The role of reassortment in the evolution of seasonal influenza

Reassortment, which is the exchange of genome sequence between viruses co-infecting a host cell, plays an important role in the evolution of segmented viruses, such as influenza. The large-scale genome reshuffling promotes diversity in the viral population and can lead to the emergence of pandemic strains. In the human influenza virus, reassortment happens most frequently between co-existing variants within the same lineage. This process breaks genetic linkage and fitness correlations between viral genome segments, but the resulting net effect on viral fitness has remained unclear. In this thesis, we first determine rate and average selective effect of reassortment processes in the human influenza lineage A/H3N2. For the surface proteins hemagglutinin and neuraminidase, reassortant variants with a mean distance of at least 3 nucleotides to their parent strains get established at a rate of about 10^(-2) in units of the neutral point mutation rate. Our inference is based on a new method to map reassortment events from joint genealogies of multiple genome segments, which is tested by extensive simulations. We show that intra-lineage reassortment processes are, on average, under substantial negative selection that increases in strength with increasing sequence distance between the parent strains. The deleterious effects of reassortment manifest themselves in two ways: there are fewer reassortment events than expected from a null model of neutral reassortment, and reassortant strains have fewer descendants than their non-reassortant counterparts. Our results suggest that influenza evolves under ubiquitous epistasis across proteins, which produces fitness barriers against reassortment even between co-circulating strains within one lineage. Second, we study the dynamics of reassortment occurring within a recent influenza clade which is likely to dominate the next epidemics. In order to handle the large amount of data collected in the last seasons, we develop a new heuristic detection method based on neuraminidase alignments and haemagglutinin phylogenies; this novel approach is faster than the joint-segment tree based algorithm and can be applied to much larger trees. We find an increase in the frequency of reassorment events, which lead to the coexistence in the viral population of three new neuraminidase clades, in addition to the ancestral variant. These imported neuraminidase segments differ from the non-reassorted version by aminoacid changes at epistatic sites. The results reported in this work are a step forward towards predicting the evolution of influenza based on the entire genome. The consequent improvement of accuracy in anticipating future evolution is the key for designing more effective vaccines