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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. Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2

   https://doi.org/10.1093/molbev/msaa178  

   Pollock, David D ; Castoe, Todd A ; Perry, Blair W ; Lytras, Spyros ; Wade, Kristen J ; Robertson, David L ; Holmes, Edward C ; Boni, Maciej F ; Kosakovsky Pond, Sergei L ; Parry, Rhys ; et al ( July 2020 , Molecular Biology and Evolution)

   Leitner, Thomas (Ed.)

   Abstract Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia’s inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited. 

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3. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

   https://doi.org/10.1073/pnas.2010146117  

   Damas, Joana ; Hughes, Graham M. ; Keough, Kathleen C. ; Painter, Corrie A. ; Persky, Nicole S. ; Corbo, Marco ; Hiller, Michael ; Koepfli, Klaus-Peter ; Pfenning, Andreas R. ; Zhao, Huabin ; et al ( September 2020 , Proceedings of the National Academy of Sciences)

   null (Ed.)

   The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care. 

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4. The species coalescent indicates possible bat and pangolin origins of the COVID-19 pandemic

   https://doi.org/10.1038/s41598-023-32622-4  

   Yang, Jialin ; Skaro, Michael ; Chen, Jiani ; Zhan, Duna ; Lyu, Leke ; Gay, Skylar ; Kandeil, Ahmed ; Ali, Mohamed A. ; Kayali, Ghazi ; Stoianova, Kateryna ; et al ( April 2023 , Scientific Reports)

   A consensus species tree is reconstructed from 11 gene trees for human, bat, and pangolin beta coronaviruses from samples taken early in the pandemic (prior to April 1, 2020). Using coalescent theory, the shallow (short branches relative to the hosts) consensus species tree provides evidence of recent gene flow events between bat and pangolin beta coronaviruses predating the zoonotic transfer to humans. The consensus species tree was also used to reconstruct the ancestral sequence of human SARS-CoV-2, which was 2 nucleotides different from the Wuhan sequence. The time to most recent common ancestor was estimated to be Dec 8, 2019 with a bat origin. Some human, bat, and pangolin coronavirus lineages found in China are phylogenetically distinct, a rare example of a class II phylogeography pattern (Avise et al. in Ann Rev Eco Syst 18:489–422, 1987). The consensus species tree is a product of evolutionary factors, providing evidence of repeated zoonotic transfers between bat and pangolin as a reservoir for future zoonotic transfers to humans.

    

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5. Coronaviruses and Australian bats: a review in the midst of a pandemic

   https://doi.org/10.1071/ZO20046  

   Peel, Alison J. ; Field, Hume E. ; Aravena, Manuel Ruiz ; Edson, Daniel ; McCallum, Hamish ; Plowright, Raina K. ; Prada, Diana ( January 2019 , Australian Journal of Zoology)

   null (Ed.)

   Australia’s 81 bat species play vital ecological and economic roles via suppression of insect pests and maintenance of native forests through pollination and seed dispersal. Bats also host a wide diversity of coronaviruses globally, including several viral species that are closely related to SARS-CoV-2 and other emergent human respiratory coronaviruses. Although there are hundreds of studies of bat coronaviruses globally, there are only three studies of bat coronaviruses in Australian bat species, and no systematic studies of drivers of shedding. These limited studies have identified two betacoronaviruses and seven alphacoronaviruses, but less than half of Australian species are included in these studies and further research is therefore needed. There is no current evidence of spillover of coronaviruses from bats to humans in Australia, either directly or indirectly via intermediate hosts. The limited available data are inadequate to determine whether this lack of evidence indicates that spillover does not occur or occurs but is undetected. Conversely, multiple international agencies have flagged the potential transmission of human coronaviruses (including SARS CoV-2) from humans to bats, and the consequent threat to bat conservation and human health. Australia has a long history of bat research across a broad range of ecological and associated disciplines, as well as expertise in viral spillover from bats. This strong foundation is an ideal platform for developing integrative approaches to understanding bat health and sustainable protection of human health. 

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