Prediction of Directional Changes of Influenza A Virus Genome Sequences with Emphasis on Pandemic H1N1/09 as a Model Case

Abstract

Influenza virus poses a significant threat to public health, as exemplified by the recent introduction of the new pandemic strain H1N1/09 into human populations. Pandemics have been initiated by the occurrence of novel changes in animal sources that eventually adapt to human. One important issue in studies of viral genomes, particularly those of influenza virus, is to predict possible changes in genomic sequence that will become hazardous. We previously established a clustering method termed ‘BLSOM’ (batch-learning self-organizing map) that does not depend on sequence alignment and can characterize and compare even 1 million genomic sequences in one run. Strategies for comparing a vast number of genomic sequences simultaneously become increasingly important in genome studies because of remarkable progresses in nucleotide sequencing. In this study, we have constructed BLSOMs based on the oligonucleotide and codon composition of all influenza A viral strains available. Without prior information with regard to their hosts, sequences derived from strains isolated from avian or human sources were successfully clustered according to the hosts. Notably, the pandemic H1N1/09 strains have oligonucleotide and codon compositions that are clearly different from those of human seasonal influenza A strains. This enables us to infer future directional changes in the influenza A viral genome.

Novel bioinformatics strategies for prediction of directional sequence changes in influenza virus genomes and for surveillance of potentially hazardous strains

“…G and C were richer on the left side of map where avian strains were mainly located, and therefore, a major portion of human seasonal strains was A- and U-richer than avian strains. This finding on Mono-BLSOM directly confirmed the G+C% rule (the host-dependent mononucleotide composition) found with the conventional oligonucleotide BLSOMs previously introduced [14]. …”

“…5000 strains reported after our previous publication [14] (Figure 1A); in the case of H1N1/09 strains, approximately 80% of the sequences were newly reported after our previous publication. Although both influenza A and B virus genomes are composed of eight segments, we analyzed genomes of individual strains by summing up mononucleotide occurrences of eight segments for each strain in order to conduct a genome-level analysis.…”

“…Influenza virus pandemics in human populations are often initiated by viral invasion from animal hosts and successive adaptation among humans through human-to-human transmission, as recently observed for the pandemic H1N1 strains (H1N1/09). Our previous BLSOM study [14] for di, tri and tetranucleotide compositions in genome sequences of 7,439 influenza A strains, which corresponded to all available data at that time, found clear separation (self-organization) of their sequences according to host, and features of the host-dependent oligonucleotide composition responsible for host-dependent separation were summarized by the following three rules. i) G- and C-rich oligonucleotides were more favored in avian strains than in human strains; G+C% effect.…”

“…We previously analyzed influenza A viruses with oligonucleotide BLSOMs and found that the oligonucleotide composition of strains isolated from avians and humans clearly differed from each other (i.e. host-dependent oligonucleotide composition) and the composition of the new pandemic H1N1/09 was different from that of human seasonal flu strains [14]. Furthermore, directional changes of oligonucleotide composition in H1N1/09 strains toward seasonal human strains were observed even within the first pandemic year.…”

Directional and reoccurring sequence change in zoonotic RNA virus genomes visualized by time-series word count

“…In fact, the G+C% of influenza A virus strains isolated from humans is lower than that of strains isolated from natural hosts, which were avian10, and the CG dinucleotide in an A/U context has been preferentially eliminated from classical H1N1 influenza viruses during human-to-human transmission11. By using BLSOM (Batch Learning Self-Organizing Map)1213, we previously found directional compositional changes in a wide range of oligonucleotides1415 that occurred after the onset of the influenza H1N1/09 pandemic of 2009161718.…”