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Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis

Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotr...

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Autores principales: Savage, Abigail L., Lopez, Ana Illera, Iacoangeli, Alfredo, Bubb, Vivien J., Smith, Bradley, Troakes, Claire, Alahmady, Nada, Koks, Sulev, Schumann, Gerald G., Al-Chalabi, Ammar, Quinn, John P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666467/
https://www.ncbi.nlm.nih.gov/pubmed/33187550
http://dx.doi.org/10.1186/s13041-020-00694-2
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author Savage, Abigail L.
Lopez, Ana Illera
Iacoangeli, Alfredo
Bubb, Vivien J.
Smith, Bradley
Troakes, Claire
Alahmady, Nada
Koks, Sulev
Schumann, Gerald G.
Al-Chalabi, Ammar
Quinn, John P.
author_facet Savage, Abigail L.
Lopez, Ana Illera
Iacoangeli, Alfredo
Bubb, Vivien J.
Smith, Bradley
Troakes, Claire
Alahmady, Nada
Koks, Sulev
Schumann, Gerald G.
Al-Chalabi, Ammar
Quinn, John P.
author_sort Savage, Abigail L.
collection PubMed
description Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80–100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process.
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spelling pubmed-76664672020-11-16 Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis Savage, Abigail L. Lopez, Ana Illera Iacoangeli, Alfredo Bubb, Vivien J. Smith, Bradley Troakes, Claire Alahmady, Nada Koks, Sulev Schumann, Gerald G. Al-Chalabi, Ammar Quinn, John P. Mol Brain Research Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80–100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process. BioMed Central 2020-11-13 /pmc/articles/PMC7666467/ /pubmed/33187550 http://dx.doi.org/10.1186/s13041-020-00694-2 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Savage, Abigail L.
Lopez, Ana Illera
Iacoangeli, Alfredo
Bubb, Vivien J.
Smith, Bradley
Troakes, Claire
Alahmady, Nada
Koks, Sulev
Schumann, Gerald G.
Al-Chalabi, Ammar
Quinn, John P.
Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title_full Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title_fullStr Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title_full_unstemmed Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title_short Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
title_sort frequency and methylation status of selected retrotransposition competent l1 loci in amyotrophic lateral sclerosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666467/
https://www.ncbi.nlm.nih.gov/pubmed/33187550
http://dx.doi.org/10.1186/s13041-020-00694-2
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