Про эволюцию "дельты"
На мой взгляд, интересная работа израильтян.
Overall, variants are characterized based on well-defined phylogenetic clades, and classified based on available evidence for increased transmissibility, virulence, or escape from the immune system / therapeutics. Variants with these characteristics are thusclassified as variantsof concern (VOC), variants of interest (VOI) or variants under monitoring (VUM)by health agencies such as the world health organization (WHO, www.who.int).Thus far, theWHO has defined four VOCs: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and four VOIs: B.1.525 (Eta), B.1.526 (Iota), B.1.617.1 (Kappa)and C.37 (Lambda). An additional twelve variantspreviously classified as VOIs, such as B.1.427/9 originating in California[6],have now been reclassifiedas VUMs. We collectively denote a VOC/VOI/VUM as a VO. Following the detection of B.1.1.7, there has been a surge of different variants reported globally, which were characterized by punctual rises in frequencies of a particular variant, often accompanied by its demise a few months later. In the past few months, focus has turned to theDelta variant, which was first detected in Indiaandhas recently increased in prevalence globally.The Delta variantcurrently seems to be displacing all other variants, including the highly dominant and contagious Alpha variant,in numerous countries across the globe [7].In this study, we utilize evolutionary genomics to explain the rise and fall of different variants across time, with an emphasis on exploring the patterns of evolution in the globally-ascending Delta variant in comparison to other VOs When focusing on the Spike protein, we found that all VOs are characterized by substitutions prevalent particularly in the N-terminal domain (NTD) and receptor binding domain (RBD), many of which have been shown to be associated with escape from neutralizing antibodies (Fig. 2C). Interestingly, the one exception is the Alpha VOC, which bears only one mutation associated with immune evasion (a deletion at position 144). All VOs bear an amino-acid replacement at either position 203, 204, or 205 of the nucleocapsidprotein(N),often combined. While it has previously been suggested that the K203/R204 polymorphisms create a non-canonical sgRNA[9], this is not expected to be the case for either the Delta or the Beta variants (Fig. S1). We thus suggest that the amino-acid replacements themselves may be adaptive. Accumulating evidence suggest that N has a crucial role in evasion from the cell autonomous innate immune response [10], [11], in viral assembly[12], and in interactions with cellular co-factors[13], and we suggest that amino-acid replacements at this region may increase replication capacity of the virus. When comparing overall Delta clades with Alpha, it wasnotable that a higher proportion of vaccinated individuals become infected with Delta as compared to Alpha, whereas no notable differences were observed between DeltaD and other Delta clades (Fig. 4C, Table S3). These resultsareline with reports on lower vaccine effectiveness against infection with regards to the Delta variant[14][15], but do not add any information why DeltaD is more prevalent. The Delta variant, however,appears to be quite differentin this context from other VOs, especially in comparisonto Alpha.The tree topology of Delta is highly structuredand includes five newly characterized clades, suggesting two possibilities: either Delta arose early on during the pandemic, and rounds of random genetic drift led to itsseparation into several clades, or -selection led to the formation of these clades. The high proportion of non-synonymous substitutions during the emergence of some, but not all of these clades supports selection, yet this is inconclusive. We further note that of the five cladesA-E, DeltaD seems to be repeatedly gaining dominance in various countries across the globe. We go on to discusstwo hypotheses: the first is that the rise in frequency of DeltaD is due to founder effects, and the second is that DeltaDarose due to positive selection. One possibility that arises, is that the increase in Delta D is a combination of founder effects together with a shift in the landscape of immunized and recovered individuals across the globe. Accordingly, Delta D initself has no selective advantage over other Delta clades; yet all Delta clades bear a selective advantage over the Alpha variant that predated Delta. In particular, it is possible that the advantage Delta bears is in its ability to overcome some of the defenses of immunized individuals as compared to Alpha, as evident from the data herein and elsewhere A second hypothesis is that Delta A may be under positive selection. In line with this, 82% of the lineage specific mutations of this clade are non-synonymous, similar to what characterizes VOs(Table S2, Fig. 2A). However,thisclade lacks additional substitutions in itsSpike gene(as opposed to clades A and E),andis characterized by seven amino-acid replacements in the ORF1a/bpolyprotein. This is particularly perplexing as the lineagedefining mutations of the main Delta lineage are depleted of mutations in ORF1a/b(Table S2). Anadditional non-synonymous substitutionis evident in the ORF7b gene (T40I) and in the Ngene(G215C) at position 215, quite proximalto the 203-205 region discussed above. Only two of the eleven substitutionsunique to theDeltaD clade are seen in other clades worldwide(Table S2), and thus the functional implications of DeltaDsubstitutions remain to be further investigated. we have used a comparative approach to detect a unique mode of evolution present in Delta. This step-wise mode of evolution characterized boththeformation of the Delta D clade, and its subsequent spread, and is in stark contrast to the evolution observed in other VOCs.In particular, the global increase in Delta frequency has occurred concurrently with the increase in Delta D, suggesting that what is now labelled as “Delta” worldwide is actually specifically the Delta D clade.
