ; Embryos ; Female ; Gene sequencing ; Genome, Human - genetics ; Genomes ; Human tissues ; Humanities and Social Sciences ; Humans ; Mesoderm - cytology ; Mosaicism ; multidisciplinary ; Mutagenesis ; Mutation ; Mutation Rate ; Phylogenetics ; Phylogeny ; Placenta ; Placenta - cytology ; Placenta - metabolism ; Pregnancy ; Science ; Science (multidisciplinary) ; Tissues ; Trisomy - genetics ; Trophoblasts - cytology ; Trophoblasts - metabolism ; Umbilical cord ; Whole genome sequencing ; Zygote - cytology</subject><ispartof>Nature (London), 2021-04, Vol.592 (7852), p.80-85</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature 2021. corrected publication 2022</rights><rights>Copyright Nature Publishing Group Apr 1, 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-8d6611fe6dc5176d417a11dd9c8e4ef4247bcf41aa8200335c32618ec7b1c2e33</citedby><cites>FETCH-LOGICAL-c540t-8d6611fe6dc5176d417a11dd9c8e4ef4247bcf41aa8200335c32618ec7b1c2e33</cites><orcidid>0000-0002-5826-3554 ; 0000-0002-1839-7785 ; 0000-0002-0799-1105 ; 0000-0002-9870-8474 ; 0000-0002-7703-9216 ; 0000-0002-3927-2084 ; 0000-0003-4306-0102 ; 0000-0002-6142-4443 ; 0000-0003-2124-0997 ; 0000-0002-3921-0510 ; 0000-0002-6600-7665 ; 0000-0002-2936-4890</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03345-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03345-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33692543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coorens, Tim H. H.</creatorcontrib><creatorcontrib>Oliver, Thomas R. W.</creatorcontrib><creatorcontrib>Sanghvi, Rashesh</creatorcontrib><creatorcontrib>Sovio, Ulla</creatorcontrib><creatorcontrib>Cook, Emma</creatorcontrib><creatorcontrib>Vento-Tormo, Roser</creatorcontrib><creatorcontrib>Haniffa, Muzlifah</creatorcontrib><creatorcontrib>Young, Matthew D.</creatorcontrib><creatorcontrib>Rahbari, Raheleh</creatorcontrib><creatorcontrib>Sebire, Neil</creatorcontrib><creatorcontrib>Campbell, Peter J.</creatorcontrib><creatorcontrib>Charnock-Jones, D. Stephen</creatorcontrib><creatorcontrib>Smith, Gordon C. S.</creatorcontrib><creatorcontrib>Behjati, Sam</creatorcontrib><title>Inherent mosaicism and extensive mutation of human placentas</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Placentas can exhibit chromosomal aberrations that are absent from the fetus
1
. 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.
Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.</description><subject>45/23</subject><subject>631/136/2086/1986</subject><subject>631/208/135</subject><subject>631/208/212</subject><subject>631/443/494</subject><subject>692/308/2056</subject><subject>Aneuploidy</subject><subject>Biopsy</subject><subject>Blastocyst Inner Cell Mass - cytology</subject><subject>Bulk sampling</subject><subject>Children</subject><subject>Chromosome aberrations</subject><subject>Cloning</subject><subject>Copy number</subject><subject>Embryos</subject><subject>Female</subject><subject>Gene sequencing</subject><subject>Genome, Human - genetics</subject><subject>Genomes</subject><subject>Human tissues</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Mesoderm - cytology</subject><subject>Mosaicism</subject><subject>multidisciplinary</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Mutation Rate</subject><subject>Phylogenetics</subject><subject>Phylogeny</subject><subject>Placenta</subject><subject>Placenta - cytology</subject><subject>Placenta - metabolism</subject><subject>Pregnancy</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Tissues</subject><subject>Trisomy - genetics</subject><subject>Trophoblasts - cytology</subject><subject>Trophoblasts - metabolism</subject><subject>Umbilical cord</subject><subject>Whole genome sequencing</subject><subject>Zygote - cytology</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kEtLAzEQx4Motla_gAdZ8BzN5LUpiCDFR6HgRc8hzWbbLd1sTXaLfntTW6tePM1h_o-ZH0LnQK6AMHUdOQglMaGACWNcYDhAfeC5xFyq_BD1CaEKE8VkD53EuCCECMj5MeoxJodUcNZHN2M_d8H5NqubaCpbxTozvsjce-t8rNYuq7vWtFXjs6bM5l1tfLZaGpscJp6io9IsozvbzQF6fbh_GT3hyfPjeHQ3wVZw0mJVSAlQOlnY1C8LDrkBKIqhVY67klOeT23JwRhFSfpEWEYlKGfzKVjqGBug223uqpvWrtiUB7PUq1DVJnzoxlT678ZXcz1r1jpPvZLzFHC5CwjNW-diqxdNF3y6WVNBhoQJRWVS0a3KhibG4Mp9AxC9Ia63xHUirr-Ia0imi9-37S3fiJOAbQUxrfzMhZ_uf2I_AfvljLA</recordid><startdate>20210401</startdate><enddate>20210401</enddate><creator>Coorens, Tim H. 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H.</au><au>Oliver, Thomas R. W.</au><au>Sanghvi, Rashesh</au><au>Sovio, Ulla</au><au>Cook, Emma</au><au>Vento-Tormo, Roser</au><au>Haniffa, Muzlifah</au><au>Young, Matthew D.</au><au>Rahbari, Raheleh</au><au>Sebire, Neil</au><au>Campbell, Peter J.</au><au>Charnock-Jones, D. Stephen</au><au>Smith, Gordon C. S.</au><au>Behjati, Sam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inherent mosaicism and extensive mutation of human placentas</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-04-01</date><risdate>2021</risdate><volume>592</volume><issue>7852</issue><spage>80</spage><epage>85</epage><pages>80-85</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Placentas can exhibit chromosomal aberrations that are absent from the fetus
1
. 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.
Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33692543</pmid><doi>10.1038/s41586-021-03345-1</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-5826-3554</orcidid><orcidid>https://orcid.org/0000-0002-1839-7785</orcidid><orcidid>https://orcid.org/0000-0002-0799-1105</orcidid><orcidid>https://orcid.org/0000-0002-9870-8474</orcidid><orcidid>https://orcid.org/0000-0002-7703-9216</orcidid><orcidid>https://orcid.org/0000-0002-3927-2084</orcidid><orcidid>https://orcid.org/0000-0003-4306-0102</orcidid><orcidid>https://orcid.org/0000-0002-6142-4443</orcidid><orcidid>https://orcid.org/0000-0003-2124-0997</orcidid><orcidid>https://orcid.org/0000-0002-3921-0510</orcidid><orcidid>https://orcid.org/0000-0002-6600-7665</orcidid><orcidid>https://orcid.org/0000-0002-2936-4890</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-04, Vol.592 (7852), p.80-85 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7611644 |
| source | MEDLINE; SpringerLink Journals; Nature Journals Online |
| subjects | 45/23 631/136/2086/1986 631/208/135 631/208/212 631/443/494 692/308/2056 Aneuploidy Biopsy Blastocyst Inner Cell Mass - cytology Bulk sampling Children Chromosome aberrations Cloning Copy number Embryos Female Gene sequencing Genome, Human - genetics Genomes Human tissues Humanities and Social Sciences Humans Mesoderm - cytology Mosaicism multidisciplinary Mutagenesis Mutation Mutation Rate Phylogenetics Phylogeny Placenta Placenta - cytology Placenta - metabolism Pregnancy Science Science (multidisciplinary) Tissues Trisomy - genetics Trophoblasts - cytology Trophoblasts - metabolism Umbilical cord Whole genome sequencing Zygote - cytology |
| title | Inherent mosaicism and extensive mutation of human placentas |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T03%3A08%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inherent%20mosaicism%20and%20extensive%20mutation%20of%20human%20placentas&rft.jtitle=Nature%20(London)&rft.au=Coorens,%20Tim%20H.%20H.&rft.date=2021-04-01&rft.volume=592&rft.issue=7852&rft.spage=80&rft.epage=85&rft.pages=80-85&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-021-03345-1&rft_dat=%3Cproquest_pubme%3E2509035826%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2509035826&rft_id=info:pmid/33692543&rfr_iscdi=true |