Extensive Hidden Genomic Mosaicism Revealed in Normal Tissue

Abstract

Genomic mosaicism arising from post-zygotic mutation has recently been demonstrated to occur in normal tissue of individuals ascertained with varied phenotypes, indicating that detectable mosaicism may be less an exception than a rule in the general population. A challenge to comprehensive cataloging of mosaic mutations and their consequences is the presence of heterogeneous mixtures of cells, rendering low-frequency clones difficult to discern. Here we applied a computational method using estimated haplotypes to characterize mosaic megabase-scale structural mutations in 31,100 GWA study subjects. We provide in silico validation of 293 previously identified somatic mutations and identify an additional 794 novel mutations, most of which exist at lower aberrant cell fractions than have been demonstrated in previous surveys. These mutations occurred across the genome but in a nonrandom manner, and several chromosomes and loci showed unusual levels of mutation. Our analysis supports recent findings about the relationship between clonal mosaicism and old age. Finally, our results, in which we demonstrate a nearly 3-fold higher rate of clonal mosaicism, suggest that SNP-based population surveys of mosaic structural mutations should be conducted with haplotypes for optimal discovery.

A characterization of postzygotic mutations identified in monozygotic twins

“…We replicated the finding by Lodato () that coding exons are enriched for postzygotic mutations (Lodato et al., ). The enrichment we found for mosaicism in genes associated with GTPase activity, involved in tumor growth, is in line with recent findings that larger‐scale genomic mosaicisms in genes are associated with cancer (Laurie et al., ; Machiela et al., ; Vattathil & Scheet, ). The continuing discovery of even more cases of mosaicism provides much‐needed insights into postzygotic mutational signatures (see, e.g., Ju et al.…”

“…The differences between twins we identified point to clustering of postzygotic mutations around hotspots up to 10 Mb in size. We found similar patterns of strong enrichments for variant types and gene sets in both twin pairs, suggesting that postzygotic mutations follow a nonrandom pattern, confirming recent findings (Vattathil & Scheet, ). The enrichment of regulatory elements suggests a relevant role for mosaicisms.…”

The ageing genome, clonal mosaicism and chronic disease

“…Recently, new bioinformatic algorithms have been applied to SNP microarrays analyzed in large adult population-based studies, providing estimates of the frequencies of different types of events[46,47]. Examination of B allele frequency and log R ratio intensity signals yields high-resolution karyotypes capable of detecting large (>2 Mb) structural mosaicism in samples of tens of thousands of individuals[46,48–50].…”

The cat in between: Nature, nurture, . . . neither!

“…A somatic mutation is transmitted to all cells in the body that descend from the initially affected cell, but will not be passed on to the next generation. This is a long‐known fact, but improved technology that compares DNA from different tissues in the same individual is leading to a regular flow of new papers reporting different aspects of this phenomenon …”

“…This is a long-known fact, but improved technology that compares DNA from different tissues in the same individual is leading to a regular flow of new papers reporting different aspects of this phenomenon. [2][3][4][5][6] Evolution has produced an array of genetic mechanisms that detect and repair mutations, providing some protection against the potential chaos that any mutation, germline or somatic, might cause. These mechanisms are terrific but imperfect.…”