Overall, variants are characterized based on well-defined phylogenetic clades, and classified based on available evidence for increased transmissibility, virulence, or escape from the immune system / therapeutics. Variants with these characteristics are thusclassified as variantsof concern (VOC), variants of interest (VOI) or variants under monitoring (VUM)by health agencies such as the world health organization (WHO, www.who.int).Thus far, theWHO has defined four VOCs: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and four VOIs: B.1.525 (Eta), B.1.526 (Iota), B.1.617.1 (Kappa)and C.37 (Lambda). An additional twelve variantspreviously classified as VOIs, such as B.1.427/9 originating in California[6],have now been reclassifiedas VUMs. We collectively denote a VOC/VOI/VUM as a VO. Following the detection of B.1.1.7, there has been a surge of different variants reported globally, which were characterized by punctual rises in frequencies of a particular variant, often accompanied by its demise a few months later. In the past few months, focus has turned to theDelta variant, which was first detected in Indiaandhas recently increased in prevalence globally.The Delta variantcurrently seems to be displacing all other variants, including the highly dominant and contagious Alpha variant,in numerous countries across the globe [7].In this study, we utilize evolutionary genomics to explain the rise and fall of different variants across time, with an emphasis on exploring the patterns of evolution in the globally-ascending Delta variant in comparison to other VOs When focusing on the Spike protein, we found that all VOs are characterized by substitutions prevalent particularly in the N-terminal domain (NTD) and receptor binding domain (RBD), many of which have been shown to be associated with escape from neutralizing antibodies (Fig. 2C). Interestingly, the one exception is the Alpha VOC, which bears only one mutation associated with immune evasion (a deletion at position 144). All VOs bear an amino-acid replacement at either position 203, 204, or 205 of the nucleocapsidprotein(N),often combined. While it has previously been suggested that the K203/R204 polymorphisms create a non-canonical sgRNA[9], this is not expected to be the case for either the Delta or the Beta variants (Fig. S1). We thus suggest that the amino-acid replacements themselves may be adaptive. Accumulating evidence suggest that N has a crucial role in evasion from the cell autonomous innate immune response [10], [11], in viral assembly[12], and in interactions with cellular co-factors[13], and we suggest that amino-acid replacements at this region may increase replication capacity of the virus. When comparing overall Delta clades with Alpha, it wasnotable that a higher proportion of vaccinated individuals become infected with Delta as compared to Alpha, whereas no notable differences were observed between DeltaD and other Delta clades (Fig. 4C, Table S3). These resultsareline with reports on lower vaccine effectiveness against infection with regards to the Delta variant[14][15], but do not add any information why DeltaD is more prevalent. The Delta variant, however,appears to be quite differentin this context from other VOs, especially in comparisonto Alpha.The tree topology of Delta is highly structuredand includes five newly characterized clades, suggesting two possibilities: either Delta arose early on during the pandemic, and rounds of random genetic drift led to itsseparation into several clades, or -selection led to the formation of these clades. The high proportion of non-synonymous substitutions during the emergence of some, but not all of these clades supports selection, yet this is inconclusive. We further note that of the five cladesA-E, DeltaD seems to be repeatedly gaining dominance in various countries across the globe. We go on to discusstwo hypotheses: the first is that the rise in frequency of DeltaD is due to founder effects, and the second is that DeltaDarose due to positive selection. One possibility that arises, is that the increase in Delta D is a combination of founder effects together with a shift in the landscape of immunized and recovered individuals across the globe. Accordingly, Delta D initself has no selective advantage over other Delta clades; yet all Delta clades bear a selective advantage over the Alpha variant that predated Delta. In particular, it is possible that the advantage Delta bears is in its ability to overcome some of the defenses of immunized individuals as compared to Alpha, as evident from the data herein and elsewhere A second hypothesis is that Delta A may be under positive selection. In line with this, 82% of the lineage specific mutations of this clade are non-synonymous, similar to what characterizes VOs(Table S2, Fig. 2A). However,thisclade lacks additional substitutions in itsSpike gene(as opposed to clades A and E),andis characterized by seven amino-acid replacements in the ORF1a/bpolyprotein. This is particularly perplexing as the lineagedefining mutations of the main Delta lineage are depleted of mutations in ORF1a/b(Table S2). Anadditional non-synonymous substitutionis evident in the ORF7b gene (T40I) and in the Ngene(G215C) at position 215, quite proximalto the 203-205 region discussed above. Only two of the eleven substitutionsunique to theDeltaD clade are seen in other clades worldwide(Table S2), and thus the functional implications of DeltaDsubstitutions remain to be further investigated. we have used a comparative approach to detect a unique mode of evolution present in Delta. This step-wise mode of evolution characterized boththeformation of the Delta D clade, and its subsequent spread, and is in stark contrast to the evolution observed in other VOCs.In particular, the global increase in Delta frequency has occurred concurrently with the increase in Delta D, suggesting that what is now labelled as “Delta” worldwide is actually specifically the Delta D clade.