Abstract
BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.
Highlights
Genomic sequence variants may be inherited vertically or generated after zygote formation
Dozens of somatic single-nucleotide variants (SNVs) are present at high variant allele fractions (VAFs) across multiple tissues, indicating that they arose during early development [17, 23]
We mixed genomic DNAs derived from transformed lymphoblastoid cell lines of four unrelated individuals at different proportions (Fig. 1a and Additional file 1: Fig. S1; see Mix 1 and Mix 2), sequenced the resultant mixtures to ~ 100× coverage, and assessed the ability of the callers to detect the simulated somatic SNVs (Fig. 1b and S2)
Summary
Genomic sequence variants may be inherited vertically (i.e., transmitted through the germline) or generated after zygote formation (i.e., leading to somatic or gonadal mosaicism). It is well established that somatic mosaicism occurs in cells of phenotypically normal individuals [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17] and can lead to various diseases [18]. Dozens of somatic SNVs are present at high variant allele fractions (VAFs) across multiple tissues, indicating that they arose during early development [17, 23]. Detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, if the variants only are present in a small fraction of cells
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