Identification of endogenous neural reverse transcriptase activity and the transcriptomic diversity of L1 ORF2 in the human brain
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Identification of endogenous neural reverse transcriptase activity and the transcriptomic diversity of L1 ORF2 in the human brain

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Abstract

The postmitotic nature of neurons allows for the proliferation and accumulation of genomic changes in the brain across an individual’s lifetime. This genomic mosaicism can take many forms, including somatic gene recombination.Chapter 1 is an introduction of the forms of somatic genomic mosaicism in the brain, especially as they relate to the aging and diseased brain. Chapter 2 examines the presence and prevalence of endogenous reverse transcriptase (RT) activity across the human brain. Examination of the prefrontal cortex, basal ganglia, hippocampus and cerebellum revealed widespread RT activity across the human brain. Inhibition of endogenous brain RT activity with nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs) showed highly specific inhibitory profiles, including differences between regions. Endogenous RT activity in the mouse brain exhibited disparate inhibitory profiles, pointing to species specificity in endogenous RT source, activity, and susceptibilities. Chapter 3 examines the diversity of the neural L1 (LINE-1/Long-Interspersed- Element-1) transcriptome. L1 retrotransposons bicistronically express open reading frame 2 (ORF2), which contains RT and endonuclease (EN) domains, along with the RNA-binding protein ORF1. We utilize spatial transcriptomics and targeted long-read (PacBio) sequencing to show discordance in expression of ORF1 and ORF2 and wide variation in sequence diversity and coding potential of L1 transcripts. Bicistronic L1 constituted <0.01% of L1 transcripts, while over 80% of the neural L1 transcriptome is non-coding. Greater than 600 distinct, monocistronic ORF2 variants were identified, with functional variant analyses revealing a range of RT and EN activities in both full-length and truncated ORF2 variants. Thus, monocistronic ORF2 variants predominate, contributing diverse RT and/or EN functions independent of full-length L1 retrotransposition, thus promoting RT-mediated genome instability within the human brain.

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This item is under embargo until June 21, 2026.