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KMID : 1377020220190040809
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Tissue Engineering and Regenerative Medicine
2022 Volume.19 No. 4 p.809 ~ p.821
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Asymmetric Contribution of Blastomere Lineages of First Division of the Zygote to Entire Human Body Using Post-Zygotic Variants
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Kwon Seong-Gyu
Bae Geon-Hue
Choi June-Hyug
Mali Nanda Maya
Jun Mee-Sook
Kim Dong-Sun
Han Man-Hoon
Park Seong-Yeol
Ju Young-Seok
Choi Seock-Hwan
Oh Ji-Won
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Abstract
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Background: In humans, after fertilization, the zygote divides into two 2n diploid daughter blastomeres. During this division, DNA is replicated, and the remaining mutually exclusive genetic mutations in the genome of each cell are called post-zygotic variants. Using these somatic mutations, developmental lineages can be reconstructed. How these two blastomeres are contributing to the entire body is not yet identified. This study aims to evaluate the cellular contribution of two blastomeres of 2-cell embryos to the entire body in humans using post-zygotic variants based on whole genome sequencing.
Methods: Tissues from different anatomical areas were obtained from five donated cadavers for use in single-cell clonal expansion and bulk target sequencing. After conducting whole genome sequencing, computational analysis was applied to find the early embryonic mutations of each clone. We developed our in-house bioinformatics pipeline, and filtered variants using strict criteria, composed of mapping quality, base quality scores, depth, soft-clipped reads, and manual inspection, resulting in the construction of embryological phylogenetic cellular trees.
Results: Using our in-house pipeline for variant filtering, we could extract accurate true positive variants, and construct the embryological phylogenetic trees for each cadaver. We found that two daughter blastomeres, L1 and L2 (lineage 1 and 2, respectively), derived from the zygote, distribute unequally to the whole body at the clonal level. From bulk target sequencing data, we validated asymmetric contribution by means of the variant allele frequency of L1 and L2. The asymmetric contribution of L1 and L2 varied from person to person.
Conclusion: We confirmed that there is asymmetric contribution of two daughter blastomeres from the first division of the zygote across the whole human body.
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KEYWORD
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Clonal expansion, Somatic mutation, Lineage tracing, Asymmetry, Early embryonic mutations, Mutation filtering
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