Although the underlying medical condition plays an important role, many aspects of why the severity of COVID-19 can vary widely from each other remain unclear.
New studies identify dozens of genomic mutations that can make these unpredictable differences in clinical outcomes. According to a study led by scientists at the University of Pennsylvania, genomic mutations in four genes important for SARS-CoV-2 infection, including the ACE2 gene, are targets of spontaneous selection and lead to the health status seen in patients with COVID-19. It was related.
Studies using genomic data from diverse world populations suggest that these mutants may have evolved in response to past encounters with SARS-CoV-2-like viruses. ..The team published the findings in the journal Minutes of the National Academy of Sciences..
“This study exemplifies my laboratory’s approach to genomics research. We use the characteristics of what happens in nature and natural selection to be functionally important in impacting health and illness. We will identify variants, “said Saratishkov, co-author of the study and the University of Pennsylvania. Professor of Knowledge University appointed to the University of Pennsylvania School of Medicine and the Faculty of Arts and Sciences. “Nature has already done a lot of screening and can give us clues as to which parts of genes like ACE2 are important for infection.”
Another group performed a genome-wide association study to identify genetic mutations associated with the severity of COVID-19, which is a highly diverse dataset from ethnically diverse Africans and Penn Medicine BioBank. The first to include. Including these often overlooked groups reveals new variants that may be clinically important.
Signal of choice
Before COVID-19 was declared a pandemic, Giorgio Silgo of Perelman School of Medicine hypothesized that there was a genetic basis for susceptibility or defense against more serious consequences.
“This idea is really classic, and infectious diseases contain the genetic elements of the host,” said Silgo, co-author of this paper. He contacted Tishkoff and other colleagues and began tackling the problem with a population genetics approach.
Researchers focused on a few genes known to play a role in the way SARS-CoV-2 invades cells: ACE2, TMPRSS2, DPP4, and LY6E. They are 2,012 ethnically diverse, including those practicing the lifestyles of traditional hunter-gatherers, herders and farmers, and 15,977 European and African heritage of the Penn Medical Biobank. We used the genomic data of a Japanese African. Available.
Looking for mutations in these genes that provided evidence of selection during evolution, researchers discovered 41 variants of the ACE2 gene that affect the amino acid sequence of proteins. These variants were rare when the team examined the pooled world population, but three variants were common in the hunter-gatherer population of Central Africa.
“This really stood out to us,” says Tishkoff. “This is a group that lives in a tropical environment, spends a lot of time in the woods and keeps looking for bushmeat. They may be exposed to all kinds of viruses brought in from animals. And, of course, SARS-CoV-2 is believed to have made a leap from animal to human, so this population is exposed to similar types of virus, even if it has not been exposed to this exact virus in the past. It may have been. “
In other words, these variants may have evolved to provide a protective effect against viruses similar to SARS-CoV-2. There was more evidence that these variants showed signs of positive selection and provided fitness benefits.
Signs of natural selection were present not only in the parts of the genome that encode ACE2 and other genes, but also in the parts known as regulatory regions that influence how and where those genes are expressed. .. Many of these varieties appeared to be influenced by what is known as purification choices, which occur when evolutionary forces choose to remove varieties that adversely affect fitness.
“There were important signs of natural selection in the regulated areas of ACE2,” said Chao Zhang, a postdoctoral fellow at Tishkoff’s lab. “I personally think it will be very important in thinking about clinical outcomes.”
“It is important that three non-synonymous variants were found in ACE2, an indigenous Cameroonian, from the perspective of Africa, especially Central Africa,” said co-author and professor of neurology and neuroscience at the University of Yaoundé in Cameroon. One Alfred K. Njamnshi says. “The regulatory mutations found in ACE2 suggest a target for recent natural selection in some African populations, which may lead to significant disease risk or resistance effects that require further investigation. I have.”
The team says that rare mutations are also likely to affect health outcomes, explaining individual differences in the severity of the disease. In the East Asian population, we have discovered changes in the ACE2 regulatory region that may increase ACE2 expression. This can affect the extent to which SARS-CoV-2 infects host cells.
“To be sure, we need to test the function of this subspecies to see if we can get any indication that changes in this region are associated with susceptibility and severity of COVID infection. “on paper.
These changes in the non-coding regions of the genome can also affect the organs in which the gene is expressed. This is a characteristic associated with the known effects of COVID-19 on the heart, brain, lungs, kidneys, and other organs. In addition, the ACE2 receptor does more than just play a role in binding to the SARS-CoV-2 spike protein. It is also involved in blood pressure regulation and may affect health other than COVID infection.
Beyond ACE2, signals of natural selection are also evident in the coding and regulatory regions of the TMPRSS2 gene, including mutations that appear to have evolved after the early human population split from other great apes. “The protein has a lot of human-specific substitutions, which is really interesting,” says Tishkoff. This suggests that natural selection acted on these sites in the history of human evolution after divergence from chimpanzee ancestors over 5 million years ago. .. The team also identified dozens more variants of the DPP4 and LY6E genes.
The connection between the genome and health
To understand the clinical relevance of these variants, researchers used data from PennMedicine BioBank. The results of COVID-19 disease were not part of the patient’s medical records at the time, as the analysis was largely done before the pandemic swept the United States. However, because biobank data contains gene sequence information, researchers look for the gene mutations they have just identified to see if they are associated with a medical condition that may be associated with COVID-19 infection. I was able to.
“Our data can be used to examine the variants identified by Sarah’s team and correlate them with clinical data,” said Anurag Verma of the University of Pennsylvania School of Medicine, co-lead author of this paper. I am.
The team actually associated with a condition in which a particular variant of the identified coding area was associated with or overlapped with COVID-19, such as respiratory disease, respiratory syncytial virus infection, liver disease, etc. I found that.
Based on these initial findings, researchers could reveal much more about how proteins function in the context of COVID-19 or other diseases by further investigation of major genetic mutations. It states that it has sex.
“From a medical point of view, we can also identify new therapeutic targets and provide personalized medicine depending on the mutations that people have,” says Sirugo.
The team emphasizes the importance of examining diverse populations for genomic research. Some of the newly identified variants that may be clinically important have only been identified in African populations that have not previously been investigated in this way.
“That’s a very important and unique aspect of this study,” says Tishkoff.
reference: Relationship between the effects of Zhang C, Verma A, Feng Y, and other natural selection on the global pattern of genetic variation and the clinical phenotype of genes involved in SARS-CoV-2 infection. Minutes of the National Academy of Sciences. 2022; 119 (21): e2123000119. Doi: 10.1073 / pnas.2123000119.
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