The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evoluti...The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.展开更多
The winter of 2009 witnessed the concurrent spread of 2009 pandemic H1N1 with 2009 seasonal H1N1. It is clinically important to develop knowledge of the key features of these two different viruses that make them uniqu...The winter of 2009 witnessed the concurrent spread of 2009 pandemic H1N1 with 2009 seasonal H1N1. It is clinically important to develop knowledge of the key features of these two different viruses that make them unique. A robust pattern recognition technique, Random Forests, was employed to uncover essential amino acid markers to differentiate the two viruses. Some of these markers were also part of the previously discovered genomic signature that separate avian or swine from human viruses. Much research to date in search of host markers in 2009 pandemic H1N1 has been primarily limited in the context of traditional markers of avian-human or swine-human host shifts. However, many of the molecular markers for adaptation to human hosts or to the emergence of a pandemic virus do not exist in 2009 pandemic H1N1, implying that other previously unrecognized molecular determinants are accountable for its capability to infect humans. The current study aimed to explore novel host markers in the proteins of 2009 pandemic H1N1 that were not present in those classical markers, thus providing fresh and unique insight into the adaptive genetic modifications that could lead to the generation of this new virus. Random Forests were used to find 18 such markers in HA, 15 in NA, 9 in PB2, 11 in PB1, 13 in PA, 10 in NS1, 1 in NS2, 11 in NP, 3 in M1, and 1 in M2. The amino acids at many of these novel sites in 2009 pandemic H1N1 were distinct from those in avian, human, and swine viruses that were identical at these positions, reflecting the uniqueness of these novel sites.展开更多
In the efforts to understand the molecular characteristics responsible for the ability of influenza viruses to cross species, various amino acid host markers in influenza viruses were uncovered. Our previous study ide...In the efforts to understand the molecular characteristics responsible for the ability of influenza viruses to cross species, various amino acid host markers in influenza viruses were uncovered. Our previous study identified a collection of novel amino acid host markers in ten proteins of 2009 pandemic H1N1. As an extension of our prior work, the objective of the current study was to employ Random Forests, a robust pattern recognition technique, to discover nucleotide host makers in the ten corresponding genes of 2009 pandemic H1N1, along with those in the genes of avian and swine viruses. Although different, there was an association between the amino acid markers in proteins and the nucleotide markers in the related genes due to codon translations. Moreover, nucleotide host markers have the capability to indicate important positions within a codon for host switches as well as the significance of synonymous mutations on host shifts, all of which amino acid markers could not provide. Our findings highlighted that two or even three nucleotide markers could coexist within a single codon, and the different importance values of these markers could further discri- minate the multiple markers within a codon. The nucleotide markers found in this study rendered a comprehensive genomic view of the complex and systemic nature of host adaptation. They verified and enriched the known amino acid markers and offered a larger set of finer host markers for further experimental confirmation.展开更多
The capacity of zoonotic influenza to cross species boundaries to infect humans poses a global health threat. A previous study identified sites in 10 influenza proteins that characterize the host shifts from avian to ...The capacity of zoonotic influenza to cross species boundaries to infect humans poses a global health threat. A previous study identified sites in 10 influenza proteins that characterize the host shifts from avian to human influenza. Here, we used seven feature selection algorithms based on machine learning techniques to generate a novel and extensive selection of diverse sites from the nine internal proteins of influenza based on statistically importance to differentiating avian from human viruses. A set of 131 sites was generated by processing each protein independently, and a selection of 113 sites was found by analyzing a concatenation of sequences from all nine proteins. These new sites were analyzed according to their annual mutational trends. The correlation of each site with all other sites (one-to-many) and the connectivity within groups of specific sites (one-to-one) were identified. We compared the performance of these new sites evaluated by four classifiers against those recorded in previous research, and found our sites to be better suited to host distinction in all but one protein, validating the significance of our site selection. Our findings indicated that, in our selection of sites, human influenza tended to mutate more than avian influenza. Despite this, the correlation and connectivity between the avian sites was stronger than that of the human sites, and the percentage of sites with high connectivity was also greater in avian influenza.展开更多
The highly pathogenic avian H5N1 influenza virus could infect humans with high mortality rate, even though it has not yet become efficiently transmissible among humans. This proteomic study investigated the molecular ...The highly pathogenic avian H5N1 influenza virus could infect humans with high mortality rate, even though it has not yet become efficiently transmissible among humans. This proteomic study investigated the molecular basis of interspecies transmission and host range of this lethal virus in Asia, due to its potential pandemic threat. Although there are host markers located in previous research between general avian and human influenza viruses, the novelty of our work was to uncover host markers between highly pathogenic avian and human H5N1 viruses in Asia. Many host markers we found were not present in the previous general markers, thus expanding the current repertoire of host markers with these strain-specific host markers. Ranked by their order of importance, the top 10 host markers discovered in this report were PB2_627, HA_325, NS1_205, PB2_524, HA_86, NA_201, NP_373, NS1_7, HA_156, NA_74, confirming our current knowledge that PB2_627 is the most critical site for distinguishing avian and human H5N1. We also identified several naturally-occurred mutations in the HA protein that might shift the receptor binding preference of Asian avian H5N1, since early detection of mutations that might lead to emergence of a new pandemic virus is of prime importance. Finally, we analyzed the distinctive interaction patterns within and between proteins of avian and human H5N1 in Asia at protein level and individual residue level. From multiple viewpoints, our findings reinforced the experimental observation that multiple genes of Asian avian H5N1 are involved in its gradual adaptation to human hosts.展开更多
文摘The influenza A viruses have three gene segments, M, NS, and PB1, which code for more than one protein. The overlapping genes from the same segment entail their interdependence, which could be reflected in the evolutionary constraints, host distinction, and co-mutations of influenza. Most previous studies of overlapping genes focused on their unique evolutionary constraints, and very little was achieved to assess the potential impact of the overlap on other biological aspects of influenza. In this study, our aim was to explore the mutual dependence in host differentiation and co-mutations in M, NS, and PB1 of avian, human, 2009 H1N1, and swine viruses, with Random Forests, information entropy, and mutual information. The host markers and highly co-mutated individual sites and site pairs (P values < 0.035) in the three gene segments were identified with their relative significance between the overlapping genes calculated. Further, Random Forests predicted that among the three stop codons in the current PB1-F2 gene of 2009 H1N1, the significance of a mutation at these sites for host differentiation was, in order from most to least, that at 12, 58, and 88, i.e., the closer to the start of the gene the more important the mutation was. Finally, our sequence analysis surprisingly revealed that the full-length PB1-F2, if the three stop codons were all mutated, would function more as a swine protein than a human protein, although the PB1 of 2009 H1N1 was derived from human H3N2.
