De novo mutations accumulate with zygotic cell divisions. However, the occurrence of these mutations and the way they are inherited by somatic cells and germ cells remain unclear. Here, we present a novel method to reconstruct cell lineages. We identified mosaic mutations in mice using deep whole-genome sequencing and reconstructed embryonic cell lineages based on the variant allele frequencies of the mutations. The reconstructed trees were confirmed using nuclear transfer experiments and the genotyping of approximately 50 offspring of each tree. The most detailed tree had 32 terminal nodes and showed cell divisions from the fertilized egg to germ cell– and somatic cell–specific lineages, indicating at least five independent cell lineages that would be selected as founders of the primordial germ cells. The contributions of each lineage to germ cells and offspring varied widely. At the emergence of the germ cell–specific lineages, 10–15 embryonic mutations had accumulated, suggesting that the pregastrulation mutation rate is 1.0 mutation per mitosis. Subsequent mutation rates were 0.7 for germ cells and 13.2 for tail fibroblasts. Our results show a new framework to assess embryonic lineages; further, we suggest an evolutionary strategy for preserving heterogeneity owing to postzygotic mutations in offspring.

中文翻译：

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早期胚胎突变揭示了小鼠体细胞和生殖细胞谱系的动态

从头突变随着合子细胞分裂而积累。然而，这些突变的发生以及它们被体细胞和生殖细胞遗传的方式仍不清楚。在这里，我们提出了一种重建细胞谱系的新方法。我们使用深度全基因组测序鉴定了小鼠的镶嵌突变，并根据突变的变异等位基因频率重建了胚胎细胞谱系。使用核移植实验和每棵树的大约 50 个后代的基因分型来确认重建的树。最详细的树有 32 个末端节点，显示了从受精卵到生殖细胞和体细胞特异性谱系的细胞分裂，表明至少有五个独立的细胞谱系将被选为原始生殖细胞的创始人。每个谱系对生殖细胞和后代的贡献差异很大。在生殖细胞特异性谱系出现时，已经积累了 10-15 个胚胎突变，这表明原肠胚形成前的突变率为每个有丝分裂 1.0 个突变。生殖细胞的后续突变率为 0.7，尾成纤维细胞的突变率为 13.2。我们的结果显示了评估胚胎谱系的新框架；此外，我们提出了一种进化策略来保留由于后代的合子后突变而导致的异质性。我们的结果显示了评估胚胎谱系的新框架；此外，我们提出了一种进化策略来保留由于后代的合子后突变而导致的异质性。我们的结果显示了评估胚胎谱系的新框架；此外，我们提出了一种进化策略来保留由于后代的合子后突变而导致的异质性。