COVID-19 Mutations, Human Genetic Variation, and the Resulting Clinical Effects
By Stuart M. Caplen, M.D.
Genetic mutations occur randomly in nature and may have differing effects on the organism involved. In humans, sickle cell anemia is caused by the mutation of just a single gene.[1] Once a mutation occurs it is then passed on to the progeny of that organism. Mutations may have a negative effect, a positive effect or no effect on the organism’s survival. If a mutation increases survival chances, that strain will typically become the dominant one in a species. If it decreases survival, the organisms with the mutation may die out.
Viral RNA
Coronaviruses are essentially protein shells with a surrounding lipid membrane, carrying genetic material inside. SARS-COV-2(severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19, is an RNA virus. The SARS-COV-2 virus RNA has slightly less than 30,000 nucleotides that are linked together in a long chain. Humans, in comparison, have about 3 billion nucleotides.[2]
The genetic code in RNA is made up of a combination of 4 nucleotides, also called bases, in varying order, two purines, adenine (A), and guanine (G), and two pyrimidines, uracil (U) and cytosine (C). A strand of viral RNA is essentially a coded message that contain instructions to a host cell for duplication of viral RNA, protein production for needed enzymes or parts of the viral shell and finally assembly of viral RNA and proteins into new viruses.
For protein production, the RNA genetic chain is subdivided into codons, which consist of 3 adjacent nucleotides. Each codon contains a coded instruction to create a specific amino acid. As an example, CUA GCC UAU are three viral RNA codons specifying that the host cell’s transfer RNA should bring the amino acids leucine, alanine and tyrosine together, in that order, to be part of a newly created protein. This protein building process is called translation and occurs in the ribosomes, the cell’s protein manufacturing area.[3]
RNA Mutations
If there is a random or environmentally caused error in the RNA replication process, the new RNA strand will have different genetic coding than the original one, and a mutation has taken place.
RNA single base/nucleotide substitutions are called point mutations. A nucleotide can also be deleted, or a completely new one inserted. More extensive mutations in the viral RNA may also occur.[4]
All the descendants of a mutated coronavirus will then carry that mutation. These mutations can cause changes to the genetic code carried in the viral RNA leading to different proteins being created, or different instructions being given to the host cell when the virus infects it.
Viruses can also undergo a process called recombination when there are 2 virus infections in the host’s cell at the same time. The result can be a combination of the two viruses’ genetic material creating a hybrid viral RNA with new properties. It is thought that COVID-19 virus may have arisen from viral recombination in bats or Malayan pangolins.[5,6]
How Does the SARS-COV-2 Virus Infect a Host Cell and Reproduce Itself?
The coronavirus is named after the corona or crown of protein spikes that surrounds each viral particle. These spikes can attach to a cell’s membrane via the ACE2 (Angiotensin-Converting Enzyme 2) receptor located on many cells in the human body. The virus then injects its RNA into the cell and turns the cell into a living virus factory.[7] A cell invaded by the SARS-COV-2 virus essentially stops producing what it needs for survival and just produces new viruses. The injected viral RNA goes to the host’s ribosomes. There the viral RNA causes the cell’s transfer RNA to bring amino acids together forming proteins as dictated by the viral RNA code. The proteins made initially are used to create substances needed for producing more viral RNA. Once the components needed for viral RNA replication have been created and set up, the viral RNA starts duplicating itself.[8] It is during this duplication process that mutations frequently occur. The virus then directs the cell to produce enzymes and new SARS-COV-2 protein shells needed to create new viruses. The newly made viral RNA strands are inserted into the protein shells, creating completed new viruses. Eventually the host cell lyses(disintegrates), releasing the newly created viruses to infect other cells.
