Over the past two years, two evolutionary forces have caused variants of the Covid-19 virus to emerge: mutation and natural selection. The first spontaneously produces genetic variability during the replication of the virus’s genetic material, and the second selects, within this universe, mutations that increase its ability to reproduce and transmit.
Mutations also produce genetic variation in humans. Projects that have sequenced the genomes of thousands of people have revealed the existence of variations that can affect the amino acid sequence of our proteins, those molecular machines that govern a large part of the functions of our cells. There is a protein called ACE2 (or Angiotensin Converting Enzyme 2), which is precisely the gateway to SARS-CoV-2 in our body. The virus uses its S protein (Spike) as a key that binds to the ACE2 lock, opening a door that gives access to the interior of our cells, where it finds the resources necessary for its reproduction. The disease arises as a consequence of this invasion.
But it seems that this is not always the case. Our research group analyzed the genomes of a few thousand people and managed to identify at least a dozen slightly different versions of the ACE2 protein. Just as SARS-CoV-2 variants have slightly different S keys, our species also has variations in the ACE2 lock. Could these small changes in the human lock affect how the coronavirus key works? To investigate this hypothesis and understand how each atom fits into this lock and key game, we turned to supercomputers and structural biology.
Even supercomputers need many days to simulate the interaction between a pair of proteins. After a few months of calculations and more calculations, which also took into account the differences in the S protein of the SARS-CoV-2 variants, it became clear that over the course of the pandemic the virus developed better keys to open our cells. All the variants we tested were more efficient at binding to the ACE2 protein than the original virus identified in Wuhan, China.
As SARS-CoV-2 belongs to a lineage of viruses from bats, it would be expected that, when jumping to humans, it would evolve by natural selection in order to interact more and more effectively with our cells, increasing their transmissibility. However, it caught our attention that some rare people had versions of the ACE2 protein that interfered with the virus binding: it was as if it had more difficulty opening the door of the cells of some individuals.
Some variants have evolved generalist S proteins, which are able to bind well to virtually any version of ACE2, as is the case with Alpha (identified in the UK) and Gamma, which ravaged Brazil, especially Manaus. Others, however, such as Beta (identified in South Africa), seem to be more adept at binding to the more common version of ACE2, the one present in the vast majority of people.
The results showed that genetic variations in the ACE2 protein are also important for understanding how the virus attaches to our cells and transmits itself to other people. Unfortunately for us, versions of ACE2 that disrupt the virus binding appear to be rare, occurring in well under 1% of people. Most of us have a version of the ACE2 protein to which SARS-CoV-2 variants have developed a very efficient binding, which helps explain how this coronavirus produced a pandemic.
Our work shows how the medicine of the future will be able to make diagnoses with molecular precision and arrive at individualized prognoses, which take into account human genetic diversity. Unlike generic treatments, in a few decades we will have unique and personalized therapeutic resources, driven by the genomic revolution and the development of increasingly powerful supercomputers.
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Luiz Eduardo Del-Bem is a geneticist and professor at the Institute of Biological Sciences (ICB) at UFMG.
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