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Editorials
many cell divisions during aging. Most acquired chimerism is iatrogenic and takes place after allogeneic solid organ or hematopoietic progenitor cell transplantations. Diagnostic laboratories routinely come across such patients when test- ing peripheral blood, and hematologists and other consult- ants should be willing to share this clinically quite impor- tant patient history with the laboratory. In comparison, congenital chimerism, as sometimes found by blood group typing,19 is much less common. The diagnostic hallmark for chimerism, whether congenital or acquired, are 2 entirely different genotypes derived from 2 zygotes and found throughout the genome in 2 sets of cells or tissues. In con- trast, a typical somatic mosaicism is limited to only 1 chro- mosomal location.
In depth genotyping at the single cell level may eventual- ly reveal a host of mosaicisms in individuals and even in a set of cells that is presumed to belong to 1 cell lineage. Certain congenital diseases predispose to somatic muta- tions, such as in fragile X syndrome. Conversely, the highly individual accumulation of somatic mutations causes the great variety of phenotype in dyskeratosis congenita. The exact combination of mosaicism accrued throughout life in a variety of cell lineages constitutes the substrate of single cell medicine. Current progress in gene editing will allow somatic mutations in differentiating cells to be modified or corrected; this will raise few ethical concerns since the germline is not affected.
It was possible to clarify more molecular details and the regulatory mechanism was addressed in both of these patients. The exact break points involved in the deletion events, as defined by nucleotide sequence, can be deter- mined with current technology. This would also allow the claim that the proposed CDe haplotype is duplicated in the affected cell lineages to be corroborated. While the patterns may seem random, close inspection can reveal preferred sites. The nucleotide sequences in the break point regions often hint at distinct deletion and duplication events18,20,21 involving specific molecular repair mechanisms.
Variants of the RhCE protein are not known to exert any regulatory effect or growth advantage, and one or more of the many other genes located in the deleted or duplicated long DNA segments could be evaluated as a cause for the clonal expansion. Red cells represent 84% of all human cells.22 Isn’t it an odd coincidence that both patients happen to have approximately half of their red cells affected despite 2 distinct LOH mutations (Figure 1)? While the single pluripotent stem cell and myeloid precursor, having incurred different LOH mutations,5 can develop some clon- ality,23 they are hardly expected to produce 50% of all red cells in each patient. It might be an observation bias that these reported findings are so similar, if many clonal events of a lesser degree are overlooked in routine clinical practice.
With the advent of mass scale sequencing of whole genomes in cell lines and cell lineages, mosaicism is becom- ing more frequently observed. And it can only become more important as single cell genomics is used to study aging populations. As understanding of underlying mecha- nisms widens, we will observe similar mutation patterns and their prevalence. Each cell lineage will accumulate its distinct combination of mutations, and these are bound to vary among individuals; even between monozygotic, iden- tical twins. As 99% of all inherited nucleotide sequence in
any individual is homozygous, the acquired heterozygous sequence, along with the common inherited status, may constitute a major cause for phenotypes, and ultimately dis- eases. Today, since systematic analysis of mosaicism remains challenging, its role as a critical mechanism for dis- ease and aging may quite possibly be underappreciated.4
Acknowledgments
The author thanks Harvey Gordon Klein for his review. Supported by the Intramural Research Program (project ID Z99 CL999999) of the NIH Clinical Center.
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