Genomic Mosaicism Formed by Somatic Variation in the Aging and Diseased Brain

Abstract

Over the past 20 years, analyses of single brain cell genomes have revealed that the brain is composed of cells with myriad distinct genomes: the brain is a genomic mosaic, generated by a host of DNA sequence-altering processes that occur somatically and do not affect the germline. As such, these sequence changes are not heritable. Some processes appear to occur during neurogenesis, when cells are mitotic, whereas others may also function in post-mitotic cells. Here, we review multiple forms of DNA sequence alterations that have now been documented: aneuploidies and aneusomies, smaller copy number variations (CNVs), somatic repeat expansions, retrotransposons, genomic cDNAs (gencDNAs) associated with somatic gene recombination (SGR), and single nucleotide variations (SNVs). A catch-all term of DNA content variation (DCV) has also been used to describe the overall phenomenon, which can include multiple forms within a single cell's genome. A requisite step in the analyses of genomic mosaicism is ongoing technology development, which is also discussed. Genomic mosaicism alters one of the most stable biological molecules, DNA, which may have many repercussions, ranging from normal functions including effects of aging, to creating dysfunction that occurs in neurodegenerative and other brain diseases, most of which show sporadic presentation, unlinked to causal, heritable genes.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; aneuploidy; copy number variation; repeat expansion; retrotransposons; single-nucleotide variation; somatic gene recombination; somatic variation.

Figure 1

Neural somatic DNA content variation (DCV) encompasses many forms and sizes of somatic changes. Aneuploidies/aneusomies and copy number variations (CNVs) typically reflect large genomic gains/losses that may affect many hundreds of genes. Retrotransposons and somatic gene recombination are reverse transcriptase-mediated insertions of nucleic acids into the genome. Repeat expansions reflect increases in length of instable, small repeating sequences. Single nucleotide variations (SNVs) are the smallest, but most frequent, DNA changes. They encompass changes from one base to another or insertions/deletions of a single base. Together, these somatic changes create genomic mosaicism throughout the human brain.

Figure 2

Clonal versus private somatic mutations in the human brain. (A) Somatic mutations that occur at different timepoints within embryogenesis or neurogenesis will result in clonal mutations shared by the brain and other body tissues or between brain cells of a single lineage. Clonal somatic aneuploidies, copy number variations (CNVs), and single-nucleotide variations (SNVs) have been described between the brain and peripheral lymphocytes (occurring early in embryogenesis), between the brain and other ectodermal-derived tissues (occurring after trilaminar disc formation), and between separate brain regions (occurring during neurogenesis). (B) Private or unique somatic mutations are unique to a single neural cell and accumulate throughout one’s lifespan. These somatic events may be independent of replication, as evidenced by their presence in post-mitotic cells. Aneuploidies, CNVs, retrotransposon insertions, repeat expansions, somatic gene recombination (SGR), and SNVs have all been described as occurring in post-mitotic neurons.