Abstract
Mosaicisms caused by postzygotic mutational events are of increasing interest because of their potential association with various human diseases. Postzygotic somatic mutations have not been well characterized however in terms of their developmental lineage in humans. We conducted whole-genome sequencing (WGS) and targeted deep sequencing in 15 organs across three developmental lineages from a single male fetus with polycystic kidney disease (PKD) of 21 weeks gestational age. This fetus had no detectable neurological abnormalities at autopsy but germline mutations in the PKHD1 gene were identified that may have been associated with the PKD. Eight early embryonic mosaic variants with no alteration of protein function were detected. These variants were thought to have occurred at the two or four cell stages after fertilization with a mutational pattern involving frequent C>T and T>C transitions. In our current analyses, no tendency toward organ-specific mutation occurrences was found as the eight variants were detected in all 15 organs. However different allele fractions of these variants were found in different organs, suggesting a tissue-specific asymmetric growth of cells that reflected the developmental germ layer of each organ. This indicated that somatic mutation occurrences, even in early embryogenesis, can affect specific organ development or disease. Our current analyses demonstrate that multi-organ analysis is helpful for understanding genomic mosaicism. Our results also provide insights into the biological role of mosaicism in embryonic development and disease.
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Acknowledgements
This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRFK) (NRF-2019R1A2C1084460), and the Bio and Medical Technology Development Program of the NRFK (NRF-2017M3A9G5061671 and NRF-2019M3E5D4066900) of the Korean government.
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COS and SMC designed the study. HJL and COS analyzed the data and interpreted the results. HJL and COS designed and generated all of the figures. ENK, SMC, JYL, and COS collected and generated data. SMC, JHK, JHO, WKK, EJC, and JL contributed to data analysis and interpretation. COS, HJL, ENK, and SMC wrote the paper.
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Lee, H., Kim, E.N., Lee, JY. et al. Characterization of early postzygotic somatic mutations through multi-organ analysis. J Hum Genet 66, 777–784 (2021). https://doi.org/10.1038/s10038-021-00908-y
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DOI: https://doi.org/10.1038/s10038-021-00908-y
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