A model for postzygotic mosaicisms quantifies the allele fraction drift, mutation rate, and contribution to de novo mutations
- Adam Yongxin Ye1,2,3,6,
- Yanmei Dou1,4,6,
- Xiaoxu Yang1,
- Sheng Wang4,5,
- August Yue Huang1 and
- Liping Wei1
- 1Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, People's Republic of China;
- 2Peking-Tsinghua Center for Life Sciences, Beijing 100871, People's Republic of China;
- 3Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, People's Republic of China;
- 4National Institute of Biological Sciences, Beijing 102206, People's Republic of China;
- 5College of Biological Sciences, China Agricultural University, Beijing 100094, People's Republic of China
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↵6 These authors contributed equally to this work.
Abstract
The allele fraction (AF) distribution, occurrence rate, and evolutionary contribution of postzygotic single-nucleotide mosaicisms (pSNMs) remain largely unknown. In this study, we developed a mathematical model to describe the accumulation and AF drift of pSNMs during the development of multicellular organisms. By applying the model, we quantitatively analyzed two large-scale data sets of pSNMs identified from human genomes. We found that the postzygotic mutation rate per cell division during early embryogenesis, especially during the first cell division, was higher than the average mutation rate in either male or female gametes. We estimated that the stochastic cell death rate per cell cleavage during human embryogenesis was ∼5%, and parental pSNMs occurring during the first three cell divisions contributed to ∼10% of the de novo mutations observed in children. We further demonstrated that the genomic profiles of pSNMs could be used to measure the divergence distance between tissues. Our results highlight the importance of pSNMs in estimating recurrence risk and clarified the quantitative relationship between postzygotic and de novo mutations.
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 http://www.genome.org/cgi/doi/10.1101/gr.230003.117.
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Freely available online through the Genome Research Open Access option.
- Received September 7, 2017.
- Accepted May 2, 2018.
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/.
