Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
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RESEARCH
Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis Abigail L. Savage1, Ana Illera Lopez1, Alfredo Iacoangeli2,3, Vivien J. Bubb1, Bradley Smith2, Claire Troakes4, Nada Alahmady2,5, Sulev Koks6,7, Gerald G. Schumann8, Ammar Al‑Chalabi2 and John P. Quinn1*
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 epige‑ netic 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 spo‑ radic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demon‑ strated tissue specificity and could be related to the disease process. Keywords: Amyotrophic lateral sclerosis, LINE-1, Retrotransposition competent, Methylation Introduction Long interspersed element-1 (LINE-1/L1) represents the only autonomous retrotransposon family in the human genome whose members are currently mobilised and it *Correspondence: [email protected] 1 Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK Full list of author information is available at the end of the article
constitutes a significant source of endogenous mutagene
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