Genomic epidemiology of SARS-CoV-2 in the UAE reveals novel virus mutation, patterns of co-infection and tissue specific host immune response.

To unravel the source of SARS-CoV-2 introduction and the pattern of its spreading and evolution in the United Arab Emirates, we conducted meta-transcriptome sequencing of 1067 nasopharyngeal swab samples collected between May 9th and Jun 29th, 2020 during the first peak of the local COVID-19 epidemic. We identified global clade distribution and eleven novel genetic variants that were almost absent in the rest of the world and that defined five subclades specific to the UAE viral population. Cross-settlement human-to-human transmission was related to the local business activity. Perhaps surprisingly, at least 5% of the population were co-infected by SARS-CoV-2 of multiple clades within the same host. We also discovered an enrichment of cytosine-to-uracil mutation among the viral population collected from the nasopharynx, that is different from the adenosine-to-inosine change previously reported in the bronchoalveolar lavage fluid samples and a previously unidentified upregulation of APOBEC4 expression in nasopharynx among infected patients, indicating the innate immune host response mediated by ADAR and APOBEC gene families could be tissue-specific. The genomic epidemiological and molecular biological knowledge reported here provides new insights for the SARS-CoV-2 evolution and transmission and points out future direction on host-pathogen interaction investigation.

PARK2 polymorphisms predict disease progression in patients infected with hepatitis C virus.

 Background. The protein encoded by PARK2 gene is a component of the ubiquitin-proteasome system that mediates targeting of proteins for the degradation pathway. Genetic variations at PARK2 gene were linked to various diseases including leprosy, typhoid and cancer. The present study investigated the association of single nucleotide polymorphisms (SNPs) in the PARK2 gene with the development of hepatitis C virus (HCV) infection and its progression to severe liver diseases. MATERIAL AND METHODS: A total of 800 subjects, including 400 normal healthy subjects and 400 HCV-infected patients, were analyzed in this study. The patients were classified as chronic HCV patients (group I), patients with cirrhosis (group II) and patients with hepatocellular carcinoma (HCC) in the context of cirrhosis (group III). DNA was extracted and was genotyped for the SNPs rs10945859, rs2803085, rs2276201 and rs1931223. RESULTS: Among these SNPs, CT genotype of rs10945859 was found to have a significant association towards the clinical progression of chronic HCV infection to cirrhosis alone (OR = 1.850; 95% C. I. 1.115-3.069; p = 0.016) or cirrhosis and HCC (OR = 1.768; 95% C. I. 1.090-2.867; p value = 0.020). CONCLUSION: SNP rs10945859 in the PARK2 gene could prove useful in predicting the clinical outcome in HCV-infected patients.

Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer.

Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies.

Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3.

BACKGROUND: Hepatitis B virus (HBV) affects millions of people worldwide. While some people are able to clear the virus following the first encounter, those who develop chronic infection manifest remarkable clinical heterogeneity that ranges from asymptomatic carrier state to cirrhosis and hepatocellular carcinoma. Despite extensive studies, little is known about genetic host factors that influence the outcome of chronic HBV infection. Thus, we conducted this study to investigate the genetic risk of developing active liver disease among chronic carriers of HBV. METHODS: In this study, we conducted a genome-wide association study (GWAS) on a cohort of patients with chronic HBV infection. RESULTS: One particular SNP that is 16 kb upstream of Ferredoxin 1 was found to have an association with complicated chronic HBV infection (cirrhosis and hepatocellular carcinoma) that reached GWAS significance, and was successfully validated on an independent set of samples. CONCLUSIONS: This first GWAS in an Arab population further demonstrates the utility of this approach in elucidating the genetic risk of HBV infection-related complications and highlights the advantage of conducting GWAS in different ethnicities to achieve that goal.

Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients.

BACKGROUND: Recent observations suggest that immune-mediated tissue destruction is dependent upon coordinate activation of immune genes expressed by cells of the innate and adaptive immune systems. METHODS: Here, we performed a retrospective pilot study to investigate whether the coordinate expression of molecular signature mostly associated with NK cells could be used to segregate breast cancer patients into relapse and relapse-free outcomes. RESULTS: By analyzing primary breast cancer specimens derived from patients who experienced either 58-116 months (~5-9 years) relapse-free survival or developed tumor relapse within 9-76 months (~1-6 years) we found that the expression of molecules involved in activating signaling of NK cells and in NK cells: target interaction is increased in patients with favorable prognosis. CONCLUSIONS: The parameters identified in this study, together with the prognostic signature previously reported by our group, highlight the cooperation between the innate and adaptive immune components within the tumor microenvironment.

