Somatic mosaicism

Somatic mosaicism is the accumulation of mutations in DNA sequence or copy number in cellular genomes after fertilization. Somatic mutations are present 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 many human cell types and tissues (Abyzov et al, Nature, 2012; Abyzov et al, Genome Research, 2017; Fasching et al, Science, 2021) including the 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.

Cell lineage tree during the earliest cell divisions (D2, D3, D4, D5…) of a human embryo. The tree was built using the co-occurrence of somatic single nucleotide variations (SNVs) in single brain precursor cells (letters) and their frequency in bulk brain regions and spleen (D2: 11.3% -> D5 1.48% average allele frequency). Using this tree, we estimated an average somatic SNVs mutation rate of 1.3 mutations/division/cell at these stages. Expected variant allele frequency at the bottom. See Bae et al (Science, 2018).

The tree is based on mosaic single nucleotide variants (black) and indels (green) discovered in 25 fibroblast-derived iPSC lines from 4 skin biopsies and also present in blood, saliva and urine. Note that the first division is drastically asymmetric, with one daughter generating 90-70% of tissues and the other only 10-30%. For details, see Fasching et al, Science 2021.