Determining the strain variability of the novel CoV-2 and underlying genetic predisposition of the host as a discovery tool for virulence and risk factors in COVID-19 pandemic

The novel coronavirus SARS-CoV-2 has caused a global spread of the Coronavirus disease COVID-19 resulting in a world pandemic and causing a global negative impact on all aspects of human society. The disease manifests itself with an astonishingly wide range of clinical symptoms and outcomes among the infected individuals, and presently neither specific vaccines nor targeted treatment of disease causes are available. With a very high variation among the symptom severity even outside the high-risk individuals, more information is needed on potential risk factors including the underlying genetic predisposition towards infection and disease progression. Combined with not fully investigated mutational potential of the SARS-CoV-2, these factors may play important roles in monitoring and diagnosing the disease spread and symptom progression, as well as provide meaningful inputs into the risk management and alleviation during the ongoing pandemic or any subsequent recurrences. The goal of this research is to leverage on the power of high-throughput sequencing of second and third generations in order to a) investigate the viral properties at the level of genetic information in order to assess its potential to mutate in a local microenvironment, and if so to identify the most affected loci, possibly associated with symptom severity, and b) to sample in parallel the genetic information of the infected human host in order to find possible associations between the symptom severity and genetic susceptibility of the infected patient. Since a very limited number of viral sequences originating from Croatia is available at the moment, isolation and sequencing of viral genomes from around 200 Croatian patients will enable us to perform the first analysis of the genetic variability of viral genomes in Croatia. In addition, phylogenetic analysis and annotation of viral sequences with geographic locations will be used to infer migration events and draw conclusions about viral entries into the Croatian territory and their subsequent propagation. In addition, the analysis of viral phylogeny will enable us to infer potential virulence determinants, ie. mutations that contribute to virulence of SARS-CoV-2. We will also use a cost-effective whole exome sequencing approach to contribute towards the amassing data collected on SARS-CoV-2 infected patients. This would in turn contribute towards identification of potential SARS-CoV-2 susceptibility variants in COVID-19 patients and examine the potential contribution of host genetic factors to symptom severity and disease outcome. In the same context, we will also explore the potential contribution of host mtDNA single nucleotide variation. Since haplogroup-related variants, as well as both homoplasmic and heteroplasmic mutations influence regulation of oxidative phosphorylation, production of reactive oxygen species and apoptosis, repercussions of mtDNA genomic landscape on the intensity of the immune response due to viral infection are to be expected. To the extent of our knowledge, no such experiments are underway related to SARS-CoV-2 at the moment. Finally, based on our and other publicly available data, we will develop machine learning models to predict clinical outcomes based on viral and host traits, biochemical parameters, and information on treatments, comorbidities and other relevant patient characteristics. Predictive models developed as part of this analysis have the potential of facilitating informed treatment decisions for future patients. We plan to register our study as a part of the international COVID-19 host genetics initiative and share the results of our analyses of host variants identified in host whole-exome and mtDNA sequencing data with the rest of the global community. This will enable us to contribute to the ongoing effort with our datasets and compare the variants potentially related to COVID-19 susceptibility found in Croatian patients to those identified in other populations. Our ultimate aim is to contribute to global knowledge of the biology of SARS-CoV-2 infection and disease.