2022-01-14

Evolutionary “landscape” can help predict the next action of covid virus

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c7c351f0ea7635e - Evolutionary "landscape" can help predict the next action of covid virus

obviously, the evolutionary chess game has not stopped. Now, we have a sars-cov-2 variant of Greek alphabet soup to prove this

at present, researchers from all over the world are trying to understand the evolution of the virus in more detail, especially how the mutation of sars-cov-2 changes its ability to spread in humans. “Today’s well adapted virus may not adapt well tomorrow because the host has developed resistance, and then it must find a new way to infect the host,” said Justin Meyer, an evolutionary biologist from the University of California, San Diego. “This promotes innovation and novelty.”

although the casualties caused by the changing pandemic are severe, the large amount of scientific data obtained by observing the movement of the virus around the world is enlightening. “Covid gives us some of the most beautiful examples of evolution,” said Luca Ferretti, a statistical geneticist at the big data Institute of Oxford University

it may never be possible to predict what the virus may do next, but virologists around the world have been deeply understanding which parts of sars-cov-2 are most likely to evolve and which key protein elements cannot be changed without affecting its survival. This information may point the way for a better and more lasting vaccine. Other studies have highlighted the way in which the virus may become resistant to monoclonal antibody therapy used to treat some severe covid-19 patients. This work also points out specific mutation combinations. If these mutations are widespread in the virus population, they may usher in a new stage of the pandemic. In addition to rapid transmission, these mutations are also good at evading our immune defense

scientists were able to make these discoveries by using modern technology to re-examine a concept proposed nearly a century ago – adaptive (or adaptive) landscape. They can use the fitness landscape to quantify the relationship between changes in the virus genome and its ability to replicate and infect new hosts. Topographic maps representing this relationship can help reconstruct the history of the virus and, at least, potentially predict its future

for Tobias Warnecke, a molecular evolutionary biologist at Imperial College London, fitness geomorphology is a valuable way to connect genotypes and phenotypes. He pointed out that by tapping their quantitative potential, scientists can ask questions about how two mutations work together to affect a trait and how they are affected by a third mutation. “In this way, you can see how this affects what you are interested in through many different combinations of genotypes.”

The value of

fitness landscape is not limited to comparison between small changes in genome or protein. Modern experimental technology also makes a strategy called deep mutation scanning possible. In this case, researchers conduct small-scale natural selection experiments and compare the fitness value of tens of thousands of mutants at one time. This process can reveal unforeseen interactions between mutations that can help or harm the virus – and determine the future evolutionary path of the virus, which may pose a new threat to humans

Charles Darwin wrote in the origin of species that natural selection is the result of “preserving favorable individual differences and variations and destroying those harmful individual differences and variations”. In those days, before the scientific understanding of genetics and mutation, biologists could only try to imagine how small, inheritable changes in an organism would affect its reproduction. This idea was fully consolidated only in the work of American biologist Sewall Wright. In his groundbreaking paper published in the proceedings of the Sixth International Conference of genetics in 1932, he used hand-painted diagrams to illustrate how an organism moves in “almost unlimited possible variation fields, and the species may pass through these variations under natural selection”

Wright pointed out that one way to visualize a large number of possible variants of linear molecules such as DNA or peptides is to treat each possibility as a unique feature in space. Then, the molecular evolution is equivalent to the path between the points of the initial and final variants, and all the points of the intermediate variants will be encountered along the way

Evolutionary “landscape” can help predict the next action of covid virus

to help understand the complex graphics of these variants and the evolutionary path between them, Wright showed that they can be expressed as a more intuitive “adaptive landscape” with only two or three dimensions. The horizontal axis depicts the variability of DNA (genotype) or physical traits (phenotype) – the more similar the two variants are, the closer they are on the plane; The vertical axis measures the impact of variation on evolutionary adaptability. Whether by increasing viable offspring or improving the function of proteins, the variants that improve the survival probability of organisms inhabit the mountains, while those that reduce the survival of organisms linger at the bottom of the valley

Adam lauring, an evolutionary biologist from the University of Michigan School of medicine, pointed out that the result is a landscape with unique terrain. If the mapped variants are not different in their health effects, the landscape looks quite flat, much like Nebraska. Variants that have a significant impact on fitness create a landscape closer to the towering hat of Bryce Canyon, Utah. Natural selection tends to the variation on the mountain. The average genotype or phenotype of a species should evolve from one peak to the next, preferably along the ridge between the peaks rather than through the valley

“if you move a few feet, you will fall down and it will be very difficult to get up again,” lauring said. “There are fewer paths you can move.”

