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.

Figure 1

BAF and LRR Deviations per SCNA The pink lines indicate the expected values for mosaic hemizygous deletions (lower line), mosaic CNLOH (middle horizontal line), and mosaic single-copy duplications (upper line) for aberrations present in 10% to 100% of the sampled cells (dashes are at 10% increments). The gray shaded area indicates the area within the thresholds used to define an SCNA as a copy-number gain or copy-number loss. Each point is colored according to the copy-number classification on the basis of these deviations.

Figure 2

SCNAs by Chromosome The red shading on each ideogram indicates the range of the plotted mutations. SCNAs are plotted as horizontal bars, colored by inferred copy-number: red, loss; green, CNLOH; blue, gain; and gray, undetermined. A thin line connecting SCNAs within a chromosome indicates the SCNAs occur in the same sample.

Figure 3

Phase Concordance versus Genomic Size The circles and diamonds represent SCNAs called by hapLOH only, Laurie et al. only, or both in samples that were included in both analyses. Many of the SCNAs called by Laurie et al. only had few or no heterozygous calls, so the phase-concordance values were incalculable or imprecise; all of these were plotted with phase concordance = 1. The triangles represent the calls made in the simulated null samples.

Figure 4

Mosaic Rate by Age The gold numbers below each age bin indicate the sample size for that bin. The numbers above each bar are the number of samples that fall in that age bin and have at least one SCNA.