Abstract B077: Ribosomal RNAs are fragmented into short RNAs in a manner that depends on a person’s sex, population origin, and race: implications for health disparities and personalized medicine

Abstract

Abstract Ribosomal RNAs (rRNAs) are the most abundant RNAs in eukaryotic cells. rRNAs combine with ribosomal proteins to form the scaffold for the small and large subunits of the ribosomes. There are six distinct rRNAs: four are encoded by the nuclear and two by the mitochondrial genome. Deep sequencing showed that short RNAs, known as “rRNA-derived fragments” or rRFs, arise from all six rRNAs. The accumulated evidence suggests that rRFs have key functional roles. Various studies showed that rRFs can modulate intracellular ATP levels, participate in the response to stress, affect ERK signaling, and are required for DNA repair. Moreover, rRFs can be loaded on Argonaute thereby entering the RNAi pathway and regulating transcript abundance. To systematically study rRFs, we developed a computational pipeline and used it to analyze the short RNA profiles of lymphoblastoid cell lines obtained from 434 healthy participants of the 1000 Genomes Project. The 434 individuals represent five human populations, and two races. Men and women are represented evenly in each of the five populations. We analyzed the rRF profiles for each of the six rRNAs in turn, and separately for the five populations and two sexes. Across the 434 individuals, we identified more than 18,000 rRFs each with a normalized abundance ≥ 10 reads per million. Each of the six rRNAs gives rise to ‘clouds of rRFs’ whose identities and abundances differ characteristically from each rRNA to the next. We found that the clouds of rRFs are produced in a population-specific, race-specific, and sex-specific manner. Like samples, i.e. samples belonging to the same sex and population group, produce rRFs with the same identities and relative abundances, which suggests that rRFs are produced in a regimented manner by currently unknown processes. Preliminary analyses of rRFs in primary cancer samples and cell lines led to similar results. Northern blotting allowed us to independently confirm several of our computational findings. Our laboratory has long focused on the study of microRNAs (miRNAs), miRNA isoforms (isomiRs), transfer RNAs (tRNAs), and tRNA-derived fragments (tRFs) in health and disease. IsomiRs and tRFs play important roles in cells by modulating transcript abundance through Argonaute-loading, translation-stalling, decoying of RNA binding proteins, etc. We were first to show that isomiRs and tRFs are produced constitutively in human tissues and that their profiles depend on a person’s sex, population origin, and race, as well as on tissue type, tissue state, and disease. We also reported sex- and/or race-dependent differences for multiple cancers, including those of the prostate, bladder, lung, kidney, and breast. Through the current study, we show for a third category of short regulatory RNAs, the rRFs, that they too depend on personal attributes such as sex, population origin, and race. The finding and the large number of rRFs have implications for the study of health disparities, in cancer and other diseases, and for efforts to practice personalized medicine. Citation Format: Tess Cherlin, Rogan Magee, Yi Jing, Phillipe Loher, Venetia Pliatsika, Isidore Rigoutsos. Ribosomal RNAs are fragmented into short RNAs in a manner that depends on a person’s sex, population origin, and race: implications for health disparities and personalized medicine [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B077.