Lan Lin1*†, Peng Jiang2†, Juw Won Park134†, Jinkai Wang1†, Zhi-xiang Lu1, Maggie P. Y. Lam5, Peipei Ping56 and Yi Xing1*
* Corresponding authors: Lan Lin , Yi Xing
† Equal contributors
1 Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles 90095, CA, USA
2 Regenerative Biology, Morgridge Institute for Research, Madison 53707, WI, USA
3 Department of Computer Engineering and Computer Science, University of Louisville, Louisville 40292, KY, USA
4 KBRIN Bioinformatics Core, University of Louisville, Louisville 40202, KY, USA
5 Department of Physiology, University of California, Los Angeles, Los Angeles 90095, CA, USA
6 Department of Medicine, University of California, Los Angeles, Los Angeles 90095, CA, USA
Alu elements are major contributors to lineage-specific new exons in primate and human genomes. Recent studies indicate that some Alu exons have high transcript inclusion levels or tissue-specific splicing profiles, and may play important regulatory roles in modulating mRNA degradation or translational efficiency. However, the contribution of Alu exons to the human proteome remains unclear and controversial. The prevailing view is that exons derived from young repetitive elements, such as Alu elements, are restricted to regulatory functions and have not had adequate evolutionary time to be incorporated into stable, functional proteins.
We adopt a proteotranscriptomics approach to systematically assess the contribution of Alu exons to the human proteome. Using RNA sequencing, ribosome profiling, and proteomics data from human tissues and cell lines, we provide evidence for the translational activities of Alu exons and the presence of Alu exon derived peptides in human proteins. These Alu exon peptides represent species-specific protein differences between primates and other mammals, and in certain instances between humans and closely related primates. In the case of the RNA editing enzyme ADARB1, which contains an Alu exon peptide in its catalytic domain, RNA sequencing analyses of A-to-I editing demonstrate that both the Alu exon skipping and inclusion isoforms encode active enzymes. The Alu exon derived peptide may fine tune the overall editing activity and, in limited cases, the site selectivity of ADARB1 protein products.
Our data indicate that Alu elements have contributed to the acquisition of novel protein sequences during primate and human evolution.
Keywords: Alu ; Transposable element; Exon; Alternative splicing; RNA editing; RNA-seq; Ribo-seq; Transcriptome; Proteome; Evolution; Primate