Genomic mosaicism in the developing and adult brain.

Suzanne Rohrback,Benjamin Siddoway,Jerold Chun,Christine S Liu

doi:10.1002/dneu.22626

Abstract

ABSTRACTSince the discovery of DNA, the normal developing and functioning brain has been assumed to be composed of cells with identical genomes, which remains the dominant view even today. However, this pervasive assumption is incorrect, as proven by increasing numbers of reports within the last 20 years that have identified multiple forms of somatically produced genomic mosaicism (GM), wherein brain cells—especially neurons—from a single individual show diverse alterations in DNA, distinct from the germline. Critically, these changes alter the actual DNA nucleotide sequences—in contrast to epigenetic mechanisms—and almost certainly contribute to the remarkably diverse phenotypes of single brain cells, including single‐cell transcriptomic profiles. Here, we review the history of GM within the normal brain, including its major forms, initiating mechanisms, and possible functions. GM forms include aneuploidies and aneusomies, smaller copy number variations (CNVs), long interspersed nuclear element type 1 (LINE1) repeat elements, and single nucleotide variations (SNVs), as well as DNA content variation (DCV) that reflects all forms of GM with greatest coverage of large, brain cell populations. In addition, technical considerations are examined, along with relationships among GM forms and multiple brain diseases. GM affecting genes and loci within the brain contrast with current neural discovery approaches that rely on sequencing nonbrain DNA (e.g., genome‐wide association studies (GWAS)). Increasing knowledge of neural GM has implications for mechanisms of development, diversity, and function, as well as understanding diseases, particularly considering the overwhelming prevalence of sporadic brain diseases that are unlinked to germline mutations. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol, 2018

Highlights

The exquisite organization and complexity of cells within the brain have been recognized since the days of Golgi and Cajal (Cajal, 1901) at the turn of the 20th century, yet molecular mechanisms from which the brain develops and functions are still not completely understood
The presence of DNA fragmentation and double strand breaks amongst developing brain cell populations associated with cell death and differentiation likely involves recurrent breaks in specific genes, as reported from studies of neural progenitor cell populations (Wei et al, 2016), which are again reminiscent of processes in the adaptive immune system (Chun, 2001; Kingsbury et al, 2006; Westra et al, 2010; Bushman and Chun, 2013)
It would not be surprising to find novel forms of DNA rearrangement within cells of the brain, given the postmitotic state of neurons and expression of different genes (e.g., recombination activating gene 1 (RAG1) but not RAG2 within the brain vs. both in the immune system). These diverse, nonmutually exclusive and pervasive forms of neural genomic mosaicism (GM) could “barcode” each brain cell by creating a unique genome, representing a small universe of genome diversity residing within a single brain

Summary

INTRODUCTION

The exquisite organization and complexity of cells within the brain have been recognized since the days of Golgi and Cajal (Cajal, 1901) at the turn of the 20th century, yet molecular mechanisms from which the brain develops and functions are still not completely understood. Possible sequelae of NHEJ loss, including genomic instability and aneuploidy, were documented in cancers (Difilippantonio et al, 2000; Deans et al, 2003; Thacker and Zdzienicka, 2004), which led to a directed search for aneuploid cells during neurogenesis within the embryonic cerebral cortex This approach identified the first definitive evidence of neural GM—that which occurred among cells of a single brain—through mosaic, complex aneuploidies among mitotic neural progenitor cells (Rehen et al, 2001) (Fig. 2), and represents a first example of DNA copy number variations (CNVs). Approximately 17% of the genome is composed of LINE1 repetitive elements

Method

Findings

CONCLUDING COMMENTS