文摘The winter of 2009 witnessed the concurrent spread of 2009 pandemic H1N1 with 2009 seasonal H1N1. It is clinically important to develop knowledge of the key features of these two different viruses that make them unique. A robust pattern recognition technique, Random Forests, was employed to uncover essential amino acid markers to differentiate the two viruses. Some of these markers were also part of the previously discovered genomic signature that separate avian or swine from human viruses. Much research to date in search of host markers in 2009 pandemic H1N1 has been primarily limited in the context of traditional markers of avian-human or swine-human host shifts. However, many of the molecular markers for adaptation to human hosts or to the emergence of a pandemic virus do not exist in 2009 pandemic H1N1, implying that other previously unrecognized molecular determinants are accountable for its capability to infect humans. The current study aimed to explore novel host markers in the proteins of 2009 pandemic H1N1 that were not present in those classical markers, thus providing fresh and unique insight into the adaptive genetic modifications that could lead to the generation of this new virus. Random Forests were used to find 18 such markers in HA, 15 in NA, 9 in PB2, 11 in PB1, 13 in PA, 10 in NS1, 1 in NS2, 11 in NP, 3 in M1, and 1 in M2. The amino acids at many of these novel sites in 2009 pandemic H1N1 were distinct from those in avian, human, and swine viruses that were identical at these positions, reflecting the uniqueness of these novel sites.
文摘In the efforts to understand the molecular characteristics responsible for the ability of influenza viruses to cross species, various amino acid host markers in influenza viruses were uncovered. Our previous study identified a collection of novel amino acid host markers in ten proteins of 2009 pandemic H1N1. As an extension of our prior work, the objective of the current study was to employ Random Forests, a robust pattern recognition technique, to discover nucleotide host makers in the ten corresponding genes of 2009 pandemic H1N1, along with those in the genes of avian and swine viruses. Although different, there was an association between the amino acid markers in proteins and the nucleotide markers in the related genes due to codon translations. Moreover, nucleotide host markers have the capability to indicate important positions within a codon for host switches as well as the significance of synonymous mutations on host shifts, all of which amino acid markers could not provide. Our findings highlighted that two or even three nucleotide markers could coexist within a single codon, and the different importance values of these markers could further discri- minate the multiple markers within a codon. The nucleotide markers found in this study rendered a comprehensive genomic view of the complex and systemic nature of host adaptation. They verified and enriched the known amino acid markers and offered a larger set of finer host markers for further experimental confirmation.
文摘The capacity of zoonotic influenza to cross species boundaries to infect humans poses a global health threat. A previous study identified sites in 10 influenza proteins that characterize the host shifts from avian to human influenza. Here, we used seven feature selection algorithms based on machine learning techniques to generate a novel and extensive selection of diverse sites from the nine internal proteins of influenza based on statistically importance to differentiating avian from human viruses. A set of 131 sites was generated by processing each protein independently, and a selection of 113 sites was found by analyzing a concatenation of sequences from all nine proteins. These new sites were analyzed according to their annual mutational trends. The correlation of each site with all other sites (one-to-many) and the connectivity within groups of specific sites (one-to-one) were identified. We compared the performance of these new sites evaluated by four classifiers against those recorded in previous research, and found our sites to be better suited to host distinction in all but one protein, validating the significance of our site selection. Our findings indicated that, in our selection of sites, human influenza tended to mutate more than avian influenza. Despite this, the correlation and connectivity between the avian sites was stronger than that of the human sites, and the percentage of sites with high connectivity was also greater in avian influenza.
文摘The highly pathogenic avian H5N1 influenza virus could infect humans with high mortality rate, even though it has not yet become efficiently transmissible among humans. This proteomic study investigated the molecular basis of interspecies transmission and host range of this lethal virus in Asia, due to its potential pandemic threat. Although there are host markers located in previous research between general avian and human influenza viruses, the novelty of our work was to uncover host markers between highly pathogenic avian and human H5N1 viruses in Asia. Many host markers we found were not present in the previous general markers, thus expanding the current repertoire of host markers with these strain-specific host markers. Ranked by their order of importance, the top 10 host markers discovered in this report were PB2_627, HA_325, NS1_205, PB2_524, HA_86, NA_201, NP_373, NS1_7, HA_156, NA_74, confirming our current knowledge that PB2_627 is the most critical site for distinguishing avian and human H5N1. We also identified several naturally-occurred mutations in the HA protein that might shift the receptor binding preference of Asian avian H5N1, since early detection of mutations that might lead to emergence of a new pandemic virus is of prime importance. Finally, we analyzed the distinctive interaction patterns within and between proteins of avian and human H5N1 in Asia at protein level and individual residue level. From multiple viewpoints, our findings reinforced the experimental observation that multiple genes of Asian avian H5N1 are involved in its gradual adaptation to human hosts.
