The role of somatic mosaicism in brain disease

Jourdon, Alexandre; Fasching, Liana; Scuderi, Soraya; Abyzov, Alexej; Vaccarino, Flora M.

doi:10.1016/j.gde.2020.05.002

Cited by 24 publications

(18 citation statements)

References 81 publications

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“…Furthermore, several pathological conditions exhibit asymmetrical manifestations such as motor symptoms in Parkinson Disease (5), hemimegaloencephaly and cortical dysplasia (6). One of the hypotheses that explain body asymmetries is through a causative role of somatic variants and their nonuniform contribution across the body (7)(8)(9), as proposed for Blaschko lines (10). However, the contribution of cell lineages to different portions of the human body is just beginning to be explored, and the timing and rules of their separation, spread and local expansion in organs are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Early developmental asymmetries in cell lineage trees in living individuals

Fasching

Jang

Tomasi

et al. 2021

Science

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Mosaic mutations can be used to track cell lineages in humans. We used cell cloning to analyze embryonic cell lineages in two living individuals and a postmortem human specimen. Of 10 reconstructed postzygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals, one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

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Section: Introductionmentioning

confidence: 99%

Early developmental asymmetries in cell lineage trees in living individuals

Fasching

Jang

Tomasi

et al. 2021

Science

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“…During the last two decades, an appreciable amount of data on chromosomal variations (aneuploidy) and CIN directly affecting the brain was provided. Currently, it is suggested that several neurodevelopmental, psychiatric and neurodegenerative disorders may be associated with CIN and somatic chromosomal mosaicism confined to the brain or even to specific brain areas [12,14,16,[18][19][20]33,34]. Brain tissue-specific chromosomal mosaicism and CIN are detectable in a significant proportion of cases of common brain diseases, including schizophrenia, autism/intellectual disability and Alzheimer's disease [7,18,30,33].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…Currently, it is suggested that several neurodevelopmental, psychiatric and neurodegenerative disorders may be associated with CIN and somatic chromosomal mosaicism confined to the brain or even to specific brain areas [12,14,16,[18][19][20]33,34]. Brain tissue-specific chromosomal mosaicism and CIN are detectable in a significant proportion of cases of common brain diseases, including schizophrenia, autism/intellectual disability and Alzheimer's disease [7,18,30,33]. However, CIN is a significantly more prominent biomarker of neurodegeneration (neurodegenerative diseases) when comparing intercellular chromosomal or (cyto)genomic variations between different types of brain disorders with a special emphasis on brain aging [12][13][14][15][16]34,35].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…If CIN is confined to the brain, one may expect a progressive neuropathological process resulting in a devastating neuropsychiatric illness. Among the latter, aging-related neurodegenerative diseases are the most common ones [7,15,18]. Accordingly, understanding the interplay between CIN and brain aging appears to be a key for unraveling the mechanisms of neurodegeneration and explaining brain deterioration in late life.…”

Section: Introductionmentioning

confidence: 99%

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Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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“…In this mini-review, we discuss the utility of hBO models for studying brain somatic mutations during development, which can directly cause certain NDDs and may be an important contributor to many other neuropsychiatric disorders (D’gama and Walsh, 2018 ; Jourdon et al, 2020 ). We describe emerging evidence that brain somatic mutations contribute to NDDs and discuss how hBOs provide an opportunity to model and understand the consequences of somatic mutations during the early stages of human brain development.…”

Section: Introductionmentioning

confidence: 99%

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

Deb

Bateup

2022

Front. Mol. Neurosci.

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Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

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The role of somatic mosaicism in brain disease

Cited by 24 publications

References 81 publications

Early developmental asymmetries in cell lineage trees in living individuals

Early developmental asymmetries in cell lineage trees in living individuals

Chromosome Instability, Aging and Brain Diseases

Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

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