Journal article
Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
Molecular Brain, Vol.13, Article 154
2020
Abstract
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.
Details
- Title
- Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
- Authors/Creators
- A.L. Savage (Author/Creator)A.I. Lopez (Author/Creator)A. Iacoangeli (Author/Creator)V.J. Bubb (Author/Creator)B. Smith (Author/Creator)C. Troakes (Author/Creator)N. Alahmady (Author/Creator)S. Kõks (Author/Creator)G.G. Schumann (Author/Creator)A. Al-Chalabi (Author/Creator)J.P. Quinn (Author/Creator)
- Publication Details
- Molecular Brain, Vol.13, Article 154
- Publisher
- BioMed Central
- Identifiers
- 991005540189307891
- Copyright
- © 2020 The Authors
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Metrics
59 File views/ downloads
82 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.54 Molecular & Cell Biology - Genetics
- 1.54.1122 Transposable Elements
- Web Of Science research areas
- Neurosciences
- ESI research areas
- Neuroscience & Behavior