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1. Conserved Genomic Terminals of SARS-CoV-2 as Coevolving Functional Elements and Potential Therapeutic Targets

   https://doi.org/10.1128/mSphere.00754-20  

   Chan, Agnes P.; Choi, Yongwook; Schork, Nicholas J. (December 2020, mSphere)

   Lee, Benhur (Ed.)

   ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 40 million people worldwide, with over 1 million deaths as of October 2020 and with multiple efforts in the development and testing of antiviral drugs and vaccines under way. In order to gain insights into SARS-CoV-2 evolution and drug targets, we investigated how and to what extent the SARS-CoV-2 genome sequence differs from those of other well-characterized human and animal coronavirus genomes, as well as how polymorphic SARS-CoV-2 genomes are generally. We ultimately sought to identify features in the SARS-CoV-2 genome that may contribute to its viral replication, host pathogenicity, and vulnerabilities. Our analyses suggest the presence of unique sequence signatures in the 3′ untranslated region (3′-UTR) of betacoronavirus lineage B, which phylogenetically encompasses SARS-CoV-2 and SARS-CoV as well as multiple groups of bat and animal coronaviruses. In addition, we identified genome-wide patterns of variation across different SARS-CoV-2 strains that likely reflect the effects of selection. Finally, we provide evidence for a possible host-microRNA-mediated interaction between the 3′-UTR and human microRNA hsa-miR-1307-3p based on the results of multiple computational target prediction analyses and an assessment of similar interactions involving the influenza A H1N1 virus. This interaction also suggests a possible survival mechanism, whereby a mutation in the SARS-CoV-2 3′-UTR leads to a weakened host immune response. The potential roles of host microRNAs in SARS-CoV-2 replication and infection and the exploitation of conserved features in the 3′-UTR as therapeutic targets warrant further investigation. IMPORTANCE The coronavirus disease 2019 (COVID-19) outbreak is having a dramatic global effect on public health and the economy. As of October 2020, SARS-CoV-2 has been detected in over 189 countries, has infected over 40 million people, and is responsible for more than 1 million deaths. The genome of SARS-CoV-2 is small but complex, and its functions and interactions with human host factors are being studied extensively. The significance of our study is that, using extensive SARS-CoV-2 genome analysis techniques, we identified potential interacting human host microRNA targets that share similarity with those of influenza A virus H1N1. Our study results will allow the development of virus-host interaction models that will enhance our understanding of SARS-CoV-2 pathogenesis and motivate the exploitation of both the interacting viral and host factors as therapeutic targets. 

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2. Visual Analytics for Robust Investigations of Placental Aquaporin Gene Expression in Response to Maternal SARS-CoV-2 Infection

   https://doi.org/10.3390/analytics3010007  

   Isokpehi, Raphael D.; Abioye, Amos O.; Hamilton, Rickeisha S.; Fryer, Jasmin C.; Hollman, Antoinesha L.; Destefano, Antoinette M.; Ezekiel, Kehinde B.; Taylor, Tyrese L.; Brooks, Shawna F.; Johnson, Matilda O.; et al (March 2024, Analytics)

   The human placenta is a multifunctional, disc-shaped temporary fetal organ that develops in the uterus during pregnancy, connecting the mother and the fetus. The availability of large-scale datasets on the gene expression of placental cell types and scholarly articles documenting adverse pregnancy outcomes from maternal infection warrants the use of computational resources to aid in knowledge generation from disparate data sources. Using maternal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection as a case study in microbial infection, we constructed integrated datasets and implemented visual analytics resources to facilitate robust investigations of placental gene expression data in the dimensions of flow, curation, and analytics. The visual analytics resources and associated datasets can support a greater understanding of SARS-CoV-2-induced changes to the human placental expression levels of 18,882 protein-coding genes and at least 1233 human gene groups/families. We focus this report on the human aquaporin gene family that encodes small integral membrane proteins initially studied for their roles in water transport across cell membranes. Aquaporin-9 (AQP9) was the only aquaporin downregulated in term placental villi from SARS-CoV-2-positive mothers. Previous studies have found that (1) oxygen signaling modulates placental development; (2) oxygen tension could modulate AQP9 expression in the human placenta; and (3) SARS-CoV-2 can disrupt the formation of oxygen-carrying red blood cells in the placenta. Thus, future research could be performed on microbial infection-induced changes to (1) the placental hematopoietic stem and progenitor cells; and (2) placental expression of human aquaporin genes, especially AQP9. 

