TY - JOUR
T1 - Extensive Hidden Genomic Mosaicism Revealed in Normal Tissue
AU - Vattathil, Selina
AU - Scheet, Paul
N1 - Funding Information:
We thank C. Laurie for sharing sample identifiers for mutations called in their analysis. X. Xiao and J. Fowler provided assistance with array processing and workflows. L. Huang performed haplotype phasing and ran hapLOH on multiple data sets. C. Huff and Y. M. Chen provided helpful comments on analyses. This work was supported by NIH grants R01HG005859 and R01HG005855.
Publisher Copyright:
© 2016 The American Society of Human Genetics.
PY - 2016/3/3
Y1 - 2016/3/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2016.02.003
DO - 10.1016/j.ajhg.2016.02.003
M3 - Article
C2 - 26942289
AN - SCOPUS:84959879502
SN - 0002-9297
VL - 98
SP - 571
EP - 578
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -