Building the brain mosaic: an expanded view

Abstract

The complexity of the brain is closely tied to its nature as a genetic mosaic, wherein each cell is distinguished by a unique constellation of somatic variants that contribute to functional and phenotypic diversity. Postzygotic variation arising during neurogenesis is recognized as a key contributor to brain mosaicism; however, recent advances have broadened our understanding to include sources of neural genomic diversity that develop throughout the entire lifespan, from embryogenesis through aging. Moving beyond the traditional confines of neurodevelopment, in this review, we delve into the complex mechanisms that enable various origins of brain mosaicism.

Keywords: clonal lineages; development; embryogenesis; neurogenesis; selection, reversion.

Figure 1:. Origins of Brain Mosaicism in Embryonic Development

(A) Acquired somatic variants are passed on to all daughters of the affected cell (indicated in red), creating a genetic mosaic characterized by cellular lineages with unique genomic profiles. (B) Conversely, mosaicism can also arise from the reversion of an inherited mutation. Postzygotic correction of a meiotic error originating in the oocyte (indicated in red) results in a genomic mosaic, with some lineages that retain the meiotic error and others reflecting its reversal. (C) Somatic mutations can potentially impact clonal expansion by influencing cellular division and proliferation. Catastrophic mutational events can halt proliferation and terminate further development of the lineage (illustrated by the red cell). Acquisition of a variant that confers a proliferative advantage may enable rapid clonal expansion in a sister lineage (green cells). Mutations that disrupt division can trigger mitotic arrest as cells initiate DNA repair processes, thereby delaying clonal expansion (yellow cells). (D) Asymmetric contributions of embryonic cells to developmental lineages, driven by complex clonal dynamics, results in somatic tissues with distinct clonal compositions. For example, different brain regions may exhibit significant variations in their representation of early embryonic clones, permitting remarkable genomic diversity even within a cell type.

Figure 2:. Embryonic Mechanisms of Genomic Rescue

(A) Aneuploid cells (indicated in red) within the inner cell mass of developing blastocysts can be preferentially reallocated to the trophectoderm. This region of the developing embryo, which contributes to the formation of extraembryonic tissues, demonstrates a higher tolerance for cells with genetic abnormalities and chromosomal imbalances. (B) Blastocysts can address chromosomal errors through the expulsion of extraneous genetic material via cellular budding and DNA shedding. (C) Several studies have identified the formation of micronuclei during this corrective process, supported by hallmarks of micronucleus involvement such as extensive chromosomal shattering and the presence of distinctive rearrangements found within some cellular debris. (D) In some instances, sequestration of abnormal genetic material within a micronucleus may result in re-ligation and reintegration of a derivative chromosome into the primary nucleus. These neochromsomes have been known to occasionally take the form of small supernumerary chromosomal markers.