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Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

View ORCID ProfileEduardo A. Maury, Attila Jones, Vladimir Seplyarskiy, Chaggai Rosenbluh, Taejong Bae, Yifan Wang, View ORCID ProfileAlexej Abyzov, Sattar Khoshkoo, Yasmine Chahine, Brain Somatic Mosaicism Network, Peter J. Park, Schahram Akbarian, Eunjung Alice Lee, Shamil R. Sunyaev, Christopher A. Walsh, Andrew Chess
doi: https://doi.org/10.1101/2022.02.23.481681
Eduardo A. Maury
1Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
2Bioinformatics & Integrative Genomics Program and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Eduardo A. Maury
Attila Jones
4Department of Cell, Developmental & Regenerative Biology, Ichan School of Medicine at Mount Sinai, New York, NY, USA
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Vladimir Seplyarskiy
6Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
7Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Chaggai Rosenbluh
4Department of Cell, Developmental & Regenerative Biology, Ichan School of Medicine at Mount Sinai, New York, NY, USA
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Taejong Bae
8Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
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Yifan Wang
8Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
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Alexej Abyzov
8Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
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  • ORCID record for Alexej Abyzov
Sattar Khoshkoo
1Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
9Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
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Yasmine Chahine
1Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Peter J. Park
6Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
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Schahram Akbarian
11Department of Psychiatry and Neuroscience, Friedman Brain Institute, Mount Sinai, New York, NY, USA
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Eunjung Alice Lee
1Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Shamil R. Sunyaev
6Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
7Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Christopher A. Walsh
1Division of Genetics and Genomics, Manton Center for Orphan Disease, Boston Children’s Hospital, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
12Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA
13Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA
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  • For correspondence: andrew.chess@mssm.edu christopher.walsh@childrens.harvard.edu
Andrew Chess
4Department of Cell, Developmental & Regenerative Biology, Ichan School of Medicine at Mount Sinai, New York, NY, USA
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
11Department of Psychiatry and Neuroscience, Friedman Brain Institute, Mount Sinai, New York, NY, USA
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  • For correspondence: andrew.chess@mssm.edu christopher.walsh@childrens.harvard.edu
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Abstract

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 Statement

The authors have declared no competing interest.

Footnotes

  • ↵10 A list of authors and their affiliations appears in Table S1

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Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites
Eduardo A. Maury, Attila Jones, Vladimir Seplyarskiy, Chaggai Rosenbluh, Taejong Bae, Yifan Wang, Alexej Abyzov, Sattar Khoshkoo, Yasmine Chahine, Brain Somatic Mosaicism Network, Peter J. Park, Schahram Akbarian, Eunjung Alice Lee, Shamil R. Sunyaev, Christopher A. Walsh, Andrew Chess
bioRxiv 2022.02.23.481681; doi: https://doi.org/10.1101/2022.02.23.481681
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Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites
Eduardo A. Maury, Attila Jones, Vladimir Seplyarskiy, Chaggai Rosenbluh, Taejong Bae, Yifan Wang, Alexej Abyzov, Sattar Khoshkoo, Yasmine Chahine, Brain Somatic Mosaicism Network, Peter J. Park, Schahram Akbarian, Eunjung Alice Lee, Shamil R. Sunyaev, Christopher A. Walsh, Andrew Chess
bioRxiv 2022.02.23.481681; doi: https://doi.org/10.1101/2022.02.23.481681

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