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Genetic mosaics and the germ line lineage.

Samuels ME, Friedman JM - Genes (Basel) (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Montreal, Montreal, QC H3T 1C5, Canada. mark.e.samuels@umontreal.ca.

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.

No MeSH data available.


Related in: MedlinePlus

Potential anatomical patterns of mosaicism based on the lineage and mutational scenarios of Figure 1. Each panel is matched to the equivalent panel in Figure 1 (panel A, germ line clonal, mutation in soma; B, germ line clonal, mutation in cell ancestral to germ line and some of soma; C, germ line clonal, mutation in germ line; D, germ line not clonal, mutation in cell ancestral to some of germ line and some of soma). The germ line is presented as two circles in the lower abdomen, either wild type (unshaded) or mutant (black). Patches of somatic tissue carrying a de novo mutation are shown as irregular black shapes and may include skin and/or any other kind of somatic cells. In panels (C) and (D), germ line mosaicism is shown in both the right and left gonad, but other gonad patterns are likely as well, depending on how the primordial gonads are populated by PGCs. Relative sizes of the germ line versus soma are not to scale; the germ line in humans is obviously much smaller than the soma in physical size and cell number. Patterns of mosaicism are also not meant to be interpreted literally, other than inclusion or exclusion of all or part of germ line versus soma.
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genes-06-00216-f002: Potential anatomical patterns of mosaicism based on the lineage and mutational scenarios of Figure 1. Each panel is matched to the equivalent panel in Figure 1 (panel A, germ line clonal, mutation in soma; B, germ line clonal, mutation in cell ancestral to germ line and some of soma; C, germ line clonal, mutation in germ line; D, germ line not clonal, mutation in cell ancestral to some of germ line and some of soma). The germ line is presented as two circles in the lower abdomen, either wild type (unshaded) or mutant (black). Patches of somatic tissue carrying a de novo mutation are shown as irregular black shapes and may include skin and/or any other kind of somatic cells. In panels (C) and (D), germ line mosaicism is shown in both the right and left gonad, but other gonad patterns are likely as well, depending on how the primordial gonads are populated by PGCs. Relative sizes of the germ line versus soma are not to scale; the germ line in humans is obviously much smaller than the soma in physical size and cell number. Patterns of mosaicism are also not meant to be interpreted literally, other than inclusion or exclusion of all or part of germ line versus soma.

Mentions: The occurrence of germ line and somatic mutations provides an opportunity to explore the early germ line lineage. Consider a new mutation arising in some cell during embryogenesis. Assuming that the mutation is not deleterious at the cellular level, this cell and all of its descendants will be heterozygous for the mutation (or hemizygous in the case of X- or Y-linked non-pseudo-autosomal mutations in males). If these descendants include only somatic cells, then various somatic tissues will carry the mutation in various proportions, depending on exactly when and where in the embryo the mutation arose (Figure 1A). The individual will be a somatic mosaic, with a completely normal germ line (Figure 2A). The lack of access to most tissues in living humans makes comprehensive studies of such somatic mosaicism difficult, although inter-tissue variation of mutant cell frequencies has been observed by analyzing multiple tissues that can be sampled routinely (blood, hair follicles, buccal epithelium, urine, or skin fibroblasts) [46]. One example with medical ascertainment is Proteus syndrome, in which mosaic mutations of the AKT1 gene are found in multiple tissues but rarely in hematopoietic cells [47,48]. Another extensively studied disorder is McCune-Albright syndrome, in which mosaic mutations in the GNAS1 gene are found in multiple endocrine and non-endocrine tissues, leading to the clinical phenotype [49,50]. Many cancers depend on somatic mutations arising in particular embryonic (or post-embryonic) cells at the right time and place to result in the particular phenotype.


Genetic mosaics and the germ line lineage.

Samuels ME, Friedman JM - Genes (Basel) (2015)

Potential anatomical patterns of mosaicism based on the lineage and mutational scenarios of Figure 1. Each panel is matched to the equivalent panel in Figure 1 (panel A, germ line clonal, mutation in soma; B, germ line clonal, mutation in cell ancestral to germ line and some of soma; C, germ line clonal, mutation in germ line; D, germ line not clonal, mutation in cell ancestral to some of germ line and some of soma). The germ line is presented as two circles in the lower abdomen, either wild type (unshaded) or mutant (black). Patches of somatic tissue carrying a de novo mutation are shown as irregular black shapes and may include skin and/or any other kind of somatic cells. In panels (C) and (D), germ line mosaicism is shown in both the right and left gonad, but other gonad patterns are likely as well, depending on how the primordial gonads are populated by PGCs. Relative sizes of the germ line versus soma are not to scale; the germ line in humans is obviously much smaller than the soma in physical size and cell number. Patterns of mosaicism are also not meant to be interpreted literally, other than inclusion or exclusion of all or part of germ line versus soma.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488662&req=5

genes-06-00216-f002: Potential anatomical patterns of mosaicism based on the lineage and mutational scenarios of Figure 1. Each panel is matched to the equivalent panel in Figure 1 (panel A, germ line clonal, mutation in soma; B, germ line clonal, mutation in cell ancestral to germ line and some of soma; C, germ line clonal, mutation in germ line; D, germ line not clonal, mutation in cell ancestral to some of germ line and some of soma). The germ line is presented as two circles in the lower abdomen, either wild type (unshaded) or mutant (black). Patches of somatic tissue carrying a de novo mutation are shown as irregular black shapes and may include skin and/or any other kind of somatic cells. In panels (C) and (D), germ line mosaicism is shown in both the right and left gonad, but other gonad patterns are likely as well, depending on how the primordial gonads are populated by PGCs. Relative sizes of the germ line versus soma are not to scale; the germ line in humans is obviously much smaller than the soma in physical size and cell number. Patterns of mosaicism are also not meant to be interpreted literally, other than inclusion or exclusion of all or part of germ line versus soma.
Mentions: The occurrence of germ line and somatic mutations provides an opportunity to explore the early germ line lineage. Consider a new mutation arising in some cell during embryogenesis. Assuming that the mutation is not deleterious at the cellular level, this cell and all of its descendants will be heterozygous for the mutation (or hemizygous in the case of X- or Y-linked non-pseudo-autosomal mutations in males). If these descendants include only somatic cells, then various somatic tissues will carry the mutation in various proportions, depending on exactly when and where in the embryo the mutation arose (Figure 1A). The individual will be a somatic mosaic, with a completely normal germ line (Figure 2A). The lack of access to most tissues in living humans makes comprehensive studies of such somatic mosaicism difficult, although inter-tissue variation of mutant cell frequencies has been observed by analyzing multiple tissues that can be sampled routinely (blood, hair follicles, buccal epithelium, urine, or skin fibroblasts) [46]. One example with medical ascertainment is Proteus syndrome, in which mosaic mutations of the AKT1 gene are found in multiple tissues but rarely in hematopoietic cells [47,48]. Another extensively studied disorder is McCune-Albright syndrome, in which mosaic mutations in the GNAS1 gene are found in multiple endocrine and non-endocrine tissues, leading to the clinical phenotype [49,50]. Many cancers depend on somatic mutations arising in particular embryonic (or post-embryonic) cells at the right time and place to result in the particular phenotype.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Montreal, Montreal, QC H3T 1C5, Canada. mark.e.samuels@umontreal.ca.

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.

No MeSH data available.


Related in: MedlinePlus