Although underlying medical conditions play an important role, many aspects of why COVID-19 severity can vary widely from one to the other have remained unclear.
A new study identifies dozens of genomic variations that may drive these difficult-to-predict differences in clinical outcomes. According to work led by researchers from the University of Pennsylvania, genomic variants in four genes critical for SARS-CoV-2 infection, including the ACE2 gene, were targets for natural selection and associated with health conditions seen in COVID-19 patients.
The study, which used genomic data from different global populations, suggests that these variants may have evolved in response to previous encounters with viruses similar to SARS-CoV-2. The team published the results in the journal Proceedings of the National Academy of Sciences.
“This study exemplifies my laboratory’s approach to genomic studies: We use what happens in nature and signatures of natural selection to identify functionally important variants that affect health and disease,” says Sarah Tishkoff, a co-corresponding author on the work and one Penn integrates Knowledge University Professor with agreements in Perelman School of Medicine and School of Arts & Sciences. “Nature has already done much of the screening and can give us clues as to which parts of a gene like ACE2 are important for infection.”
While other groups have conducted genome-wide association studies to identify genetic variants associated with COVID-19 severity, this is the first to include ethnically diverse Africans and a very diverse data set from Penn Medicine BioBank. The inclusion of these often overlooked groups revealed new variants that may be clinically significant.
Before COVID-19 was even declared a pandemic, Giorgio Sirugo from the Perelman School of Medicine assumed that there was a genetic basis for susceptibility to or protection against more severe outcomes.
“The idea is really a classic that infectious diseases have a host genetic component,” says Sirugo, a co-corresponding author on paper. He reached out to Tishkoff and other colleagues to begin addressing the issue with a population-genetic approach.
The researchers focused on a handful of genes known to play a role in how SARS-CoV-2 penetrates cells: ACE2, TMPRSS2, DPP4 and LY6E. They used genomic data from 2,012 ethnically diverse Africans, including people practicing traditional hunter-gatherer, pastoralist, and agricultural lifestyles, as well as 15,977 people with European and African heritage from Penn Medicine BioBank, all of whom had associated electronic medical records data available.
Looking for variations in these genes that showed evidence of being selected through evolutionary time, the researchers found 41 variants in the ACE2 gene that affected the amino acid sequence of the protein. Although these variants were rare when the team looked at the total global population, three variants were common among a population of Central African hunter-gatherers.
“This really stood out to us,” Tishkoff says. “This is a group that lives in a tropical environment and continues to forage for bush meat and spends a lot of time in the forest. They are probably exposed to all kinds of viruses introduced from animals. And of course, SARS-CoV-2 is thought to have sprung from an animal for humans. So even if this population would not have been exposed to this particular virus in the past, they could have been exposed to similar types of viruses. “
In other words, these variants may have evolved because they offered a protective effect against viruses with similarities to SARS-CoV-2. These variants showed signs of being positively selected, more evidence that they provide a fitness benefit.
Signs of natural selection were present not only in those parts of the genome that encode ACE2 and other genes, but also in what are known as regulatory regions, which affect how and where these genes are expressed. Many of these variants appeared to have been subject to what is known as cleansing selection, which occurs when evolutionary forces choose to remove variants with a negative impact on fitness.
“We saw significant signals of natural selection in the regulatory regions of ACE2,” said Chao Zhang, a postdoc in Tishkoff’s laboratory and co-lead author. “I personally think it becomes really important when thinking about clinical outcomes.”
“From an African and specifically Central African perspective, the discovery of three non-synonymous variants of ACE2 in Cameroon’s indigenous peoples is essential,” said Alfred K. Njamnshi, co-author and professor of neurology and neuroscience at the University of Cameroon in Yaoundé. “The regulatory variants found on ACE2 suggest targets for recent natural selection in some African populations, and this may have important disease risk or resistance implications that warrant further investigation.”
Rare variants are also likely to play a role in health outcomes, notes the team, which accounts for individual-to-individual variation in the severity of the disease. In East Asian populations, they found variations in the ACE2 regulatory region that may increase ACE2 expression, which could affect the degree to which SARS-CoV-2 infects host cells.
“To know for sure, we need to test the function of this variant and see if we can get an indication that changes in this region are related to the susceptibility and severity of COVID infection,” says Yuanqing Feng, another Tishkoff lab postdoc who shared first authorship on paper.
These variations in non-coding regions of the genome may also influence which organs the genes are expressed in, a relevant property given the known effects of COVID-19 on the heart, brain, lung, kidney and other organs. In addition, the ACE2 receptor not only plays a role in binding to the SARS-CoV-2 peak protein; it is also involved in blood pressure regulation and therefore variants can affect health in addition to only COVID infection.
In addition to ACE2, signals of natural selection were also evident in the coding and regulatory regions of the TMPRSS2 gene, including variations that appear to have evolved after early human populations separated from other apes. “There are many human-specific substitutions in that protein, which is really exciting,” says Tishkoff, a suggestion that natural selection worked at these sites during human evolutionary history after deviating from the chimpanzee’s ancestor more than 5 million years ago. The team also identified dozens more variants in the DPP4 and LY6E genes.
Genome health compounds
To determine the clinical relevance of these variants, the researchers used Penn Medicine BioBank data. The analysis was largely conducted before the pandemic swept through the United States, and therefore outcomes of COVID-19 disease were not part of the patient records at the time. However, because the biobank data contain information on genetic sequencing, the researchers were able to look at the genetic variants they had just identified and see if there was any association with medical conditions that were considered relevant to COVID-19- infection.
“With our data, we can look at the variants identified by Sarah’s team and link them to clinical data,” says Anurag Verma from Penn’s Perelman School of Medicine, a co-first author on paper.
The team found that certain variants of the coding regions they had identified were actually associated with conditions associated with or overlapping with COVID-19, including respiratory diseases, respiratory syncytial virus infection, and liver disease.
Based on these preliminary results, the researchers say that further exploration of key genetic variants can reveal much about how proteins work in conjunction with COVID-19 or other diseases.
“From a medical point of view, you could identify new therapeutic goals or even give some personalized medicine depending on what variants a person had,” Sirugo says.
The team emphasizes the importance of looking at different populations for genome studies, as some of the newly identified variants that could be clinically significant were only identified in African populations that had not been previously studied in this way.
“It is a deeply important and unique aspect of this study,” Tishkoff says.
Reference: Zhang C, Verma A, Feng Y, et al. Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes by genes involved in SARS-CoV-2 infection. Proceedings of the National Academy of Sciences. 2022; 119 (21): e2123000119. doi: 10.1073 / pnas.2123000119.
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