Yeongjun Jang1, Livia Tomasini2, Taejeong Bae1, Anna Szekely3, Flora M. Vaccarino2,4,5,* and Alexej Abyzov
1 Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
2 Child Study Center, Yale University, New Haven, CT 06520, USA
3 Department of Neurology, Yale University, New Haven, CT 06520, USA
4 Department of Neuroscience, Yale University, New Haven, CT 06520, USA
5 Yale Kavli Institute for Neuroscience, New Haven, CT 06520, USA
abyzov.alexej [at] mayo.edu and flora.vaccarino [at] yale.edu
Abstract
Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We found that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyses of public data from several multi-children families and from 1,934 familial quads confirmed this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyses of all the data consistently suggest that germline has a balanced 50:50 lineage allocation from the first two blastomeres.
Keywords: somatic mosaicism, mutations, cell lineage tracing, development, germline
Acknowledgement: We are grateful to member of NC0 family that participated in this study by donating tissue and/or blood samples. We are grateful to members of families in SSC that donated blood samples for WGS and to Simons Foundation that provided access to the data (approved project 2343.4). This work was funded by the NIH Common Fund SMaHT program (grants UG3 NS132128 and UG3 NS132146) and by the Simons Foundation (grant 399558). Y.J. was also supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number 2022R1A6A3A03055692).