COVID-19 and Molecular Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 May 2021) | Viewed by 35422

Special Issue Editors

Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: human genetics; laminopathies; gene therapy; genomics; pharmacogenomics
Department of Biology, Tor Vergata University of Rome, 00133 Rome, Italy
Interests: host genomics; mutation analysis; precision medicine; hereditary breast cancer; cancer genetics

Special Issue Information

Dear Colleagues,

With 31,926,175 confirmed cases; 977,357 deaths (3.1%); and 22,004,598 recovered (68.9%) (Sept 24, 2020), COVID-19 is currently the number one challenge for human health worldwide. The COVID-19 pandemic wave has generated many urgent questions about the origin, trajectory, tissue/host variance, and the different clinical manifestations of the causative agent SARS-CoV-2. This Special Issue of Genes will focus on examining genetic/genomic variations, pathogenic mechanisms, clinical manifestations, and epidemiological and ethical aspects of the host. Research papers addressing the identification of genetic and epigenetic factors that confer susceptibility or resistance to viral infections and increase the risk of life-threatening complications will be welcomed.

The overall objective of the Special Issue is to contribute to scientific knowledge through the identification of actionable biomarkers to improve diagnosis and management, predict clinical and immunological outcomes, and accelerate the development of new treatments.

Prof. Dr. Giuseppe Novelli
Prof. Dr. Michela Biancolella
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COVID-19
  • SARS-CoV-2
  • Genomic biomarkers
  • Genetic susceptibility
  • Genetic resistors
  • Viral accommodation

Published Papers (10 papers)

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Editorial

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3 pages, 167 KiB  
Editorial
COVID-19 and Molecular Genetics
Genes 2022, 13(4), 676; https://doi.org/10.3390/genes13040676 - 12 Apr 2022
Cited by 3 | Viewed by 1600
Abstract
Since early December 2019, the COVID-19 pandemic has impacted global society: over 400 million people have been infected with SARS-CoV-2, and there have been nearly 6 million deaths worldwide (1 [...] Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)