“this theory is very simple and clear. You just need to know your genotype, and then you measure fitness, and you can basically predict anything that may happen,” said Claudia bank, who studies evolutionary dynamics at the University of Bern, Switzerland. However, putting theory into practice is another matter

a complex problem is that neither sars-cov-2 nor human fitness landscape is static. A mutation that allows an organism to digest new food but makes it grow more slowly may be a life-saving straw or a fatal obstacle. The effect of a variant on evolutionary adaptability depends on the environment in which the organism is located. When the environment changes, the fitness status will also change. “Different variants have different effects, depending on the fitness environment,” lauring said

Evolutionary “landscape” can help predict the next action of covid virus(1)

creating a fitness landscape is also a mathematical challenge. Even a small protein with a length of only 100 amino acids will have 20100 possible variants, which is more than the number of atoms in the universe. It is hard to imagine, let alone calculate, the complex terrain of the real protein fitness landscape and the possibility of various paths through them. Therefore, for decades, fitness landscape has been a conceptual help rather than a specific measurement tool. Until recently, with advanced computing power and improved molecular biology technology, scientists began to make quantitative landscapes for single proteins and simple organisms such as bacteria and viruses

bacteria and viruses are almost ideal objects for fitness landscape. With the growth of millions or billions in test tubes, each bacterial cell or virus particle can breed a mutation from the huge variant library describing the fitness landscape. Their generation time is very short, only a few hours or days, which also enables researchers to identify new variants faster. Most viruses that use RNA as their genetic material — including HIV and hepatitis C virus (HCV) — are also very prone to mutation, because the RNA polymerase that copies its genome does not proofread copies as effectively as the DNA polymerase

the first thing scientists began to find is that although the landscape is very complex, organisms are often subject to only a few maximum fitness values and the limited path between them. A paper in Science in 2006 carefully studied a method called β- Lactamase is a protein that inactivates antibiotics such as penicillin. β- The combined action of five single nucleotide mutations in lactamase can increase its antibiotic resistance 100000 times. Daniel Weinreich, who was engaged in postdoctoral research in evolutionary biology at Harvard University and now leads a laboratory at Brown University, and his colleagues pointed out that the evolution of the gene may follow 120 paths to accumulate all five mutations

Evolutionary “landscape” can help predict the next action of covid virus(2)

however, when scientists created and tested intermediate variants in the laboratory, they found that 102 of them were impossible under natural selection because they produced defective or incomplete proteins. When they found that many of the remaining combinations failed to improve antibiotic resistance, the possibility was further reduced. “This means that the protein bands of life may be largely repeatable or even predictable,” they wrote

predicting the future evolutionary trajectory of even the smallest virus or protein requires a detailed understanding of its adaptive landscape, which is difficult to obtain. Historically, scientists have had to create one nucleotide or amino acid mutation at a time, and then purify the mutated protein and evaluate its function. It is often impractical to examine more than several possible mutations

The development of deep mutation scanning technology has changed all this. This technology enables scientists to produce tens of thousands of variants at one time, and then make all variants compete with each other to determine their relative adaptive value

researchers first created a library of mutant genes that could be cloned into cultured cells. These genes encode a protein whose activity is related to some biochemical functions and can be selected in the laboratory. Therefore, the cells that make the most appropriate and active version of these proteins will become more abundant, while the cells that make the inactive version will disappear. Through high-throughput DNA sequencing, researchers can count the number of each variant to quantitatively measure its performance in multiple generations

Valerie soo, a researcher at Warnecke laboratory in London, said: “this is a really powerful method to capture the effects of mutations.”

with mutative RNA viruses, scientists don’t even have to produce mutations in the laboratory — error prone genome replication machines will introduce mutations and do the work for them. Each of the millions of copies of the virus is slightly different from its neighbors, forming what virologists call a mutant group

“microorganisms reproduce so rapidly that evolution occurs every day,” said Samuel Alizon, an evolutionary ecologist at mivegec laboratory in Montpellier, France. “In fact, evolution can be monitored in real time.”

the researchers found that the mutations in these virus groups were very common