Inherent mosaicism and extensive mutation of human placentas.
Inherent mosaicism and extensive mutation of human placentas.
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DOI：
10.1038/s41586-021-03345-1
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发表时间：
2021-04
期刊：
影响因子：
64.8
通讯作者：
Behjati S
中科院分区：
文献类型：
--
作者：
Coorens THH;Oliver TRW;Sanghvi R;Sovio U;Cook E;Vento-Tormo R;Haniffa M;Young MD;Rahbari R;Sebire N;Campbell PJ;Charnock-Jones DS;Smith GCS;Behjati S
胎盘可能表现出胎儿所没有的染色体畸变。这种遗传分离的基础，被称为受限胎盘嵌合体，仍然是未知的。在这里，我们研究了从体细胞突变重建的人类胎盘细胞的系统发育，使用了86个大胎盘样本（中位重量为28mg）和106个显微切片的全基因组测序。我们发现，就突变负担和突变印记而言，每个大胎盘样本都代表了基因上独特的克隆扩增，表现出类似于儿童癌症的基因组景观。此外，与迄今为止研究的任何其他正常人体组织不同，胎盘基因组通常包含拷贝数变化。重建同一妊娠组织之间的系统发育关系表明，发育瓶颈通过将滋养外胚层从内细胞群衍生谱系中分离出来，在遗传上隔离了胎盘组织。特别值得注意的是，在合子的几次细胞分裂中，内细胞团衍生和胎盘谱系完全分离。这种早期胚胎瓶颈可能使合子非整倍体正常化。我们在一个马赛克三体抢救的案例中观察到直接的证据。我们的研究结果揭示了胎盘组织中广泛的突变，并将嵌合描述为胎盘发育的正常特征。
Placentas may exhibit chromosomal aberrations that are absent from the fetus. The basis of this genetic segregation, termed confined placental mosaicism, remains unknown. Here, we investigated the phylogeny of human placental cells reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (median weight 28mg) and of 106 microdissections. We found that every bulk placental sample represented a clonal expansion that is genetically distinct, exhibiting a genomic landscape akin to childhood cancer, in terms of mutation burden and mutational imprints. Furthermore, unlike any other normal human tissue studied to date, placental genomes commonly harboured copy number changes. Reconstructing phylogenetic relationships between tissues from the same pregnancy revealed that developmental bottlenecks genetically isolate placental tissues, by separating trophectodermal from inner cell mass derived lineages. Of particular note were cases in which inner cell mass derived and placental lineages fully segregated within a few cell divisions of the zygote. Such early embryonic bottlenecks may enable the normalisation 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 portray mosaicism as a normal feature of placental development.
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DOI：
10.1056/nejmoa2000962
发表时间：
2020-11-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Coorens THH;Farndon SJ;Mitchell TJ;Jain N;Lee S;Hubank M;Sebire N;Anderson J;Behjati S
通讯作者：
Behjati S
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
12.3
作者：
Buels R;Yao E;Diesh CM;Hayes RD;Munoz-Torres M;Helt G;Goodstein DM;Elsik CG;Lewis SE;Stein L;Holmes IH
通讯作者：
Holmes IH
DOI：
10.1126/science.aau3879
发表时间：
2018-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH
通讯作者：
Jones PH
影响因子：
16.6
作者：
Bolton H;Graham SJL;Van der Aa N;Kumar P;Theunis K;Fernandez Gallardo E;Voet T;Zernicka-Goetz M
通讯作者：
Zernicka-Goetz M