Abstract
Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans. De novo mutations act as cell markers, allowing the tracing of developmental trajectories of all descendants of the cell in which the new mutation arises. De novo mutations may arise at any time during development but are relatively rare. They have usually been observed through medical ascertainment, when the mutation causes unusual clinical signs or symptoms. Mutational events can include aneuploidies, large chromosomal rearrangements, copy number variants, or point mutations. In this review we focus primarily on the analysis of point mutations and their utility in addressing questions of germ line versus somatic lineages. Genetic mosaics demonstrate that the germ line and soma diverge early in development, since there are many examples of combined somatic and germ line mosaicism for de novo mutations. The occurrence of simultaneous mosaicism in both the germ line and soma also shows that the germ line is not strictly clonal but arises from at least two, and possibly multiple, cells in the embryo with different ancestries. Whole genome or exome DNA sequencing technologies promise to expand the range of studies of genetic mosaics, as de novo mutations can now be identified through sequencing alone in the absence of a medical ascertainment. These technologies have been used to study mutation patterns in nuclear families and in monozygotic twins, and in animal model developmental studies, but not yet for extensive cell lineage studies in humans.
Highlights
Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans
The first cells that have been identified in humans as contributing to the germ line are progenitor germ cells (PGCs), which are distinguished by their specific cellular morphology and high-level expression of alkaline phosphatase [2,3,4]
As other tissues were not tested, nor was deep resequencing yet available, conceivably some of the other three cases may have involved parental somatic mosaics. It remains to be seen whether similar statistics are obtained for other large ascertainments in which the requisite studies are performed, but these results suggest that combined somatic and germ line mutation is relatively common among families with some evidence of mosaicism
Summary
The cells that give rise to the germ line in humans are set aside early during embryogenesis [1]. Two or more cells with different ancestries might independently be recruited as FGCs ( referred to as FGC1,2,3,...) In humans, these alternatives are impossible to resolve through histological observation alone, given the narrow time windows, the small number of cells involved at the earliest stage of germ line recruitment, and the very limited opportunity to examine human embryos at exactly the right point in development. Germ cell development has been studied using spontaneous and mutagen-induced mosaicism in mice, providing evidence of a polyclonal origin of the germ line in both males and females [22] In another approach, animals such as mice or chicks can be created as chimeras having mixed cell populations by physically merging two or more embryos with different genetic backgrounds. Such physical chimeras have been observed as rare spontaneous events in humans, arising through fusion in multi-embryonic pregnancies [23,24]
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