Precision Public Health: How Human Whole Genome Study Helps to Eliminate The Threats of COVID-19

SARS-CoV-2, the novel coronavirus that emerged and began spreading in late 2019, has rapidly become a global pandemic, infecting more than 3 million people worldwide as of April 29, 2020. Researchers have been attempting to collect new data to understand the virus and COVID-19, the disease it causes.

The virus is an equal opportunity invader to human regardless of age, race, or sex, and underlying comorbidities play a role in the risk of severe outcomes of COVID-19, including mortality. Which makes sense, given that it’s a totally new pathogen against which approximately zero humans have preexisting immunity.

The COVID-19 pandemic has presented with confusing contradictions: While the disease poses a well-documented risk to people over 65 years old and those with some preexisting high-risk health conditions. On the other hand, clinicians are finding more SARS-CoV-2-infected cases with mild symptoms, atypical symptoms, or no symptoms at all — seemingly healthy people who might possibly spread and amplify the disease unintentionally.

Scientists have also been looking into genomic sequence that was originally generated for other purposes to go beyond what is known about the virus and try to fill in some of the many remaining unknowns.


The host genomic factors can be analyzed with the advance in technology while an outbreak is underway. The ability to quickly and accurately identify vulnerable and protective host factors could expand the effectiveness of the public health approach to COVID-19. The development of therapeutics targeting those pathways can also be informed by finding biological mechanisms for severe infection.

Information on human genetic variants associated with susceptibility to severe infection could be useful for prevention within families and healthcare workers or for directing clinical care on hospital admission. Both viral and human genomic information can be important for achieving these goals. Once the virus infects the host cell, it takes over the host cell’s machinery to produce more viruses. The host cell essentially becomes a virus factory.

When the human body is attacked by pathogens, the immune system kicks into gear to fight off the assault. Pathogens-fighting white blood cells in the body are called up to destroy the intruder. These cells target specific sites on the virus, working to destroy the infection. Also, a healthy person’s immune system creates a blueprint of the attacking agent. With this blueprint, the body effectively remembers the pathogen — enabling a person to fight off re-infection by similar viruses.

Human genomic variation is rapidly coming under scrutiny. The newly formed COVID-19 Host Genetics Initiative brings together major genome sequencing groups from around the world in an effort to uncover genetic determinants of susceptibility, severity and outcomes. Several big biobanks have agreed to share the DNA data they have been gathering since before the pandemic, including the Penn Medicine Biobank, which has 60,000 participants; FinnGen, which has collected DNA from 5 percent of Finland’s entire population; UK Biobank, one of the world’s largest with samples from 500,000 volunteers; and Genomics England, set up to deliver the 100,000 Genome Project. Humans are 99.9% genetically identical to one another. But the human genome is made up of 6 billion base pairs, that small 0.1% genetic difference leaves room for viruses and other diseases to impact different people in different ways.

There are a number of possible genomic features which may contribute to the disease. Firstly, people with genomic variants that affect their immune response may be more susceptible to severe disease, either because they have slightly impaired general antiviral responses, or conversely because they have over-vigorous antiviral responses, called a cytokine ‘explosion’ or ‘storm’. Some COVID-19 patients with severe respiratory distress may also be suffering from this type of cytokine storm with partly genetic propensity.

Secondly, resistance and susceptibility to viral infections is often associated with the surface proteins through which viruses gain entry to human cells. Variants in the ACE2 gene, the angiotensin-converting enzyme 2, for a lung cell receptor, well known for the receptor for the SARS coronavirus ( SARS-CoV), could make it easier or harder for SARS-CoV-2 to infect these cells; variants that enable viral entry might lead to more extensive lung infection and more serious symptoms, especially since these are the cells that normally produce surfactant, a substance that helps lungs to work properly and has been studied in the context of blood pressure regulation, heart disease, and other conditions.

Research publications have suggested the potential for ACE2 genetic variants, interleukin-6, HLA antigens, and blood groups to be risk factors in COVID-19 severity and outcomes. Such discoveries could help to generate hypotheses for drug repurposing, identify individuals at unusually high or low risk, and contribute to global knowledge of the biology of SARS-CoV-2 infection and disease severity.

The scientists are not alone in attempting to establish a baseline understanding of ACE2 variation. Another study publication in BioRxiv earlier this month, proposed a multiple ACE2 protein-altering variants suspected of increase host susceptibility, along with several variants predicted to show decreased SARS-CoV-2 binding.

Another project at New York hospitals, a collaboration with the New York Genome Center, aims to sequence the whole genomes of COVID-19 patients who are under the age of 50 with severe disease but no high-risk comorbidities and may have very severe defects of immunity.

Genome Canada launched this month the Canadian COVID Genomics Network (CanCOGeN), a newly formed initiative backed by $40 million in federal funding. CanCOGeN will undertake two related genomics projects to help us understand how the virus works, how it is evolving, and why people experience such different health outcomes. CanCOGeN will sequence the genomes of up to 10,000 patients and 150,000 viral samples and will build a bank of “virus to patient” data that will inform decision-making by public health authorities and support the development of therapies and vaccines.

Ultimately, better understanding could enable precision medicine for COVID-19, knowing about who is at greatest risk of serious disease, and which treatments may be more effective in individuals with severe symptoms. Scientists and engineers around the world are hard at work analyzing not only viral and human genome sequences, but also building high performance supercomputers for speeding up the analysis. Even with current technology, sequencing and analyzing huge human genomes takes quite a long time. The more and earlier we learn, the better prepared we will be for the future.

A great scientific endeavor is taking place throughout the globe right now, seeking to better understand, prevent and cure COVID-19 now and for generations to come. By washing hands frequently, wearing masks and practicing social distancing, healthy people are not only protecting themselves from infection, but also protecting those with bad immune systems and others who are at risk of becoming severely ill.

References:

[1] Precision Public Health for the Era of Precision Medicine

[2] The Public Health Impact of COVID-19: Why Host Genomics?

[3] Beyond Public Health Genomics: Can Big Data and Predictive Analytics Deliver Precision Public Health?

[4] A gene that could unlock the mysteries of COVID-19

[5] Structural Variations in Human ACE2 May Influence Its Binding With SARS-CoV-2 Spike Protein

[6] New York COVID-19 Genomics Research Network Coalesces to Battle Pandemic

[7] The COVID-19 Host Genetics Initiative

[8] THE COVID-19 DISEASE AND OUR GENES

[9] Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility #PrecisionMedicine #GenomeSequencing #NextGenerationSequencing #LightningSolution #GATK#BWA




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