Somatic Mosaicism in Schizophrenia Brains Reveals Prenatal Mutational Processes

Overview

Journal Science

Specialty Science

Date 2024 Oct 10

PMID 39388546

Authors

Eduardo A Maury

Attila Jones

Vladimir Seplyarskiy

Thanh Thanh L Nguyen

Chaggai Rosenbluh

Taejong Bae

Yifan Wang

Alexej Abyzov

Sattar Khoshkhoo

Yasmine Chahine

Sijing Zhao

Sanan Venkatesh

Elise Root

Georgios Voloudakis

Panagiotis Roussos

Peter J Park

Schahram Akbarian

Kristen Brennand

Steven Reilly

Eunjung A Lee

Shamil R Sunyaev

Christopher A Walsh

Andrew Chess

Affiliations

Soon will be listed here.

Abstract

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

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