Different mutational rates and mechanisms in human cells at pre-gastrulation and neurogenesis

摘要

Somatic mosaicism in the human brain may alter function of individual neurons. We analyzed genomes of single cells from the forebrains of three human fetuses (15 to 21 weeks post-conception) using clonal cell populations. We detected 200–400 single nucleotide variations (SNVs) per cell. SNV patterns resembled those found in cancer cell genomes, indicating a role of background mutagenesis in cancer. SNVs with a frequency of >2% in brain were shared with the spleen, revealing a pre-gastrulation origin. We reconstructed cell lineages for the first five post-zygotic cleavages and calculated a mutation rate of ~1.3 per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted towards oxidative damage and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit drastically more mutagenesis than adulthood.One-sentence summary (no more than 15 words, no acronyms, don’t repeat the title):Hundreds of oxidative damage-related somatic mutations per cells accumulate during neurogenesis.