Genome scan study of prostate cancer in Arabs: identification of three genomic regions with multiple prostate cancer susceptibility loci in Tunisians.

BACKGROUND: Large databases focused on genetic susceptibility to prostate cancer have been accumulated from population studies of different ancestries, including Europeans and African-Americans. Arab populations, however, have been only rarely studied. METHODS: Using Affymetrix Genome-Wide Human SNP Array 6, we conducted a genome-wide association study (GWAS) in which 534,781 single nucleotide polymorphisms (SNPs) were genotyped in 221 Tunisians (90 prostate cancer patients and 131 age-matched healthy controls). TaqMan SNP Genotyping Assays on 11 prostate cancer associated SNPs were performed in a distinct cohort of 337 individuals from Arab ancestry living in Qatar and Saudi Arabia (155 prostate cancer patients and 182 age-matched controls). In-silico expression quantitative trait locus (eQTL) analysis along with mRNA quantification of nearby genes was performed to identify loci potentially cis-regulated by the identified SNPs. RESULTS: Three chromosomal regions, encompassing 14 SNPs, are significantly associated with prostate cancer risk in the Tunisian population (P = 1 × 10-4 to P = 1 × 10-5). In addition to SNPs located on chromosome 17q21, previously found associated with prostate cancer in Western populations, two novel chromosomal regions are revealed on chromosome 9p24 and 22q13. eQTL analysis and mRNA quantification indicate that the prostate cancer associated SNPs of chromosome 17 could enhance the expression of STAT5B gene. CONCLUSION: Our findings, identifying novel GWAS prostate cancer susceptibility loci, indicate that prostate cancer genetic risk factors could be ethnic specific.

Colorectal cancer risk is not associated with increased levels of homozygosity in Saudi Arabia.

Purpose:Runs of homozygosity (ROHs) represent a measure of the extent of autozygosity and are correlated with the extent of inbreeding. Recently, it has been suggested that ROHs may contribute to the risk of colorectal cancer (CRC). The high rate of consanguinity and CRC in the Saudi population prompted us to test the role of autozygosity in the CRC risk.Methods:We compared 48 Saudi CRC patients to 100 ethnically matched controls, processed on the Affymetrix 250K StyI SNP GeneChip platform and analyzed using the plink package.Results:We could find no evidence of a significant relationship between autozygosity and CRC risk.Conclusion:The negative results in our study add additional significance to what has been previously reported in literature, as this is the first study to address these questions in an inbred population. Our subgroup analysis of patients with microsatellite unstable-positive tumors as compared with other groups did not significantly change our results. Although these results do not rule out the presence of recessively acting CRC-predisposing genes in a small percentage of patients, which our relatively small sample size could not capture, they suggest that such genes are unlikely to account for the disturbingly high incidence of CRC in our consanguineous population.Genet Med advance online publication 5 April 2012.

Expression biomarkers for clinical efficacy and outcome prediction in cancer.

Progress in cancer treatment has been slow, and the outlook for curing cancer is only marginally different from the situation a decade ago. Paradoxically, although the pharmaceutical industry has stepped up costly discovery research and drug development, approvals are on the decline and pipelines are dwindling. In an effort to reduce the number of drug failures and curtail burgeoning R&D costs, drug companies are exploring the use of biomarkers to evaluate toxicity and efficacy earlier in the development process. Biomarkers hold promise for optimization in dosing, adverse event prediction, efficacy evaluation, lead prioritization, and mechanism-of-action profiling of drug candidates. Furthermore, clinicians can use biomarkers to monitor patient response in clinical trials. In this perspective article, the authors explore the applications of cancer-related expression biomarkers in drug discovery and discuss how this will impact the industry and benefit the patient.

Identification of in vivo expressed vaccine candidate antigens from Staphylococcus aureus.

For the design of potent subunit vaccines, it is of paramount importance to identify all antigens immunologically recognized by a patient population infected with a pathogen. We have developed a rapid and efficient procedure to identify such commonly recognized antigens, and here we provide a comprehensive in vivo antigenic profile of Staphylococcus aureus, an important human pathogen. S. aureus peptides were displayed on the surface of Escherichia coli via fusion to one of two outer membrane proteins (LamB and FhuA) and probed with sera selected for high Ab titer and opsonic activity. A total of 60 antigenic proteins were identified, most of which are located or predicted to be located on the surface of the bacterium or secreted. The identification of these antigens and their reactivity with individual sera from patients and healthy individuals greatly facilitate the selection of promising vaccine candidates for further evaluation. This approach, which makes use of whole genome sequence information, has the potential to greatly accelerate and facilitate the formulation of novel vaccines and is applicable to any pathogen that induces Abs in humans and/or experimental animals.