[초청강연] Somatic mosaicism in developing and adult human brains

Somatic mosaicism in developing and adult human brains
Taejeong Bae
Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo
Clinic, Rochester, MN 55905
Mosaic mutations, which arise post-zygotically and exist in only a subset of the cells of a
single individual, are common in brain development of healthy individuals and may have
a role in brain diseases. Despite the advancement of high-throughput sequencing
methods, precise detection of mosaic variations remains difficult due to their presence in
such a small percentage of cells. There are two different strategies for finding mosaic
variants: single-cell and bulk-tissue based methods. We investigated somatic mosaicism
in developing and adult human brains using both methodologies. First, we grew single
cells directly obtained from three fetal brains to explore the mutational rates and

characteristics of mosaic SNVs in normal developing human brains. The massive whole-
genome sequencing data of single-cell origin clones revealed that 1) 200–400 SNVs

manifested in each cell during neurogenesis; 2) SNVs with a frequency of >2% in the
brain also appeared in the spleen, thereby indicating early post-zygotic mutations prior to
gastrulation; 3) the mutation rate had increased during neurogenesis; and 4) the mutation
spectrum shifted toward oxidative damage (Bae et al., Science, 2018). Second, after
whole genome sequencing of bulk brain tissues to a depth of over 200X, we investigated
for somatic mutations in 131 adult human brains (44 neurotypical, 19 with Tourette
syndrome, 9 with schizophrenia, and 59 with autism). Typically, brains had 20 to 60
detectable single nucleotide mutations that likely arose in early development; however,
roughly 5% of brains contained hundreds (up to 2000 on one case) of somatic mutations.
This phenomenon, which we refer to as hypermutability, was associated with age and
putative damaging mutations in genes previously implicated in cancer and likely reflects
in vivo clonal expansions (Bae et al., Science, 2022). In conclusion, we demonstrated
that analyzing somatic mutations using single clones or bulk tissues can disclose the
mutational history of early post-zygotic mutations, which may aid in disease risk
prediction.