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...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-06-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1201258/full |
| _version_ | 1827936070008832000 |
|---|---|
| author | Jonas Möhner Maurice Scheuren Valentina Woronzow Sven Schumann Hans Zischler |
| author_facet | Jonas Möhner Maurice Scheuren Valentina Woronzow Sven Schumann Hans Zischler |
| author_sort | Jonas Möhner |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T08:06:05Z |
| format | Article |
| id | doaj.art-3b764955a19842c787b65ae0b6637413 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-13T08:06:05Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-3b764955a19842c787b65ae0b66374132023-06-01T04:59:26ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-06-011110.3389/fcell.2023.12012581201258RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brainJonas Möhner0Maurice Scheuren1Valentina Woronzow2Sven Schumann3Hans Zischler4Division of Anthropology, Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, GermanyDivision of Anthropology, Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, GermanyDivision of Anthropology, Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, GermanyInstitute of Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, GermanyDivision of Anthropology, Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University Mainz, Mainz, GermanyCells 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.https://www.frontiersin.org/articles/10.3389/fcell.2023.1201258/fullSINE-VNTR-Aluretrotransposonsomatic mosaichuman brainrepresentational difference analysis |
| spellingShingle | Jonas Möhner Maurice Scheuren Valentina Woronzow Sven Schumann Hans Zischler RDA coupled with deep sequencing detects somatic SVA-retrotranspositions and mosaicism in the human brain Frontiers in Cell and Developmental Biology SINE-VNTR-Alu retrotransposon somatic mosaic human brain representational difference analysis |
| 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 | SINE-VNTR-Alu retrotransposon somatic mosaic human brain representational difference analysis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1201258/full |
| work_keys_str_mv | AT jonasmohner rdacoupledwithdeepsequencingdetectssomaticsvaretrotranspositionsandmosaicisminthehumanbrain AT mauricescheuren rdacoupledwithdeepsequencingdetectssomaticsvaretrotranspositionsandmosaicisminthehumanbrain AT valentinaworonzow rdacoupledwithdeepsequencingdetectssomaticsvaretrotranspositionsandmosaicisminthehumanbrain AT svenschumann rdacoupledwithdeepsequencingdetectssomaticsvaretrotranspositionsandmosaicisminthehumanbrain AT hanszischler rdacoupledwithdeepsequencingdetectssomaticsvaretrotranspositionsandmosaicisminthehumanbrain |