Discovery of a tRNA-like base sequence in the coronavirus genome and possible mechanism of action

Abstract

Background: The question of whether the coronavirus genome contain as-yetununderstood genetic component.

Purpose (objective): Elucidate the novel functions of the discovered tRNA-like base sequence and lead to the development of novel therapeutic agents.

Methods: A novel tRNA-like base sequence was found in the sequences complementary to the genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV. By comparing mutations in the tRNA-like base sequences of these two viruses, it was found that base pairing in the cloverleaf model of SARS-CoV-2 was more robust than that of SARS-CoV.

Results: The results of homology search between a short sequence of the coronavirus tRNA-like base sequence and human genes suggest that the molecule produced by this novel tRNA-like sequence may be involved in the splicing of human messenger RNA.

Conclusions: Experimental molecular evidence of the tRNA-like base sequence discovered in this study is urgently needed.

Keywords: Base sequence; Cloverleaf model of tRNA; Coronavirus; Intron; Mutation.

Fig. 1

Cloverleaf model of the 330-base tRNA-like sequence found in the genome of the new coronavirus SARS-CoV-2. The tRNA-like base sequence occupies 330 bases at positions 12,940–133,269 of the NCBI/Nucleotide/NC_045512-2 genome (complement). It contains an intron consisting of 260 bases. The exon regions are highlighted in color (orange, 5′ side and blue, 3′ side). The eight bases in the sequence chart (TTTAGTTA), surrounded by a red line, represent the central part of the 330-base tRNA-like sequence, which was used for homology search. Although U should be used in the cloverleaf model of tRNA, T was used for the purpose of sequence description (● indicates Watson-Crick-type pairing, and ◯ indicates non-Watson-Crick base pairing)

Fig. 2

Mutations found in the 330-base tRNA-like sequence. a The base sequence starting at position 16,635 represents the 330-base tRNA-like sequence of the new coronavirus [NCBI/Nucleotide/NC_045512.2, (+) strand], while the base sequence starting at position 16,561 represents the 330-base tRNA-like sequence of SARS-CoV Tor2 [NCBI/Nucleotide /NC_004718.3, ( +) strand]. Mutated bases are shown in capital letters between the two base sequences. Bases differing between SARS-CoV-2 (upper base sequence) and SARS-CoV (lower base sequence) are surrounded by a red line. ①– indicate the section number of the 330-base tRNA-like sequence. b Cloverleaf model of the 330-base tRNA-like sequence of SARS-CoV Tor2. Note that the model is drawn from complementary strands. → ◯ indicates a mutation in the novel strain, SARS-CoV-2 (Fig. 1)

Fig. 3

Positions and intervals of the eight-base fragment ATTGATTT and the stop codon. a Human olfactory receptor genes; b COVID-19-related human genes. Numbers in each gene name indicate their order of discovery. The numerical values on the right side indicate the position of each gene in the genome. The numbers in bold red on the semi-elliptical line indicate the distance (number of bases) between the eight-base fragments. Stop codons are enclosed in parentheses at their respective positions. The distance (number of bases) between the eight-base fragment and the stop codon is indicated by red numbers in italics

Fig. 4

Position of a pair of eight-base sequences with regular intervals in the base sequence of the human olfactory receptor gene OR2L13 (NCBI/Gene ID: 284521), and positions of stop codons located upstream of the pair of eight-base sequences. These sequences are highlighted in the gene sequence chart, and complementary pairing is shown with the TTA anticodon and the eight-base sequence from the 330-base tRNA-like sequence of SARS-CoV-2 (using uppercase letters). Complementary bonds of the Watson-Crick type, solid lines; non-Watson-Crick type, dotted lines

Fig. 5

Explanatory diagram of the hypothetical mechanism of action of the 330-base tRNA-like sequence on the splicing of messenger RNA of human genes. a The spliceosome binds to the intron and splicing occurs normally; however, b when a dimeric molecule of the 330-base tRNA-like sequence binds to the intron by complementary binding, the spliceosome cannot bind to the intron, and splicing does not occur