Clinical Effects of SARS-COV-2 Mutations
The site of a mutation is how scientists categorize COVID-19 strains. They can tell for example, by the mutation’s location and the nucleotides involved, whether a virus they are investigating originated from an Asian or European strain. [9]
In May, researchers wrote that they had found 198 recurrent mutations in SARS-CoV-2 strains around the globe.[10] The same lead author, in a prepublication article, found no evidence that any of those mutations increased infectivity.[11]
Conversely, other scientists in prepublication papers have found a mutation in COVID-19 strains from Europe and New York which may have increased the infectivity over the original Asian strain. Initially COVID viruses found in the US were from the original strain. Now however, the vast majority of infections in the US are the mutated strain. About 1,300 amino acids are the building blocks for the protein spike on the surface of the SARS-COV-2 virus. In the mutated virus, the genetic instructions for just one of those amino acids, number 614, was switched from a "D" (shorthand for aspartic acid) to a "G" (glycine). This mutation is designated as D614G. It doesn’t make people more ill, but may increase infectivity. In the original SARS-COV-2 strain, the spike protein was stiffer and sometimes broke when trying to attach to a cell. In the D614G variant there are not only more spike proteins on the outside of the virus, but the spikes also appear to be more flexible and less likely to break off when trying to attach to and infect the host cells. In lab experiments, the D614G strain was found to be about eight to nine times more infectious than the original. However, one positive finding was that vaccines currently being worked on to create antibodies to block the SARS-COV-2 spike protein should also work on this variant. [9,12,13]
In the 1918 Influenza pandemic the first wave of disease acted like a slightly more infectious influenza with the mortalities, as is typical, concentrated in the very young and very old. It is believed that the virus then mutated and when it returned in the second and third waves, the mutated virus was highly lethal to young and early middle age adults with good immune systems. It is thought the virus caused their immune systems to go into overdrive in a process called “cytokine storm”, which can cause a potentially lethal inflammatory response to the infection.[14] There is no evidence as of yet that the SARS-CoV-2 virus has had any mutations which would drastically increase mortality rates in young people as occurred in 1918.[11]
Human DNA has also been mutating and creating different genetic variants for tens of thousands of years. Some genetic variation may also be from species interbreeding long ago. Given the great disparity in how ill people become when infected with this virus, even among the elderly, it is likely much of the population have genetic mutations or variations that allow them to more successfully fend COVID-19 infection off, or conversely become more ill.
Researchers have found that people with type O blood, seem to fare better with COVID-19 infections than those with blood type A. People with type O blood, determined by genetic coding of chromosome number 9, have both a lesser chance of being infected, and if infected, a lesser chance of developing respiratory failure then those with type A blood.[15,16,17]
The human leukocyte antigen (HLA) system, coded on chromosome number 6, is an important part of the immune system that helps the body distinguish its own proteins from foreign ones such as viruses.[18] It was discovered in the SARS (severe acute respiratory syndrome) outbreak of 2003 that people with a specific genetic variant of the HLA system, seemed to have a higher chance of becoming more seriously ill then those without it.[19] It has been theorized that these individuals may also be more susceptible to serious COVID-19 infections.[20]
It is thought that variations in human chromosome number 3 may also be a factor in how ill people come to be with COVID-19 infection.[15,16] People with a specific genetic code in this chromosome are more likely to become more ill from COVID-19 infections. A prepublication paper makes the assertion that Neanderthals interbred with humans 40,000-60,000 years ago creating this variation of chromosome number 3. This is postulated because the same genetic patterns were found in the DNA of a 50,000-year-old Neanderthal, whose remains were discovered in Croatia. This variant is seen predominantly in Bangladesh where 63% of people carry it, 13% on both strands of DNA(homozygous), and it is also carried by 30% of South Asians, 8% of Europeans and 4% of people from the Americas. People who have this variant DNA, especially those that are homozygous, may be up to three times more likely to suffer from severe COVID-19 illness than others.[21,22]
It is likely that more genetic variations in human DNA that are either protective or increase susceptibility to COVID-19 infection may be found, possibly leading to future treatments for this disease.
The Genetic Battle
The fight against COVID-19 is not only about vaccines, medical treatments, socio-economic inequality and pre-existing medical conditions. It is also a battle between the frequently mutating genetic code the SARS-COV-2 virus carries, pitted against our individual genetically determined immune responses, some of which may have been carried in our DNA for tens of thousands of years. Although we are living in the 21st Century, we still rely on our ancestors’ genetic coding to help us successfully combat COVID-19 infections.
