Genetic mosaicism in the human brain: from lineage tracing to neuropsychiatric disorders

Bizzotto, Sara; Walsh, Christopher A.

doi:10.1038/s41583-022-00572-x

Cited by 48 publications

(46 citation statements)

References 152 publications

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“…The discovery of distinct and sequential functions of PRC2 in lineage progression will have profound implications for our understanding of diseases arising from postzygotic mutations in individual dividing cells (i.e., somatic cell mosaicism). Somatic cell mosaicism can occur at any point throughout development and is associated with a number of disorders, including neurological diseases and tumorigenesis ( 60 , 61 ). In the future, it will be of great relevance to investigate the contribution of the cellular environment (i.e., the niche) to cell-autonomous or non–cell-autonomous phenotype manifestations upon acquisition of mutations altering the function of particular epigenetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression

et al. 2022

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The generation of a correctly sized cerebral cortex with all-embracing neuronal and glial cell–type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb repressive complex 2 (PRC2), and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here, we use mosaic analysis with double markers (MADM)–based single-cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide properties. In a broader context, our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.

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Section: Discussionmentioning

confidence: 99%

Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression

et al. 2022

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“…1 Interactomes of genes involved in somatic genome variations affecting the diseased brain (see Table 1) generated by STRING v11 [151]: (A) Alzheimer's disease; (B) autism; (C) epileptic disorders that pathway-centric (cyto)genomic studies are likely to be the most promising. To this end, it is to note that modern molecular cytogenetic and genomic techniques are able to generate new data on the role of somatic mosaicism in the aging and diseased brain [147][148][149][150].…”

Section: What Is Now and What Is Next?mentioning

confidence: 99%

Somatic mosaicism in the diseased brain

et al. 2022

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It is hard to believe that all the cells of a human brain share identical genomes. Indeed, single cell genetic studies have demonstrated intercellular genomic variability in the normal and diseased brain. Moreover, there is a growing amount of evidence on the contribution of somatic mosaicism (the presence of genetically different cell populations in the same individual/tissue) to the etiology of brain diseases. However, brain-specific genomic variations are generally overlooked during the research of genetic defects associated with a brain disease. Accordingly, a review of brain-specific somatic mosaicism in disease context seems to be required. Here, we overview gene mutations, copy number variations and chromosome abnormalities (aneuploidy, deletions, duplications and supernumerary rearranged chromosomes) detected in the neural/neuronal cells of the diseased brain. Additionally, chromosome instability in non-cancerous brain diseases is addressed. Finally, theoretical analysis of possible mechanisms for neurodevelopmental and neurodegenerative disorders indicates that a genetic background for formation of somatic (chromosomal) mosaicism in the brain is likely to exist. In total, somatic mosaicism affecting the central nervous system seems to be a mechanism of brain diseases.

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“…In recent years, interest has been increasing in the roles of somatic mutations in other diseases, including neuropsychiatric diseases such as autism and schizophrenia. 2 , 3 But their causal relationships with somatic mutations remain unclear. To investigate the role of somatic mutations in the development of neuropsychiatric disorders, the Brain Somatic Mosaicism Network (BSMN) was formed as a consortium effort through the support of the National Institute of Mental Health.…”

Section: Figurementioning

confidence: 99%