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Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia

The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a lar...

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Autores principales: Singh, Shiva M., Castellani, Christina A., Hill, Kathleen A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642466/
https://www.ncbi.nlm.nih.gov/pubmed/33192734
http://dx.doi.org/10.3389/fpsyt.2020.587162
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author Singh, Shiva M.
Castellani, Christina A.
Hill, Kathleen A.
author_facet Singh, Shiva M.
Castellani, Christina A.
Hill, Kathleen A.
author_sort Singh, Shiva M.
collection PubMed
description The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some of which are altered by mutational and epi-mutational mechanisms in a threshold liability model of schizophrenia development. The results, however, have limited predictability and the actual cause of the disease remains unknown. This current state asks for conceptualizing the problem differently in light of novel insights into the nature of mutations, the biology of the brain and the fine precision and resolution of emerging technologies. There is mounting evidence that mutations acquired during postzygotic development are more common than germline mutations. Also, the postzygotic somatic mutations including epimutations (PZMs), which often lead to somatic mosaicism, are relatively common in the mammalian brain in comparison to most other tissues and PZMs are more common in patients with neurodevelopmental mental disorders, including schizophrenia. Further, previously inaccessible, detection of PZMs is becoming feasible with the advent of novel technologies that include single-cell genomics and epigenomics and the use of exquisite experimental designs including use of monozygotic twins discordant for the disease. These developments allow us to propose a working hypothesis and expand the threshold liability model of schizophrenia that already encompasses familial genetic, epigenetic and environmental factors to include somatic de novo PZMs. Further, we offer a test for this expanded model using currently available genome sequences and methylome data on monozygotic twins discordant for schizophrenia (MZD) and their parents. The results of this analysis argue that PZMs play a significant role in the development of schizophrenia and explain extensive heterogeneity seen across patients. It also offers the potential to convincingly link PZMs to both nervous system health and disease, an area that has remained challenging to study and relatively under explored.
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spelling pubmed-76424662020-11-13 Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia Singh, Shiva M. Castellani, Christina A. Hill, Kathleen A. Front Psychiatry Psychiatry The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some of which are altered by mutational and epi-mutational mechanisms in a threshold liability model of schizophrenia development. The results, however, have limited predictability and the actual cause of the disease remains unknown. This current state asks for conceptualizing the problem differently in light of novel insights into the nature of mutations, the biology of the brain and the fine precision and resolution of emerging technologies. There is mounting evidence that mutations acquired during postzygotic development are more common than germline mutations. Also, the postzygotic somatic mutations including epimutations (PZMs), which often lead to somatic mosaicism, are relatively common in the mammalian brain in comparison to most other tissues and PZMs are more common in patients with neurodevelopmental mental disorders, including schizophrenia. Further, previously inaccessible, detection of PZMs is becoming feasible with the advent of novel technologies that include single-cell genomics and epigenomics and the use of exquisite experimental designs including use of monozygotic twins discordant for the disease. These developments allow us to propose a working hypothesis and expand the threshold liability model of schizophrenia that already encompasses familial genetic, epigenetic and environmental factors to include somatic de novo PZMs. Further, we offer a test for this expanded model using currently available genome sequences and methylome data on monozygotic twins discordant for schizophrenia (MZD) and their parents. The results of this analysis argue that PZMs play a significant role in the development of schizophrenia and explain extensive heterogeneity seen across patients. It also offers the potential to convincingly link PZMs to both nervous system health and disease, an area that has remained challenging to study and relatively under explored. Frontiers Media S.A. 2020-10-22 /pmc/articles/PMC7642466/ /pubmed/33192734 http://dx.doi.org/10.3389/fpsyt.2020.587162 Text en Copyright © 2020 Singh, Castellani and Hill. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Psychiatry
Singh, Shiva M.
Castellani, Christina A.
Hill, Kathleen A.
Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title_full Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title_fullStr Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title_full_unstemmed Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title_short Postzygotic Somatic Mutations in the Human Brain Expand the Threshold-Liability Model of Schizophrenia
title_sort postzygotic somatic mutations in the human brain expand the threshold-liability model of schizophrenia
topic Psychiatry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642466/
https://www.ncbi.nlm.nih.gov/pubmed/33192734
http://dx.doi.org/10.3389/fpsyt.2020.587162
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