Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis

Science. 2018 Feb 2;359(6375):550-555. doi: 10.1126/science.aan8690. Epub 2017 Dec 7.


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 postconception) using clonal cell populations. We detected 200 to 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 also present in the spleen, revealing a pregastrulation origin. We reconstructed cell lineages for the first five postzygotic cleavages and calculated a mutation rate of ~1.3 mutations per division per cell. Later in development, during neurogenesis, the mutation spectrum shifted toward oxidative damage, and the mutation rate increased. Both neurogenesis and early embryogenesis exhibit substantially more mutagenesis than adulthood.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / embryology*
  • Cell Lineage / genetics
  • Gastrulation / genetics*
  • Genome, Human
  • Humans
  • Mosaicism*
  • Mutagenesis*
  • Mutation
  • Mutation Rate*
  • Neoplasms / genetics
  • Neurogenesis / genetics*
  • Neurons
  • Polymorphism, Single Nucleotide
  • Single-Cell Analysis