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Clonal dynamics in early human embryogenesis inferred from somatic mutation

机译：早期人类胚胎发生中的克隆动力学从躯体突变推断

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摘要

Cellular dynamics and fate decision in early human embryogenesis remain largely unknown owing to the challenges of performing studies in human embryos~(1). Here, we explored whole-genomes of 334 single-cell colonies and targeted deep sequences of 379 bulk tissues obtained from various anatomical locations of seven recently deceased adult human donors. Using somatic mutations as an intrinsic barcode, we reconstructed early cellular phylogenies that demonstrate (1) an endogenous mutational rate that is higher in the first cell division but decreases to approximately one per cell per cell division later in life; (2) universal unequal contribution of early cells to embryo proper, resulting from early cellular bottlenecks that stochastically set aside epiblast cells within the embryo; (3) examples of varying degrees of early clonal imbalances between tissues on the left and right sides of the body, different germ layers and specific anatomical parts and organs; (4) emergence of a few ancestral cells that will substantially contribute to adult cell pools in blood and liver; and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach also provides insights into the age-related mutational processes and loss of sex chromosomes in normal somatic cells. In sum, this study provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.
机译：由于在人胚胎中进行研究〜（1）的挑战，早期人类胚胎发生的细胞动力学和命运决定仍然很好。在这里，我们探讨了334个单细胞菌落的全基因组，并靶向从七个最近已故的成年人体供体的各种解剖学位置获得的379个散装组织的深层序列。使用体细胞突变作为内在条形码，我们重建早期细胞生成，证明（1）在第一细胞分裂中更高的内源性突变率，但在寿命后面的每种细胞分裂下降至每种细胞的大约一个细胞; （2）普及早期细胞对胚胎的不等贡献适当，是由于早期细胞瓶颈，随机预留在胚胎内的外壳细胞; （3）体内左侧和右侧的组织之间的不同程度的早期克隆性失调的实例，不同的胚层和特异性解剖部件和器官; （4）少数祖先细胞的出现，将对血液和肝脏的成人细胞库产生显着贡献; （5）受精卵中的线粒体DNA异质存在。我们的方法还提供了与正常体细胞中与年龄相关的突变过程和性染色体丧失的见解。总而言之，本研究为未来的研究提供了在人胚胎发生中完全细胞发育的研究基础。

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  • 来源
    《Nature》 |2021年第7876期|393-397|共5页
  • 作者

    Seongyeol Park; Nanda Maya Mali; Ryul Kim; Jeong-Woo Choi; Junehawk Lee; Joonoh Lim; Jung Min Park; Jung Woo Park; Donghyun Kim; Taewoo Kim; Kijong Yi; June Hyug Choi; Seong Gyu Kwon; Joo Hee Hong; Jeonghwan Youk; Yohan An; Su Yeon Kim; Soo A Oh; Youngoh Kwon; Dongwan Hong; Moonkyu Kim; Dong Sun Kim; Ji Young Park; Ji Won Oh; Young Seok Ju;

  • 作者单位

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST)|GENOME INSIGHT Inc;

    Department of Anatomy School of Medicine Kyungpook National University;

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Department of Anatomy School of Medicine Kyungpook National University|Immune Square Inc;

    Korea Institute of Science and Technology Information (KISTI);

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Department of Anatomy School of Medicine Kyungpook National University|Immune Square Inc;

    Korea Institute of Science and Technology Information (KISTI);

    Department of Anatomy School of Medicine Kyungpook National University|Immune Square Inc;

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Department of Anatomy School of Medicine Kyungpook National University;

    Department of Anatomy School of Medicine Kyungpook National University;

    Department of Anatomy School of Medicine Kyungpook National University;

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST);

    GENOME INSIGHT Inc;

    Department of Medical Informatics College of Medicine Catholic University of Korea;

    Department of Immunology School of Medicine Kyungpook National University;

    Department of Anatomy School of Medicine Kyungpook National University;

    Department of Pathology Kyungpook National University Chilgok Hospital School of Medicine Kyungpook National University;

    Department of Anatomy School of Medicine Kyungpook National University|Immune Square Inc|Biomedical Research Institute Kyungpook National University Hospital;

    Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST)|GENOME INSIGHT Inc;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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