Extensive phylogenies of human development inferred from somatic mutations
Extensive phylogenies of human development inferred from somatic mutations
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DOI：
10.1038/s41586-021-03790-y
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发表时间：
2021-08-25
期刊：
影响因子：
64.8
通讯作者：
Stratton, Michael R.
中科院分区：
文献类型：
--
作者：
Coorens, Tim H. H.;Moore, Luiza;Stratton, Michael R.
从受精卵开始，人体内的所有细胞都不断获得突变。不同细胞之间共享的突变意味着共同的祖先，因此是谱系追踪的天然存在的标记物（1，2）。在这里，我们重建了广泛的正常组织从三个成年人使用511激光捕获显微切割全基因组测序。同一世代的重组胚胎祖细胞往往对成体有不同程度的贡献。这种不对称的程度因个体而异，受精卵的两个重建子细胞之间的比例从60：40到93：7不等。不对称性在后代中普遍存在，并且可以在同一个体的组织之间存在差异。胚胎干细胞能分辨出组织的空间胚胎模式，揭示出成年结肠上皮中平均301个隐窝的连续斑块，这些隐窝来自最近的胚胎细胞，也是大脑发育中的空间效应。利用另外10名男性的数据，我们研究了索马和生殖细胞之间的发育分裂，结果表明胚胎外对原始生殖细胞的贡献。这项研究表明，尽管达到了相同的最终组织模式，早期瓶颈和血统承诺导致个体内部和个体之间的胚胎模式发生重大变化。
Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing(1,2). Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.