Genomic Mosaicism of the Brain: Origin, Impact, and Utility

Abstract

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype-motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism.

Keywords: Brain development; Brain homeostasis; Genomic mosaicism; Genomics.

Fig. 1

Developmental and aging mosaicism. A In development, mutations that occur at very early stages are transmitted to daughter lineages. Subsequent mutations further distinguish distinct lineages or sub-lineages. Developmental mutations are obligatory clonal mosaic variants. B Differentiated cells (here exemplified by a postmitotic neuron) already carry developmental mutations and accumulate additional aging mutations. In postmitotic cells, these aging mutations are obligatory private mosaic variants. Note that developmental and aging mutators are primarily distinguished by their timing, but may share intrinsic or extrinsic mutagenic stressors.

Fig. 2

Types and Scale of Mosaic Variants. Small mosaic variant types like mSNVs, mIndels, or mSTR∆s are the most common types of mosaic genetic variation. However, larger mosaic variants can be grouped as mSVs. Each type of observed mosaic variant is illustrated in this figure with an example. mSNV: a T to G base pair substitution; mInDel: a one-base pair deletion; mSTRΔ: a one unit CAG expansion; mCNV: two examples for a genomic tandem duplication and a deletion; aneuploidies: duplication on one chromosome; mCN-LOH: duplication of a part of the green haplotype while partially losing the blue haplotype; retrotransposition: insertion of the red retroviral mRNA sequence into the locus.

Fig. 3

Types and scale of mosaicism detection approaches. A Mosaic mutations in a subpopulation of cells may be detected by three theoretical approaches: (1) through direct visualization of mutations employing FISH or chromosome spreads, (2) through bulk analysis of genomic material, or (3) through assessment of genomic material at the level of single cells. B Biological insights obtained from mosaicism analysis are heavily dependent on the scale of sampling. For instance, mosaicism may be detected from an entire tissue like the neocortex, microdissection, or microdissections, all of which provide distinct information due to their drastically different scale.

Fig. 4

Impact and utility of natural mosaicism. A Mosaic mutations may act as a driver of disease. Clones harboring mosaic mutations can be positively selected for continued expansion and proliferation which may directly result in disease. Alternatively, mosaic mutations may exhibit a dominant phenotype. Note that these two scenarios are not mutually exclusive. B Natural mosaicism marks cellular lineages and can be used for lineage reconstruction or clonal analysis. For instance, in this example, distinct clones are marked by Neutral Mutation (NM) 1 and NM 3, whereas NM 3 marks a sub-clonal lineage in combination with NM 1. C Natural mosaicism can be used as a molecular readout of the microenvironment that cells are encountering. Exposure to different environmental mutagens such as reactive oxygen species or toxins can lead to very specific ‘mutational signatures’.

Fig. 5

Types of engineered mosaicism. A One of the most utilized methods to track lineages involves the use of fluorescent markers, such as GFP. One possible configuration employs a stop cassette which is flanked by Loxp sites and prevents the transcription of GFP. When Cre recombinase is expressed from a lineage-defined locus, the stop cassette is removed and the GFP is expressed in this cell and its daughters. B A more recent innovation used to track lineages employs ‘genomic writers’ (e.g., Cas9) that are targeted to a defined locus, often denoted as ‘genomic tape’. Here these writers can introduce either random or defined mutations that act as genomic barcodes to distinguish cells and their lineages. These barcodes are subsequently read through targeted sequencing. C Using writers in combination with other systems, it is possible to further encode the temporal resolution of defined signals (i), the expression status of a cell (ii), or protein binding to genomic regions (iii).