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Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis
Molecular Brain ( IF 3.6 ) Pub Date : 2020-11-13 , DOI: 10.1186/s13041-020-00694-2
Abigail L Savage 1 , Ana Illera Lopez 1 , Alfredo Iacoangeli 2, 3 , Vivien J Bubb 1 , Bradley Smith 2 , Claire Troakes 4 , Nada Alahmady 2, 5 , Sulev Koks 6, 7 , Gerald G Schumann 8 , Ammar Al-Chalabi 2 , John P Quinn 1
Affiliation  

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.

中文翻译:

肌萎缩侧索硬化中选定的逆转录转座能力 L1 基因座的频率和甲基化状态

Long interspersed element-1 (LINE-1/L1) 是人类基因组中唯一可在种系和体细胞组织中动员的自主转座因子。最近的研究已经确定了部分患者的反转录转座子表达改变与致命的神经退行性疾病肌萎缩侧索硬化症 (ALS) 之间的相关性。个体患 ALS 的风险取决于生命中遗传变异和后续修饰物的相互作用。这些修饰物可能包括环境因素,这些因素可能导致表观遗传和基因组变化,例如体细胞突变,发生在随着疾病发展而退化的神经元细胞中。今天,人类基因组中有超过 100 万个 L1 拷贝,但参考基因组中只有 80-100 个 L1 基因座被认为是具有反转录转座能力 (RC) 的,并且这些 RC-L1 基因座中的更少数量是高度活跃的。我们假设 RC-L1 可以通过其在神经元细胞中逆转录转座的能力赋予的致突变潜力以及通过 L1 编码的 ORF2 蛋白的内切核酸酶活性引起的 DNA 损伤来影响正常的细胞功能。为了研究 RC-L1 基因组负担的增加或 RC-L1 改变其表达的表观遗传变化是否可能在疾病发展中发挥作用,我们选择了一组早期报道的七个特征良好的基因组 RC-L1 基因座在细胞 L1 逆转录转座报告基因检测中具有高度活性或作为种系和/或体细胞逆转录转座事件的主要来源元件。对七个多态性 RC-L1 的插入等位基因频率的分析,对于它们的存在或不存在,没有发现单独或在患有疾病的个体中增加的数量。然而,我们确实发现与对照大脑相比,那些患有家族性和散发性 ALS 的个体的运动皮层中 RC-L1 的甲基化水平降低。包含这些 RC-L1 的基因座调控的变化证明了组织特异性,并且可能与疾病过程有关。我们确实发现与对照大脑相比,那些患有家族性和散发性 ALS 的个体的运动皮层中 RC-L1 的甲基化水平降低。包含这些 RC-L1 的基因座调控的变化证明了组织特异性,并且可能与疾病过程有关。我们确实发现与对照大脑相比,那些患有家族性和散发性 ALS 的个体的运动皮层中 RC-L1 的甲基化水平降低。包含这些 RC-L1 的基因座调控的变化证明了组织特异性,并且可能与疾病过程有关。
更新日期:2020-11-15
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