Omicron's Intrinsic Gene-Gene Interactions Jumped Away from Earlier SARS-CoV-2 Variants and Gene Homologs between Humans and Animals (preprint)

Omicron and its subvariants have become the predominant SARS-CoV-2 variants worldwide. The Omicron's basic reproduction number (R0) has been close to 20 or higher. However, it is not known what caused such an extremely high R0. This work aims to find an explanation for such high R0 Omicron infection. We found that Omicron's intrinsic gene-gene interactions jumped away from earlier SARS-CoV-2 variants which can be fully described by a miniature set of genes reported in our earlier work. We found that the gene PTAFR (Platelet Activating Factor Receptor) is highly correlated with Omicron variants, and so is the gene CCNI (Cyclin I), which is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. The combination of PTAFR and CCNI can lead to a 100% accuracy of differentiating Omicron COVID-19 infection and COVID-19 negative. We hypothesize that Omicron variants were potentially jumped from COVID-19-infected animals back to humans. In addition, there are also several other two-gene interactions that lead to 100% accuracy. Such observations can explain Omicron's fast-spread reproduction capability as either of those two-gene interactions can lead to COVID-19 infection, i.e., multiplication of R0s leads to a much higher R0. At the genomic level, PTAFR, CCNI, and several other genes identified in this work rise to Omicron druggable targets and antiviral drugs besides the existing antiviral drugs.

The Initial COVID-19 Reliable Interactive DNA Methylation Markers and Biological Implications (preprint)

Earlier research has established the existence of reliable interactive genomic biomarkers. However, reliable DNA methylation biomarkers, not to mention interactiveness, have yet to be identified at the epigenetic level. This study, from 865,859 methylation sites, discovered two miniature sets of Infinium MethylationEPIC sites, each having eight CpG sites (genes) to interact with each other and disease subtypes. They led to nearly perfect (96.87-100% accuracy) prediction of COVID-19 patients from patients with other diseases or healthy controls. These CpG sites can jointly explain some post-COVID-19-related conditions. These CpG sites and the optimum performed genomic biomarkers reported in the literature rise to be potential druggable targets. Among these CpG sites, cg16785077 (gene MX1), cg25932713 (gene PARP9), and cg22930808 (gene PARP9) at DNA methylation levels indicate that the initial SARS-CoV-2 may be better treated as transcribed viral DNA into RNA virus, i.e., not as an RNA virus that has been concerned by scientists. Such a discovery can significantly change the scientific thinking and knowledge of viruses.

Genomic Benefits and Potential Harms of COVID-19 Vaccines Indicated from High-Performance Genomic Biomarkers (preprint)

COVID-19 vaccines can be the tugboats of preventing SARS-CoV-2 infections when they are practical and, more importantly, without adverse effects. However, the reality is that they may result in short-term or long-term impacts on COVID-19-related diseases and even trigger the formation of new variants of SARS-CoV-2. Using published data, we use a set of high-performance COVID-19 genomic biomarkers (MND1, CDC6, ZNF282) to study the benefits and adverse effects of the BNT162b2 vaccine. We found that the vaccine lowered expression values of genes MND1 and CDC6 while heightening the expression values of ZNF282 of individuals with SARS-CoV-2-naive, which is expected and satisfies the biological equivalence between the COVID-19 disease and the genomic signature patterns established in the literature. However, we also found that the vaccine adversely affected COVID-19 convalescent octogenarians. It heightened the expression values of MND1 and CDC6. In addition, it lowered the expression values of ZNF282. Such adverse effects raise outstanding concerns about whether or not COVID-19 convalescent individuals should take the current vaccine or when they can take it. These findings are new at the genomic level and can provide insights into developing the next-generation vaccines, antiviral drugs, and pandemic management guidance.

The Existence of At Least Three Genomic Signature Patterns and At Least Seven Subtypes of COVID-19 and the End of the Disease (preprint)

Hoping to find genomic clues linked to COVID-19 and end the pandemic has driven scientists' tremendous efforts to try all kinds of research. Signs of progress have been achieved but are still limited. This paper intends to prove the existence of at least three genomic signature patterns and at least seven subtypes of COVID-19 driven by five critical genes (the smallest subset of genes). These signatures and subtypes provide crucial genomic information in COVID-19 diagnosis (including ICU patients), research focuses, and treatment methods. Unlike existing approaches focused on gene fold-changes and pathways, gene-gene nonlinear and competing interactions are the driving forces in finding the signature patterns and subtypes. Furthermore, the method leads to 100\% accuracy, which shows biological and mathematical equivalences between COVID-19 status and the signature patterns and a methodological advantage over other existing methods that cannot lead to 100\% accuracy. As a result, as new biomarkers, the new findings can be much more informative than other findings for interpreting biological mechanisms, developing the second (third) generation of vaccines, antiviral drugs, and treatment methods, and eventually bringing new hopes to an end of the pandemic.

ATP6V1B2 and IFI27 and their intrinsic functional genomic characteristics associated with SARS-CoV-2 (preprint)

Genes functionally associated with SARS-CoV-2 and genes functionally related to COVID-19 disease can be different, whose distinction will become the first essential step for successfully fighting against the COVID-19 pandemic. Unfortunately, this first step has not been completed in all biological and medical research. Using a newly developed max-competing logistic classifier, two genes, ATP6V1B2 and IFI27, stand out to be critical in transcriptional response to SARS-CoV-2 with differential expressions derived from NP/OP swab PCR. This finding is evidenced by combining these two genes with one another gene in predicting disease status to achieve better-indicating power than existing classifiers with the same number of genes. In addition, combining these two genes with three other genes to form a five-gene classifier outperforms existing classifiers with ten or more genes. With their exceptional predicting power, these two genes can be critical in fighting against the COVID-19 pandemic as a new focus and direction. Comparing the functional effects of these genes with a five-gene classifier with 100% accuracy identified and tested from blood samples in the literature, genes and their transcriptional response and functional effects to SARS-CoV-2 and genes and their functional signature patterns to COVID-19 antibody are significantly different, which can be interpreted as the former is the point of a phenomenon, and the latter is the essence of the disease. Such significant findings can help explore the causal and pathological clue between SARS-CoV-2 and COVID-19 disease and fight against the disease with more targeted vaccines, antiviral drugs, and therapies.

Electrical probing of COVID-19 spike protein receptor binding domain via a graphene field-effect transistor (preprint)

Here, in an effort towards facile and fast screening/diagnosis of novel coronavirus disease 2019 (COVID-19), we combined the unprecedently sensitive graphene field-effect transistor (Gr-FET) with highly selective antibody-antigen interaction to develop a coronavirus immunosensor. The Gr-FET immunosensors can rapidly identify (about 2 mins) and accurately capture the COVID-19 spike protein S1 (which contains a receptor binding domain, RBD) at a limit of detection down to 0.2 pM, in a real-time and label-free manner. Further results ensure that the Gr-FET immunosensors can be promisingly applied to screen for high-affinity antibodies (with binding constant up to 2*10^11 M^-1 against the RBD) at concentrations down to 0.1 pM. Thus, our developed electrical Gr-FET immunosensors provide an appealing alternative to address the early screening/diagnosis as well as the analysis and rational design of neutralizing-antibody locking methods of this ongoing public health crisis.