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3. Host-Genome Similarity Characterizes the Adaption of SARS-CoV-2 to Humans

   https://doi.org/10.3390/biom12070972  

   Sun, Weitao (July 2022, Biomolecules)

   The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high mutation rate and many variants have emerged in the last 2 years, including Alpha, Beta, Delta, Gamma and Omicron. Studies showed that the host-genome similarity (HGS) of SARS-CoV-2 is higher than SARS-CoV and the HGS of open reading frame (ORF) in coronavirus genome is closely related to suppression of innate immunity. Many works have shown that ORF 6 and ORF 8 of SARS-CoV-2 play an important role in suppressing IFN-β signaling pathway in vivo. However, the relation between HGS and the adaption of SARS-CoV-2 variants is still not clear. This work investigates HGS of SARS-CoV-2 variants based on a dataset containing more than 40,000 viral genomes. The relation between HGS of viral ORFs and the suppression of antivirus response is studied. The results show that ORF 7b, ORF 6 and ORF 8 are the top 3 genes with the highest HGS. In the past 2 years, the HGS values of ORF 8 and ORF 7B of SARS-CoV-2 have increased greatly. A remarkable correlation is discovered between HGS and inhibition of antivirus response of immune system, which suggests that the similarity between coronavirus and host gnome may be an indicator of the suppression of innate immunity. Among the five variants (Alpha, Beta, Delta, Gamma and Omicron), Delta has the highest HGS and Omicron has the lowest HGS. This finding implies that the high HGS in Delta variant may indicate further suppression of host innate immunity. However, the relatively low HGS of Omicron is still a puzzle. By comparing the mutations in genomes of Alpha, Delta and Omicron variants, a commonly shared mutation ACT > ATT is identified in high-HGS strain populations. The high HGS mutations among the three variants are quite different. This finding strongly suggests that mutations in high HGS strains are different in different variants. Only a few common mutations survive, which may play important role in improving the adaptability of SARS-CoV-2. However, the mechanism for how the mutations help SARS-CoV-2 escape immunity is still unclear. HGS analysis is a new method to study virus–host interaction and may provide a way to understand the rapid mutation and adaption of SARS-CoV-2. 

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4. Single-nucleotide conservation state annotation of the SARS-CoV-2 genome

   https://doi.org/10.1038/s42003-021-02231-w  

   Kwon, Soo Bin; Ernst, Jason (June 2021, Communications Biology)

   Abstract Given the global impact and severity of COVID-19, there is a pressing need for a better understanding of the SARS-CoV-2 genome and mutations. Multi-strain sequence alignments of coronaviruses (CoV) provide important information for interpreting the genome and its variation. We apply a comparative genomics method, ConsHMM, to the multi-strain alignments of CoV to annotate every base of the SARS-CoV-2 genome with conservation states based on sequence alignment patterns among CoV. The learned conservation states show distinct enrichment patterns for genes, protein domains, and other regions of interest. Certain states are strongly enriched or depleted of SARS-CoV-2 mutations, which can be used to predict potentially consequential mutations. We expect the conservation states to be a resource for interpreting the SARS-CoV-2 genome and mutations. 

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5. Exceptional diversity and selection pressure on coronavirus host receptors in bats compared to other mammals

   https://doi.org/10.1098/rspb.2022.0193  

   Frank, Hannah K; Enard, David; Boyd, Scott D (July 2022, Proceedings of the Royal Society B: Biological Sciences)

   Pandemics originating from non-human animals highlight the need to understand how natural hosts have evolved in response to emerging human pathogens and which groups may be susceptible to infection and/or potential reservoirs to mitigate public health and conservation concerns. Multiple zoonotic coronaviruses, such as severe acute respiratory syndrome-associated coronavirus (SARS-CoV), SARS-CoV-2 and Middle Eastern respiratory syndrome-associated coronavirus (MERS-CoV), are hypothesized to have evolved in bats. We investigate angiotensin-converting enzyme 2 (ACE2), the host protein bound by SARS-CoV and SARS-CoV-2, and dipeptidyl-peptidase 4 (DPP4 or CD26), the host protein bound by MERS-CoV, in the largest bat datasets to date. Both the ACE2 and DPP4 genes are under strong selection pressure in bats, more so than in other mammals, and in residues that contact viruses. Additionally, mammalian groups vary in their similarity to humans in residues that contact SARS-CoV, SARS-CoV-2 and MERS-CoV, and increased similarity to humans in binding residues is broadly predictive of susceptibility to SARS-CoV-2. This work augments our understanding of the relationship between coronaviruses and mammals, particularly bats, provides taxonomically diverse data for studies of how host proteins are bound by coronaviruses and can inform surveillance, conservation and public health efforts. 

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