Brain Somatic Mutation in Aging and Alzheimer's Disease

Abstract

Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, including in the brain. Technological advances in nucleic acid sequencing have enabled recent breakthroughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer's disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

“…Recent studies have found that pTau promotes neuronal cell cycle reentry and the subsequent aneuploidy, hyperploidy, and somatic mosaicism documented in both viral infections and neurodegenerative disorders ( Knight and Robertson, 2004 ; Dove et al., 2006 ; Mosch et al., 2007 ; Lopes et al., 2009 ; Arendt, 2012 ; Miller et al., 2021 ). Indeed, other novel studies have revealed that pTau can destabilize the genome, activating transposable element (TE), a hallmark of cancer and neurodegeneration ( Grundman et al., 2021 ).…”

“…In return, this pathology may alter glial homeostasis, contributing to neuronal loss by neurotoxic astrocytes and microglia ( Liddelow et al., 2017 ; Zhang et al., 2020 ). In this regard, phenomena previously associated with both neurodegeneration and viral infections, including neuronal cycle reentry, aneuploidy, hyperploid DNA, and somatic mosaicism, may be explained by fusion-mediated multinucleation ( Knight and Robertson, 2004 ; Dove et al., 2006 ; Mosch et al., 2007 ; Lopes et al., 2009 ; Arendt, 2012 ; Miller et al., 2021 ).…”

Tracing brain genotoxic stress in Parkinson’s disease with a novel single-cell genetic sensor

“…Age-dependent accumulation of somatic mutations has been associated with aging and neurodegenerative cases ( 4 , 5 ). Multiple studies have identified a low allele frequency of mutations of genes causing the familial form of NDDs in human brains ( 6 ). For example, mosaicism from the somatic mutation of presenilin-1 was identified in 14% of cortical cells in a patient with AD.…”

Editorial: Somatic genomic mosaicism & human disease

“…Additionally, somatic (chromosomal and single-gene) mosaicism appears to be a mechanism for human interindividual diversity, development and aging (Campbell et al, 2015;D'Gama and Walsh, 2018;Iourov et al, 2012;Heng, 2019;Vijg, 2014). More precisely, monogenic and chromosomal diseases, neurodevelopmental/neurobehavioral and neuropsychiatric disorders, neurodegeneration, cancer and healthy/unhealthy aging are associated with a wide spectrum of somatic genomic mosaicism types (D'Gama and Walsh, 2018;Iourov et al, 2012;Heng, 2019;Vijg, 2014;Iourov et al, 2019;Yurov et al, 2019;Vorsanova et al, 2020;Ye et al, 2020;Miller et al, 2021;Iourov et al, 2021a;Iourov et al, 2021b). According to the Genome Architecture Theory, somatic mosaicism-mediated heterogeneity is essential for cellular adaptation, and at the same time, as an evolutionary trade-off, somatic mosaicism may be a disease mechanism, as well (Heng, 2019;Ye et al, 2019;Iourov et al, 2020;Iourov et al, 2021b;Heng and Heng, 2021).…”