RT Journal Article
SR Electronic
T1 Clonal dynamics in early human embryogenesis inferred from somatic mutation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.23.395244
DO 10.1101/2020.11.23.395244
A1 Seongyeol Park
A1 Nanda Maya Mali
A1 Ryul Kim
A1 Jeong-Woo Choi
A1 Junehawk Lee
A1 Joonoh Lim
A1 Jung Min Park
A1 Jung Woo Park
A1 Donghyun Kim
A1 Taewoo Kim
A1 Kijong Yi
A1 June Hyug Choi
A1 Seong Gyu Kwon
A1 Joo Hee Hong
A1 Jeonghwan Youk
A1 Yohan An
A1 Su Yeon Kim
A1 Moonkyu Kim
A1 Dong Sun Kim
A1 Ji Young Park
A1 Ji Won Oh
A1 Young Seok Ju
YR 2020
UL http://biorxiv.org/content/early/2020/11/24/2020.11.23.395244.abstract
AB The trillions of cells that constitute the human body are developed from a fertilized egg through embryogenesis. However, cellular dynamics and developmental outcomes of embryonic cells in humans remain to be largely unknown due to the technical and ethical challenges. Here, we explored whole-genomes of 334 single-cell expanded clones and targeted deep-sequences of 379 bulk tissues obtained from various anatomical locations from seven individuals. Using the discovered 1,688,652 somatic mutations as an intrinsic barcode, we reconstructed cellular phylogenetic trees that provide novel insights into early human embryogenesis. Our findings suggest (1) endogenous mutational rate that is higher in the first cell division of life but decreases to ~1 per cell per cell division later in life, (2) universal unequal contribution of early cells into embryo proper resulting from early cellular bottlenecks that stochastically separate epiblasts from embryonic cells (3) uneven differential outcomes of early cells into three germ layers, left-right and cranio-caudal tissues, (4) emergence of a few ancestral cells that will contribute to the substantial fraction of adult blood cells, and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach additionally provides insights into the age-related mutational processes including UV-mediated mutagenesis and loss of chromosome X or Y in normal somatic cells. Taken together, this study scrutinized somatic mosaicism, clonal architecture, and cellular dynamics in human embryogenesis at an unprecedented level and provides a foundation for future studies to complete cellular phylogenies in human embryogenesis.Competing Interest StatementThe authors have declared no competing interest.