RT Journal Article
SR Electronic
T1 Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.23.481681
DO 10.1101/2022.02.23.481681
A1 Eduardo A. Maury
A1 Attila Jones
A1 Vladimir Seplyarskiy
A1 Chaggai Rosenbluh
A1 Taejong Bae
A1 Yifan Wang
A1 Alexej Abyzov
A1 Sattar Khoshkoo
A1 Yasmine Chahine
A1 Brain Somatic Mosaicism Network
A1 Peter J. Park
A1 Schahram Akbarian
A1 Eunjung Alice Lee
A1 Shamil R. Sunyaev
A1 Christopher A. Walsh
A1 Andrew Chess
YR 2022
UL http://biorxiv.org/content/early/2022/02/23/2022.02.23.481681.abstract
AB Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process “skiagenesis” (from the Greek skia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset (∼13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes. Skiagenesis provides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.Competing Interest StatementThe authors have declared no competing interest.