Research

Jump to: Editorial

13 pages, 1991 KiB  
Article
Poking COVID-19: Insights on Genomic Constraints among Immune-Related Genes between Qatari and Italian Populations
Genes 2021, 12(11), 1842; https://doi.org/10.3390/genes12111842 - 22 Nov 2021
Cited by 1 | Viewed by 2418
Abstract
Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to [...] Read more.
Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory-confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton-Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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9 pages, 13650 KiB  
Article
Different Strategies for the Identification of SARS-CoV-2 Variants in the Laboratory Practice
Genes 2021, 12(9), 1428; https://doi.org/10.3390/genes12091428 - 16 Sep 2021
Cited by 9 | Viewed by 1973
Abstract
A considerable effort has been devoted in all countries to react to the COVID-19 pandemic by tracing infected individuals, containing the spread of the disease, identifying therapies, and producing and distributing vaccines. Currently, a significant concern is the appearance of variants of the [...] Read more.
A considerable effort has been devoted in all countries to react to the COVID-19 pandemic by tracing infected individuals, containing the spread of the disease, identifying therapies, and producing and distributing vaccines. Currently, a significant concern is the appearance of variants of the virus that may frustrate these efforts by showing increased transmissibility, increased disease severity, reduced response to therapy or vaccines, and ability to escape diagnosis. All countries have therefore devoted a massive attempt to the identification and tracking of these variants, which requires a vast technological effort to sequence a large number of viral genomes. In this paper, we report our experience as one of the Italian laboratories involved in SARS-CoV-2 variant tracing. We summarize the different approaches used, and outline a potential model combining several techniques to increase tracing ability while at the same time minimizing costs. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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8 pages, 246 KiB  
Communication
The TNFRSF13C H159Y Variant Is Associated with Severe COVID-19: A Retrospective Study of 500 Patients from Southern Italy
Genes 2021, 12(6), 881; https://doi.org/10.3390/genes12060881 - 08 Jun 2021
Cited by 13 | Viewed by 2520
Abstract
To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing [...] Read more.
To identify host genetic determinants involved in humoral immunity and associated with the risk of developing severe COVID-19, we analyzed 500 SARS-CoV-2 positive subjects from Southern Italy. We examined the coding sequences of 10 common variable immunodeficiency-associated genes obtained by the whole-exome sequencing of 121 hospitalized patients. These 10 genes showed significant enrichment in predicted pathogenic point mutations in severe patients compared with the non-severe ones. Moreover, in the TNFRSF13C gene, the minor allele of the p.His159Tyr variant, which is known to increase NF-kB activation and B-cell production, was significantly more frequent in the 38 severe cases compared to both the 83 non-severe patients and the 375 asymptomatic subjects further genotyped. This finding identified a potential genetic risk factor of severe COVID-19 that not only may serve to unravel the mechanisms underlying the disease severity but, also, may contribute to build the rationale for individualized management based on B-cell therapy. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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15 pages, 2213 KiB  
Article
Mutational Asymmetries in the SARS-CoV-2 Genome May Lead to Increased Hydrophobicity of Virus Proteins
Genes 2021, 12(6), 826; https://doi.org/10.3390/genes12060826 - 27 May 2021
Cited by 7 | Viewed by 3617
Abstract
The genomic diversity of SARS-CoV-2 has been a focus during the ongoing COVID-19 pandemic. Here, we analyzed the distribution and character of emerging mutations in a data set comprising more than 95,000 virus genomes covering eight major SARS-CoV-2 lineages in the GISAID database, [...] Read more.
The genomic diversity of SARS-CoV-2 has been a focus during the ongoing COVID-19 pandemic. Here, we analyzed the distribution and character of emerging mutations in a data set comprising more than 95,000 virus genomes covering eight major SARS-CoV-2 lineages in the GISAID database, including genotypes arising during COVID-19 therapy. Globally, the C>U transitions and G>U transversions were the most represented mutations, accounting for the majority of single-nucleotide variations. Mutational spectra were not influenced by the time the virus had been circulating in its host or medical treatment. At the amino acid level, we observed about a 2-fold excess of substitutions in favor of hydrophobic amino acids over the reverse. However, most mutations constituting variants of interests of the S-protein (spike) lead to hydrophilic amino acids, counteracting the global trend. The C>U and G>U substitutions altered codons towards increased amino acid hydrophobicity values in more than 80% of cases. The bias is explained by the existing differences in the codon composition for amino acids bearing contrasting biochemical properties. Mutation asymmetries apparently influence the biochemical features of SARS CoV-2 proteins, which may impact protein–protein interactions, fusion of viral and cellular membranes, and virion assembly. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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17 pages, 1990 KiB  
Article
Genome-Scale Metabolic Model of Infection with SARS-CoV-2 Mutants Confirms Guanylate Kinase as Robust Potential Antiviral Target
Genes 2021, 12(6), 796; https://doi.org/10.3390/genes12060796 - 24 May 2021
Cited by 20 | Viewed by 5807
Abstract
The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines [...] Read more.
The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines have lower efficacy. This highlights the urgent need for antiviral therapies even more. This article describes how the genome-scale metabolic model (GEM) of the host-virus interaction of human alveolar macrophages and SARS-CoV-2 was refined by incorporating the latest information about the virus’s structural proteins and the mutant variants B.1.1.7, B.1.351, B.1.28, B.1.427/B.1.429, and B.1.617. We confirmed the initially identified guanylate kinase as a potential antiviral target with this refined model and identified further potential targets from the purine and pyrimidine metabolism. The model was further extended by incorporating the virus’ lipid requirements. This opened new perspectives for potential antiviral targets in the altered lipid metabolism. Especially the phosphatidylcholine biosynthesis seems to play a pivotal role in viral replication. The guanylate kinase is even a robust target in all investigated mutation variants currently spreading worldwide. These new insights can guide laboratory experiments for the validation of identified potential antiviral targets. Only the combination of vaccines and antiviral therapies will effectively defeat this ongoing pandemic. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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15 pages, 1149 KiB  
