Wankun Deng1,5, Citu Citu1,5, Andi Liu1 and Zhongming Zhao1,2,3,4 1Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA; 2MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, USA; 3Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA; 4Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA

↵5 These authors contributed equally to this work.

Corresponding author: zhongming.zhaouth.tmc.edu Abstract

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.

Received March 17, 2024. Accepted September 18, 2024.