Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

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 pregastrulation 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.