Communication
Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women
Genes 2021, 12(4), 596; https://doi.org/10.3390/genes12040596 - 19 Apr 2021
Cited by 38 | Viewed by 5269
Abstract
The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in [...] Read more.
The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in Italy. Nine relatively common variants (allele frequency > 0.01) and six missense variants which may affect the protease activity according to PolyPhen-2 in HumVar-trained mode were identified. Among them, p.V197M (p.Val197Met) (rs12329760) emerges as a common variant that has a deleterious effect on the protease and a protective effect on the patients. Its role appears particularly relevant in two subgroups of patients—young males and elderly women—and among those affected by co-morbidities, where the variant frequency is higher among individuals who were mildly affected by the disease and did not need hospitalization or oxygen therapy than among those more severely affected, who required oxygen therapy, ventilation or intubation. This study provides useful information for the identification of patients at risk of developing a severe form of COVID-19, and encourages the usage of drugs affecting the expression of TMPRSS2 or inhibiting protein activity. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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14 pages, 312 KiB  
Article
Deepening of In Silico Evaluation of SARS-CoV-2 Detection RT-qPCR Assays in the Context of New Variants
Genes 2021, 12(4), 565; https://doi.org/10.3390/genes12040565 - 13 Apr 2021
Cited by 23 | Viewed by 3346
Abstract
For 1 year now, the world is undergoing a coronavirus disease-2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most widely used method for COVID-19 diagnosis is the detection of viral RNA by RT-qPCR with a specific set [...] Read more.
For 1 year now, the world is undergoing a coronavirus disease-2019 (COVID-19) pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most widely used method for COVID-19 diagnosis is the detection of viral RNA by RT-qPCR with a specific set of primers and probe. It is important to frequently evaluate the performance of these tests and this can be done first by an in silico approach. Previously, we reported some mismatches between the oligonucleotides of publicly available RT-qPCR assays and SARS-CoV-2 genomes collected from GISAID and NCBI, potentially impacting proper detection of the virus. In the present study, 11 primers and probe sets investigated during the first study were evaluated again with 84,305 new SARS-CoV-2 unique genomes collected between June 2020 and January 2021. The lower inclusivity of the China CDC assay targeting the gene N has continued to decrease with new mismatches detected, whereas the other evaluated assays kept their inclusivity above 99%. Additionally, some mutations specific to new SARS-CoV-2 variants of concern were found to be located in oligonucleotide annealing sites. This might impact the strategy to be considered for future SARS-CoV-2 testing. Given the potential threat of the new variants, it is crucial to assess if they can still be correctly targeted by the primers and probes of the RT-qPCR assays. Our study highlights that considering the evolution of the virus and the emergence of new variants, an in silico (re-)evaluation should be performed on a regular basis. Ideally, this should be done for all the RT-qPCR assays employed for SARS-CoV-2 detection, including also commercial tests, although the primer and probe sequences used in these kits are rarely disclosed, which impedes independent performance evaluation. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
11 pages, 2248 KiB  
Article
A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection
Genes 2021, 12(3), 450; https://doi.org/10.3390/genes12030450 - 22 Mar 2021
Cited by 6 | Viewed by 2671
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying [...] Read more.
The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host–cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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9 pages, 912 KiB  
Communication
Impact of Genetic Variability in ACE2 Expression on the Evolutionary Dynamics of SARS-CoV-2 Spike D614G Mutation
Genes 2021, 12(1), 16; https://doi.org/10.3390/genes12010016 - 24 Dec 2020
Cited by 18 | Viewed by 3987
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein D614G mutation became the predominant globally circulating variant after its emergence in the early coronavirus disease 2019 (COVID-19) pandemic. Studies showed that this mutation results in an open conformation of the S [...] Read more.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein D614G mutation became the predominant globally circulating variant after its emergence in the early coronavirus disease 2019 (COVID-19) pandemic. Studies showed that this mutation results in an open conformation of the S glycoprotein receptor-binding domain (RBD), and increased angiotensin 1-converting enzyme 2 (ACE2) binding and fusion, which result in an increase in SARS-CoV-2 transmissibility and infectivity. Dynamic tracking of SARS-CoV-2 showed that the D614G variant became predominant after emergence in Europe and North America, but not in China. The current absence of selective pressures from antiviral treatment suggests that the driving force for viral evolution could be variations in human population genetics. Results show that ACE2 expression is higher in Asian populations than that in European, North American, and African populations. This supports the idea that lower ACE2 expression is a driving force in the positive selection for the D614G mutation. This study suggests that the dynamics of the SARS-CoV-2 D614G mutation during the early-to-mid pandemic is associated with enhanced transmission efficiency in populations with lower ACE2 expression. Understanding the role that human genetic diversity plays in the adaptive evolution of SARS-CoV-2 may have an important impact on public health and measures to control the pandemic. Full article
(This article belongs to the Special Issue COVID-19 and Molecular Genetics)
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