Early embryonic mutations reveal dynamics of somatic and germ cell lineages in mice
- Arikuni Uchimura1,2,
- Hirotaka Matsumoto3,4,
- Yasunari Satoh1,
- Yohei Minakuchi5,
- Sayaka Wakayama6,
- Teruhiko Wakayama6,7,
- Mayumi Higuchi2,
- Masakazu Hashimoto8,
- Ryutaro Fukumura9,
- Atsushi Toyoda5,
- Yoichi Gondo9 and
- Takeshi Yagi2
- 1Department of Molecular Biosciences, Radiation Effects Research Foundation, Hiroshima, Hiroshima, 732-0815, Japan;
- 2KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan;
- 3School of Information and Data Sciences, Nagasaki University, Nagasaki, Nagasaki, 852-8521, Japan;
- 4Laboratory for Bioinformatics Research, RIKEN Center for Biosystems and Dynamics Research, Wako, Saitama, 351-0198, Japan;
- 5Comparative Genomics Laboratory, National Institute of Genetics, Mishima, Shizuoka, 411-8540, Japan;
- 6Advanced Biotechnology Centre, University of Yamanashi, Kofu, Yamanashi, 400-8510, Japan;
- 7Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Yamanashi, 400-8510, Japan;
- 8Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan;
- 9Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276363.121.
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Freely available online through the Genome Research Open Access option.
- Received November 8, 2021.
- Accepted April 1, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
