Somatic mosaicism is the accumulation of mutations in DNA sequence or copy number in cellular genomes after fertilization (typically in the form of copy number variations, single nucleotide mutations, new retrotransposon insertions). Somatic mosaicism has been detected in both normal cells and in various diseases. Somatic variations have been suggested to play a major role in driving neuronal diversity and genome evolution. We have demonstrated and quantified widespread somatic mosaicism in normal human fibroblasts (Abyzov et al, Nature, 2012; Abyzov et al, Genome Research, 2017) and in the fetal in human brain (Bae et al, Science, 2018). We are part of the Brain Somatic Mosaicism network, sponsored by the National Institute of Mental Health (NIMH) and encompassing laboratories from several major centers in the US.
Our main strategy to investigate somatic mosaicism in the brain involves generating clonal populations derived from a single precursor cells of the human brain, sequence them to discover somatic mutations and then validate these mutations in the original tissue.
Counts of DNA sequence reads mapped to a region of chromosome 2, indicating a DNA copy number variations (CNV) and specifically a deletion in a segment of DNA in a clone derived from parietal cortex, absent in other clones and undetectable in tissue due to extremely low frequency.
Reconstruction of mosaic SNV mutations during early development. Hierarchical clustering of SNVs (black squares: a,b,c,…) genotyped in the different brain regions and spleen by their allele frequency (red shading) revealed grouping consistent with SNVs sharing between clones (left: #11, 9b….). Using corresponding average allel frequency (show underneath each cluster) we reconstructed the cell lineage tree during the earliest post-zygotic divisions and assigned specific SNVs to each division (D1, D2, D3…). The tree was used to estimate the average mutation rate at pregastrulation stages of development. See Bae et al, 2017.