Influenza A virusu alt tiplerinin karşılaştırmalı çeşitlilik dinamikler

Influenza A virus subtypes continue to be a pandemic threat to humanity despite having caused multiple pandemics in the past. All influenza A viruses (IAVs) that currently infect humans originated from non-human hosts and achieved the ability to infect humans through diversification factors, such as mutation and reassortment. The World Health Organization redesigns the IAV vaccines twice every year in order to keep up with the high diversity of IAVs that infect humans. The large availability of sequence data of IAVs in public databases enable diversity studies of existing human infecting IAVs, which is necessary to gain better understanding of the diversity, thereby facilitating design of effective interventions, such as vaccines against the IAVs. A quantitative approach to the diversity with all available data, with comparative analyses across subtypes and between host species (avian and human) is much needed. The thesis herein aimed to conduct a comprehensive inter-host (human and avian) study on the diversity dynamics of three (3) influenza A virus subtypes selected and categorized as: (i) established human (H3N2), (ii) emerging human (H7N9) and (iii) only avian (H4N6). Trends in the variation of protein sequences of these subtypes were comparatively studied by quantifying the diversity through use of Shannon's entropy, as well as calculating the incidences (occurrences) of distinct diversity motifs at each aligned overlapping nonamer (9-mer) position of the proteins. Nonamers (9-mers) were selected for immunological applications and the 9-mers were generated by use of a sliding-window approach, where each 9-mer overlapped eight amino acids with the next 9-mer, such as 1-9, 2-10, 3-11, etc. The diversity motifs comprised of index and its variants (major, minor and unique). The index is the predominant sequence at a nonamer position and all the other nonamers (at that position) are referred to as variants, with one or more amino acid difference from the index. The major variant is the variant nonamer sequence that occurred more than all other variant nonamer sequences, making it the most common variant nonamer, while the unique variants are singletons that occurred only once. The minor variants are those 9-mers that occurred more than once and yet with incidences not up to the incidence of the major variant. Across all the subtypes, the protein PB1-F2 was observed to be constantly more diverse (unstable) in the avian IAVs compared to the human IAVs. Furthermore, PB1 and PB2 proteins were found to be the most conserved proteins across all the subtypes and hosts. In addition, nearly every 9-mer position had a variant 9-mer, beside the 9-mer with the highest incidence/occurrence (index) at the same position. The entropy values of the 9-mer positions also showed a high positive correlation to total variants, with Pearson correlation coefficient (r) of greater than 0.90 across all the subtypes analysed. Further, each variant motif (major, minor, and unique) had a unique relationship with increasing total variants across the proteome. Major variant exhibited a peak incidence at 50% total variants, beyond which only the minor variants continued to rise and were collectively predominant. The unique variants were observed for nearly all positions, but were of low incidence and showed a uniform trend.