Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network

Abstract

Neuropsychiatric disorders have a complex genetic architecture. Human genetic population-based studies have identified numerous heritable sequence and structural genomic variants associated with susceptibility to neuropsychiatric disease. However, these germline variants do not fully account for disease risk. During brain development, progenitor cells undergo billions of cell divisions to generate the ~80 billion neurons in the brain. The failure to accurately repair DNA damage arising during replication, transcription, and cellular metabolism amid this dramatic cellular expansion can lead to somatic mutations. Somatic mutations that alter subsets of neuronal transcriptomes and proteomes can, in turn, affect cell proliferation and survival and lead to neurodevelopmental disorders. The long life span of individual neurons and the direct relationship between neural circuits and behavior suggest that somatic mutations in small populations of neurons can significantly affect individual neurodevelopment. The Brain Somatic Mosaicism Network has been founded to study somatic mosaicism both in neurotypical human brains and in the context of complex neuropsychiatric disorders.

Machine learning reveals bilateral distribution of somatic L1 insertions in human neurons and glia

“…MEIs are germline mutations 44 . In human brain, somatic single nucleotide variants (SNVs) with low tissue allele frequencies (tAF, the fraction of chromosomes carrying an alternative allele) in known risk genes can drive functional anomalies 28 , such as Sturge-Weber syndrome (1-18% tAF) 45 , focal cortical dysplasia (1.3-12%) 46 , and hemimegalencephaly (8-40% tAF) 47,48 . Our observation of somatic MEIs in 0.05-3.46% of brain cells in multiple regions translates to 0.025-1.73% tAF.…”

Genome integrity and disease prevention in the nervous system

“…Notably, loss-of-function mutations associated with these singlenucleotide variants have been linked to autism spectrum disorder risk (D'Gama et al 2015). Thus, these somatic mutations may have particular consequences associated with neurologic disease predisposition in the human population (McConnell et al 2017). Although these genomic changes are prevalent in the brain, the underlying mechanism associated with DNA damage/repair resulting in altered individual genomes is presently unknown.…”

A characterization of postzygotic mutations identified in monozygotic twins

“…Postzygotic mosaic mutations are usually associated with cancer development (Abyzov et al., ; Biesecker & Spinner, ; Buntinx, Campbell, & van den Akker, ; Cohen, Wilson, Trinh, & Ye, ; Forsberg, Absher, & Dumanski, ; Iourov, Vorsanova, & Yurov, ; Jacobs et al., ; Laurie et al., ), but they are also an important confounder in medical genetic testing (Forsberg, Gisselsson, & Dumanski, ). A recent study suggests that somatic mosaicism in the brain might represent a potential mechanism contributing to neuronal diversity and the etiology of neuropsychiatric disorders (McConnell et al., ). The number of clonal SNVs has been estimated at 1,000–1,500 per neuronal genome which are enriched in coding exons (Lodato et al., ).…”