Early developmental asymmetries in cell lineage trees in living individuals

Abstract

Mosaic mutations can be used to track cell lineages in humans. We used cell cloning to analyze embryonic cell lineages in two living individuals and a postmortem human specimen. Of 10 reconstructed postzygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals, one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

Single-Cell Approaches to Deconvolute the Development of HSCs

“…Notably, a high fraction of indels occurred among the recessive lineage compared with the dominant lineage, which indicated that DNA repair efficiency contributed to this imbalanced lineage differentiation. Further analysis confirmed that most SNVs resulted from the consecutive deamination of 5-methylcytosine [ 46 ]. Another paper in the same issue of Science led by Peter J.…”

All2: A tool for selecting mosaic mutations from comprehensive multi-cell comparisons

“…Such mutations are likely present at a higher fraction of cells in a tissue, yet at a lower fraction than germline variant. For example, such mutations could occur during early development and be present in a high fraction of cells across tissues in the human body (6). The distribution of mutations (as dots) on a plane with axes corresponding to the two scores can be used to divide the calls into mosaic mutations, germline variants, noise or false positive (low mosaic and low germline score) and high frequency mosaic mutations (high mosaic and high germline score) (Fig.…”

“…2A&C), all mutations from All 2 , bulk, and pairwise comparison were used. For details, including calling mosaic mutation from bulk tissue and lineage tree construction please refer to the method section of Fasching et al (6).…”

“…All primary data for iPSC lines we used for lineage reconstruction were accessed from at NIH NIHM Data Archives (https://nda.nih.gov/study.html?id=1057) (6). All primary data for fetal brain we used in ADA mode were accessed from NIH NIMH Data Archives(https://nda.nih.gov/edit_collection.html?id=2330)…”

Somatic mutations reveal hypermutable brains and are associated with neuropsychiatric disorders

“…Somatic mutations naturally occur in proliferative and post-mitotic cells throughout human development and during aging, starting from the first cleavage of the zygote (1)(2)(3)(4). An open question is: how frequent are somatic mutations in the population, and are they a contributing factor to the etiology of neuropsychiatric disorders (5)?…”