Early embryonic mutations reveal dynamics of somatic and germ cell lineages in mice

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.

Comprehensive benchmarking and guidelines of mosaic variant calling strategies

“…In summary, we anticipate that our study will guide researchers to the best use of current algorithms. We expect that accurate analysis of mosaic variants will broaden our understanding of fundamental human development, as well as other model organisms 5,31 . Also, for method developers, our study will be a good starting point for technical advances in mosaic variant calling to the germline and somatic variant levels.…”

“…Postzygotic mutations continuously occur along the zygote-to-adult trajectory, resulting in genetic mosaicism. Recently, the capabilities to examine the mosaic mutations at the genome level have led to a series of discoveries, including the mutational processes and landscapes involved in the development [1][2][3] and aging 4 of human and nonhuman organisms 5 , the causes of neurological disorders 6 and cancer predispositions 7 . As research questions are being answered, growing attention and demand are required for the complete investigation of mosaicism, warranted by the accurate detection of mosaic mutations.…”

Massive expansion of multiple clones in the mouse hematopoietic system long after whole-body X-irradiation

“…The Nell2 SNV, an early embryogenic SNV mutation identified in this study, was expanded massively in hematopoietic cells; however, when this expansion occurred remains unknown. We recently developed a method for reconstructing early embryonic cell lineages using spontaneous de novo mutations that are detected directly using deep-coverage whole-genome sequencing of adult tissues to reconstruct the lineages based on the relationship of VAFs between mosaic mutations 36 . Using this method, we revealed that one spontaneous mutation occurs per cell division in early mouse embryos (before gastrulation) and that its distribution varies between embryonic tissues after gastrulation.…”

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era

“…Interestingly, de novo genetic mutations accumulate even with the first zygotic cell divisions [208], so in-womb development represents a "sensitive window" for the introduction of mutations because of a higher rate of cellular proliferation [209]. A human cell must repair over 10,000 DNA lesions per day to counteract the intrinsic causes of DNA damage, but it is also necessary to consider the lesions induced by environmental sources of DNA damage [210].…”