Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Perron Institute for Neurological and Translational Science, Perth, WA, Australia.
Sci Rep. 2023 Aug 24;13(1):13857. doi: 10.1038/s41598-023-41052-1.
Long interspersed nuclear element-1 (LINE-1/L1) retrotransposons make up 17% of the human genome. They represent one class of transposable elements with the capacity to both mobilize autonomously and in trans via the mobilization of other elements, primarily Alu and SVA elements. Reference LINE-1 elements are, by definition, found in the reference genome, however, due to the polymorphic nature of these elements, variation for presence or absence is present within the population. We used a combination of clinical and transcriptomic data from the Parkinson's Progression Markers Initiative (PPMI) and applied matrix expression quantitative trait loci analysis and linear mixed-effects models involving 114 clinical, biochemical and imaging data from the PPMI cohort to elucidate the role of reference LINE-1 insertion polymorphism on both gene expression genome-wide and progression of Parkinson's disease (PD). We demonstrate that most LINE-1 insertion polymorphisms are capable of regulating gene expression, preferentially in trans, including previously identified PD risk loci. In addition, we show that 70 LINE-1 elements were associated with longitudinal changes of at least one PD progression marker, including ipsilateral count density ratio and UPDRS scores which are indicators of degeneration and severity. In conclusion, this study highlights the effect of the polymorphic nature of LINE-1 retrotransposons on gene regulation and progression of PD which underlines the importance of analyzing transposable elements within complex diseases.
长散布核元件-1（LINE-1/L1）逆转录转座子占人类基因组的 17%。它们代表一类可自主移动的转座元件，也可以通过其他元件（主要是 Alu 和 SVA 元件）的移动在转座中移动。参考 LINE-1 元件根据定义存在于参考基因组中，但是，由于这些元件的多态性，在人群中存在或不存在的变体。我们结合了帕金森病进展标志物倡议（PPMI）的临床和转录组数据，应用矩阵表达数量性状基因座分析和线性混合效应模型，涉及 PPMI 队列的 114 项临床、生化和成像数据，以阐明参考 LINE-1 插入多态性对基因表达全基因组和帕金森病（PD）进展的作用。我们证明，大多数 LINE-1 插入多态性能够调节基因表达，优先在转座中，包括先前确定的 PD 风险基因座。此外，我们还表明，70 个 LINE-1 元件与至少一个 PD 进展标志物的纵向变化相关，包括同侧计数密度比和 UPDRS 评分，这是退化和严重程度的指标。总之，这项研究强调了 LINE-1 逆转录转座子多态性对基因调控和 PD 进展的影响，这突显了在复杂疾病中分析转座元件的重要性。
