Sequence complementarity between human noncoding RNAs and SARS-CoV-2 genes: What are the implications for human health?

Abstract

Objectives: To investigate in silico the presence of nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human non-coding (nc)RNA genes.

Methods: The FASTA sequence (NC_045512.2) of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes was retrieved from NCBI.nlm.nih.gov/gene and the Ensembl.org library interrogated for any base-pair match with human ncRNA genes. SARS-CoV-2 gene-matched human ncRNAs were screened for functional activity using bioinformatic analysis. Finally, associations between identified ncRNAs and human diseases were searched in GWAS databases.

Results: A total of 252 matches were found between the nucleotide sequence of SARS-CoV-2 genes and human ncRNAs. With the exception of two small nuclear RNAs, all of them were long non-coding (lnc)RNAs expressed mainly in testis and central nervous system under physiological conditions. The percentage of alignment ranged from 91.30% to 100% with a mean nucleotide alignment length of 17.5 ± 2.4. Thirty-three (13.09%) of them contained predicted R-loop forming sequences, but none of these intersected the complementary sequences of SARS-CoV-2. However, in 31 cases matches fell on ncRNA regulatory sites, whose adjacent coding genes are mostly involved in cancer, immunological and neurological pathways. Similarly, several polymorphic variants of detected non-coding genes have been associated with neuropsychiatric and proliferative disorders.

Conclusion: This pivotal in silico study shows that SARS-CoV-2 genes have Watson-Crick nucleotide complementarity to human ncRNA sequences, potentially disrupting ncRNA epigenetic control of target genes. It remains to be elucidated whether this could result in the development of human disease in the long term.

Keywords: Bioinformatics; COVID-19; Epigenetics; Long non-coding RNA; SARS-CoV-2; Small nuclear RNA.

Fig. 1

Regulatory pathways potentially disrupted by binding of SARS-CoV-2 sequences to lncRNA gene regulatory sites. SARS-CoV-2 genes contain nucleotide sequence homology to the regulatory site of 31 human lncRNA genes whose adjacent coding genes may be involved in oncological, immunological, neurological, cardiovascular, pulmonary, metabolic and musculoskeletal diseases. Abbreviations: ACMSD, aminocarboxymuconate semialdehyde decarboxylase; AMZ2, archaelysin family metallopeptidase 2 ARSG, arylsulfatase G; BLID, BH3-like motif containing, cell death inducer; CA5B, carbonic anhydrase 5B; CAPRIN2, caprin family member 2; CD47, cluster of differentiation 47; CDK6, cyclin dependent kinase 6; CNOT2, CCR4-NOT transcription complex subunit 2; ENAM, enamelin; GABRA2, gamma-aminobutyric acid type A receptor alpha2 subunit; GJA9, gap junction protein alpha 9; IFT57, intraflagellar transport 57; IGF1R, insulin-like growth factor 1 receptor; IGH, immunoglobulin heavy chain Locus; IKBKB, inhibitor of nuclear factor kappa B kinase subunit beta; IL12B, interleukin-12B; INO80, INO80 complex subunit; JCHAIN, joining chain of multimeric IgA and IgM; LAMA2, laminin subunit alpha 2; LMCD1, LIM And Cysteine Rich Domains 1; LYPD6B, LY6/PLAUR domain containing 6B; MAP3K19, mitogen-activated protein kinase 19; PDE1A, phosphodiesterase 1A; PLAT, plasminogen activator, tissue type; PPIAL4A, peptidylprolyl isomerase A like 4A; RUFY3, RUN and FYVE domain containing 3; SGCA, sarcoglycan alpha; SLC16A6, solute carrier family 16 member 6; SLFN, Schlafen family member; SRSF1, serine and arginine rich splicing factor 1; TLN2, Talin2; TMEM163, transmembrane protein 163; UTP3, UTP3 small subunit processome component; VEZF1, vascular endothelial zinc finger 1; ZBED5, zinc finger BED-type containing 5.

Fig. 2

Absolute number and percentage of detected ncRNAs whose polymorphic variants are associated with human diseases according to EBI GWAS Catalog and GeneCards database.Abbreviations: BMI, body mass index.

Fig. 3

Hypothetical scenarios triggered by SARS-CoV-2 and host nucleic acid crosstalk. In the first scenario (a), ncRNAs are pre-existent and hyper-expressed in a cell undergoing SARS-CoV-2 infection. Due to sequence complementarity to SARS-CoV-2 RNA, these transcripts may intercept the viral genome in the cytosol and prevent translation into functional proteins and interaction with PRRs. In addition, they may compete with viral RNA for PRRs and thus mediate a downstream inhibitory signal on the activation of the immune response. In the second scenario (b), SARS-CoV-2 infection may alter the expression of ncRNAs. Taking advantage by its sequence complementarity, SARS-CoV-2 RNA may interfere with the binding of transcription factors and other proteins to regulatory sites of lncRNA genes, thereby indirectly affecting the transcription of adjacent genes. This would lead to a profound alteration of the epigenetic landscape that eventually translates into uncontrolled proliferation pathways. Furthermore, binding of the SARS-CoV-2 genome to complementary snRNA sequences may generate novel epitopes within the RNP complex that fuel autoimmunity. Abbreviations: SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; ncRNA, non-coding RNA; PRR: pattern recognition receptor; snRNA, small nuclear RNA.