LINE-1 retrotransposons in healthy and diseased human brain

Abstract

Long interspersed element-1 (LINE-1 or L1) is a transposable element with the ability to self-mobilize throughout the human genome. The L1 elements found in the human brain is hypothesized to date back 56 million years ago and has survived evolution, currently accounting for 17% of the human genome. L1 retrotransposition has been theorized to contribute to somatic mosaicism. This review focuses on the presence of L1 in the healthy and diseased human brain, such as in autism spectrum disorders. Throughout this exploration, we will discuss the impact L1 has on neurological disorders that can occur throughout the human lifetime. With this, we hope to better understand the complex role of L1 in the human brain development and its implications to human cognition. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 434-455, 2018.

Keywords: LINE-1; autism; brain; neurological disorders; retrotransposition.

Figure 1

a. Structure of active human L1 element. The relative positions of the 5’ untranslated region (5’ UTR), the open reading frames: ORF0, ORF1, and ORF2, 3’ untranslated region (3’ UTR), and poly A tail are shown. EN denotes endonuclease, RT denotes reverse transcriptase, and C denotes cysteine-rich domain (all encoded by ORF2). The arrows located on the 5’ UTR symbolize the sense and antisense promoters. More details provided in the main text. b. Model of the retrotransposition cycle. 1) Generation of full-length L1 mRNA using the sense promoter in 5’ UTR. 2) mRNA is transported to the cytoplasm, where ORF1p and ORF2p are translated. ORF1p and ORF2p bind to the L1 mRNA to form a ribonucleotide particle (RNP) through a process called cis-preference. 3) Return to the nucleus (Mechanism is still undetermined). Once in the nucleus, the ORF2 EN activity will make a break in the DNA, exposing a free 3’OH in the bottom strand, serving as a template for the RT to generate the first cDNA strand linked to the genome. 4) This mechanism called target-primed reverse transcription (TPRT) will allow the integration of a new L1 copy. More detail provided in the main text.

Figure 2

Timeline of impact of L1 in the human brain during a single lifetime. The top curves represent a timeline of major events occurring in brain development from conception to adulthood (adapted from Thompson and Nelson (2001)). The L1-associated neurodevelopmental, neurodegenerative and neurological disorders discussed in the main text are graphed with respect to the age of impact in a human lifetime.