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RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain

Cells of the developing human brain are affected by the progressive acquisition of genetic and epigenetic alterations that have been reported to contribute to somatic mosaicism in the adult brain and are increasingly considered a possible cause of neurogenetic disorders. A recent work uncovered that...

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Autores principales: Möhner, Jonas, Scheuren, Maurice, Woronzow, Valentina, Schumann, Sven, Zischler, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267396/
https://www.ncbi.nlm.nih.gov/pubmed/37325565
http://dx.doi.org/10.3389/fcell.2023.1201258
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author Möhner, Jonas
Scheuren, Maurice
Woronzow, Valentina
Schumann, Sven
Zischler, Hans
author_facet Möhner, Jonas
Scheuren, Maurice
Woronzow, Valentina
Schumann, Sven
Zischler, Hans
author_sort Möhner, Jonas
collection PubMed
description Cells of the developing human brain are affected by the progressive acquisition of genetic and epigenetic alterations that have been reported to contribute to somatic mosaicism in the adult brain and are increasingly considered a possible cause of neurogenetic disorders. A recent work uncovered that the copy–paste transposable element (TE) LINE-1 (L1) is mobilized during brain development, and thus mobile non-autonomous TEs like AluY and SINE-VNTR-Alu (SVA) families can use L1 activity in trans, leading to de novo insertions that may influence the variability of neural cells at genetic and epigenetic levels. In contrast to SNPs and when considering substitutional sequence evolution, the presence or absence of TEs at orthologous loci represents highly informative clade markers that provide insights into the lineage relationships between neural cells and how the nervous system evolves in health and disease. SVAs, as the ‘youngest’ class of hominoid-specific retrotransposons preferentially found in gene- and GC-rich regions, are thought to differentially co-regulate nearby genes and exhibit a high mobility in the human germline. Therefore, we determined whether this is reflected in the somatic brain and used a subtractive and kinetic enrichment technique called representational difference analysis (RDA) coupled with deep sequencing to compare different brain regions with respect to de novo SINE-VNTR-Alu insertion patterns. As a result, we detected somatic de novo SVA integrations in all human brain regions analyzed, and the majority of de novo insertions can be attributed to lineages of telencephalon and metencephalon, since most of the examined integrations are unique to different brain regions under scrutiny. The SVA positions were used as presence/absence markers, forming informative sites that allowed us to create a maximum parsimony phylogeny of brain regions. Our results largely recapitulated the generally accepted evo-devo patterns and revealed chromosome-wide rates of de novo SVA reintegration targets and preferences for specific genomic regions, e.g., GC- and TE-rich regions as well as close proximity to genes that tend to fall into neural-specific Gene Ontology pathways. We concluded that de novo SVA insertions occur in the germline and somatic brain cells at similar target regions, suggesting that similar retrotransposition modes are effective in the germline and soma.
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spelling pubmed-102673962023-06-15 RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain Möhner, Jonas Scheuren, Maurice Woronzow, Valentina Schumann, Sven Zischler, Hans Front Cell Dev Biol Cell and Developmental Biology Cells of the developing human brain are affected by the progressive acquisition of genetic and epigenetic alterations that have been reported to contribute to somatic mosaicism in the adult brain and are increasingly considered a possible cause of neurogenetic disorders. A recent work uncovered that the copy–paste transposable element (TE) LINE-1 (L1) is mobilized during brain development, and thus mobile non-autonomous TEs like AluY and SINE-VNTR-Alu (SVA) families can use L1 activity in trans, leading to de novo insertions that may influence the variability of neural cells at genetic and epigenetic levels. In contrast to SNPs and when considering substitutional sequence evolution, the presence or absence of TEs at orthologous loci represents highly informative clade markers that provide insights into the lineage relationships between neural cells and how the nervous system evolves in health and disease. SVAs, as the ‘youngest’ class of hominoid-specific retrotransposons preferentially found in gene- and GC-rich regions, are thought to differentially co-regulate nearby genes and exhibit a high mobility in the human germline. Therefore, we determined whether this is reflected in the somatic brain and used a subtractive and kinetic enrichment technique called representational difference analysis (RDA) coupled with deep sequencing to compare different brain regions with respect to de novo SINE-VNTR-Alu insertion patterns. As a result, we detected somatic de novo SVA integrations in all human brain regions analyzed, and the majority of de novo insertions can be attributed to lineages of telencephalon and metencephalon, since most of the examined integrations are unique to different brain regions under scrutiny. The SVA positions were used as presence/absence markers, forming informative sites that allowed us to create a maximum parsimony phylogeny of brain regions. Our results largely recapitulated the generally accepted evo-devo patterns and revealed chromosome-wide rates of de novo SVA reintegration targets and preferences for specific genomic regions, e.g., GC- and TE-rich regions as well as close proximity to genes that tend to fall into neural-specific Gene Ontology pathways. We concluded that de novo SVA insertions occur in the germline and somatic brain cells at similar target regions, suggesting that similar retrotransposition modes are effective in the germline and soma. Frontiers Media S.A. 2023-06-01 /pmc/articles/PMC10267396/ /pubmed/37325565 http://dx.doi.org/10.3389/fcell.2023.1201258 Text en Copyright © 2023 Möhner, Scheuren, Woronzow, Schumann and Zischler. https://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 Cell and Developmental Biology
Möhner, Jonas
Scheuren, Maurice
Woronzow, Valentina
Schumann, Sven
Zischler, Hans
RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title_full RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title_fullStr RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title_full_unstemmed RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title_short RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain
title_sort rda coupled with deep sequencing detects somatic sva-retrotranspositions and mosaicism in the human brain
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267396/
https://www.ncbi.nlm.nih.gov/pubmed/37325565
http://dx.doi.org/10.3389/fcell.2023.1201258
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