The COVID-19 pandemic has highlighted the huge impact pathogens can have on human life, health and the economy. The necessity to rapidly identify novel treatments, vaccines and means of identifying people at risk of more severe effects upon infection is clear. In an attempt to overcome infection, the body produces molecules sometimes at levels so high they kill the host or causing severe effects.
In TargetID: Novel Drug Targets for Infectious Diseases, we have developed a novel strategy to identify genes that regulate levels of molecules that show deranged expression after infection with SARS-Cov-2 or that are likely to influence COVID-19 severity. We first analysed publicly available data from COVID-19 patients to identify which molecules have deranged expression during the infection. Transcriptome RNASeq (the product of the genome) and whole genome sequencing of around 1,000 individuals from a collection of samples banked by the University of Malta was then carried out.
Aided by bioinformatics and a large multidisciplinary team, a combination of approaches, including family-based studies and extreme phenotype analysis, was adopted to mine this high throughput sequencing data for relevant genes and genetic variants to help identify novel drug targets and genes that can make some more susceptible to severe COVID-19.
The bioinformatics tools and the strategy we have developed allow us to speed up the analysis of millions of genetic variants, finding those that are crucial in regulating gene expression
The extensive data obtained will be useful beyond the end of this project as it can be used for any other pathogen that influences gene expression in blood, besides being useful for identifying drug targets for other conditions, including highly complex ones such as myocardial infarction. The accompanying data on the health of the research subjects, including blood test results, medical history and family history, add value to this scope.
Through TargetID, we now also have a clear picture of the genetics of the Maltese population which will greatly facilitate genetic diagnostics locally. The bioinformatics tools and the strategy we have developed allow us to speed up the analysis of millions of genetic variants, finding those that are crucial in regulating gene expression – which then highlight the genes that can be targeted by novel drugs. It is a new era for research in this field.
TargetID is a University of Malta project funded through the MCST COVID-19 R&D Fund 2020 jointly administered by the Malta Council for Science & Technology and Malta Enterprise and led by Prof. Stephanie Bezzina Wettinger, Dr Rosienne Farrugia and Dr Jean Paul Ebejer. For more details visit here.
Prof. Stephanie Bezzina Wettinger, BSc, MPhil, PhD, has worked in molecular genetics for 30 years with experience in biobanking, genomics and transcriptomics. Currently focusing on research, she has worked full-time at the university since 2007. She is the principal investigator of several projects (the MAMI Study, the Malta NGS Project, TargetID and BioGeMT) leading large multidisciplinary teams searching for disease-causing genetic variants and novel drug targets.
Sound Bites
• There is evidence of horizontal gene transfer between human maternal microbiome and infant gut microbiome: Researchers have now found that there is a possibility of horizontal transmission of genetic mobile elements from the gut microbiome of the mother to the infant, from the period extending immediately before birth to a few weeks after birth. It was shown that the gut microbiome in the mother and the infant shared genes, and that the infant gut contains thousands of unique metabolites, which probably impact the immune system and cognitive development.
For more soundbites, listen to Radio Mocha every Saturday at 7.30pm on Radju Malta and the following Monday at 9pm on Radju Malta 2. https://www.fb.com/RadioMochaMalta/.
DID YOU KNOW?
• Genetic variants (mutations) are not necessarily harmful: Indeed, most genetic variants occur on a single nucleotide level and have no effect whatsoever on the individual. The influence of a genetic variant depends on where it is located – it can be within a part of a gene that codes for protein or in a regulatory region that influences gene output, or it could be in a region that has no effect. Even genetic variants in coding regions might not result in significant changes to the proteins which they code for, and hence they are less likely to have an effect. In some cases, genetic variants could even result in a positive effect in an individual, for example, providing resistance to a particular disease (for example, a mutation in the CCR5 gene, which reduces the risk of developing AIDS).
• Only 5-10% of different cancer types are inherited. While there are a few cancer types that may be brought about through inherited variants, the larger proportion (90-95%) of cancers are indeed caused by genetic variants occurring throughout an individual’s life, as a result of ageing and environmental factors. As such, only a few cancer types are likely to be passed down from parents to offspring, and as such, familial cancers are the exception, not the norm.
For more trivia, see: www.um.edu.mt/think.