Author’s note: A prepublication paper is one that has been released on the internet, but has not yet been peer-reviewed for accuracy, or officially published in a scientific journal.
References
[1] Clancy, S. Genetic mutation. Nature Education, (2008) 1(1):187. Retrieved from: https://www.nature.com/scitable/topicpage/genetic-mutation-441/
[2]Corum J, Zimmer C, How Coronavirus Hijacks Your Cells, The New York Times, Updated March 13, 2020. Retrieved from: https://www.nytimes.com/interactive/2020/03/11/science/how-coronavirus-hijacks-your-cells.html
[3]Clancy, S, Brown W, Translation: DNA to mRNA to Protein. Nature Education, 2008, 1(1):101. Retrieved from: https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/
[4]Sturm N, DNA Mutation and Repair, 2019. Retrieved from: http://www2.csudh.edu/nsturm/CHEMXL153/DNAMutationRepair.htm
[5]Mandal A, SARS-CoV-2 emergence could be due to genetic selection and recombination, News Medical Life Sciences, , Jun 1 2020. Retrieved from https://www.news-medical.net/news/20200601/SARS-CoV-2-emergence-could-be-due-to-genetic-selection-and-recombination.aspx
[6]Li X, et al., Emergence of SARS-CoV-2 through recombination and strong purifying selection, Science Advances, July 1, 2020. Retrieved from: https://advances.sciencemag.org/content/6/27/eabb9153
[7]Caplen S, COVID-19 Antibody Testing, What Do the Results Mean and Will It Be Helpful? Fibonacci MD, May 13, 2020. Retrieved from: https://www.fibonaccimd.com/post/covid-19-antibody-testing
[8]Positive stranded RNA virus replication, Viral Zone. Retrieved from: https://viralzone.expasy.org/1116
[9]Kaplan S, Achenbach J, Coronavirus mutation has taken over the world. Scientists are trying to understand why. The Washington Post, June 29, 2020. Retrieved from: https://www.lmtonline.com/news/article/Coronavirus-mutation-has-taken-over-the-world-15373472.php
[10] Van Dorp L, et al., Emergence of genomic diversity and recurrent mutations in SARS-CoV-2, Infection, Genetics and Evolution, May 5, 2020. Retrieved from: https://www.sciencedirect.com/science/article/pii/S1567134820301829?via%3Dihub
[11]Van Dorp L, et al., No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2, bioRxiv May 21, 2020. Retrieved from: https://www.biorxiv.org/content/10.1101/2020.05.21.108506v4
[12]Zhang L, et al., The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity, The Scripps Research Institute, June 12, 2020. Retrieved from: https://www.scripps.edu/_files/pdfs/news-and-events/The%20D614G%20mutation%20in%20the%20SARS-CoV-2%20spike%20protein%20reduces%20S1.pdf
[13]Daniloski Z, et al., The D614G mutation in SARS-CoV-2 Spike increases transduction of multiple human cell types, bioRxiv, June 15, 2020. Retrieved from https://www.biorxiv.org/content/10.1101/2020.06.14.151357v1
[14]Taubenberger JK, Morens DM, 1918 Influenza: the mother of all pandemics. Emerg Infect Dis. 2006;12(1):15-22. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291398/
[15]Zimmer C, Genes May Leave Some People More Vulnerable to Severe Covid-19, the New York Times, Last updated June 16,2020. Retrieved from: https://www.nytimes.com/2020/06/03/health/coronavirus-blood-type-genetics.html?action=click&module=RelatedLinks&pgtype=Article
[16] Ellinghaus D, Genomewide Association Study of Severe Covid-19 with Respiratory Failure, The New England Journal of Medicine, June 17, 2020. Retrieved from: https://www.nejm.org/doi/full/10.1056/NEJMoa2020283?query=featured_coronavirus#article_references
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ABOUT THE AUTHOR
Stuart M. Caplen, MD, FACEP, MSM
Dr. Caplen is a former emergency physician and emergency department medical director, now retired from clinical practice. His current interests include how quality is produced and maintained in health care, and he recently achieved greenbelt certification in lean/six sigma.
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