Identifying Changes in Selective Constraints: Host Shifts in Influenza

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Abstract
The natural reservoir of Influenza A is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or through whole host shift events, genetic material from waterfowl viruses is introduced into the human population causing worldwide pandemics. Identifying which mutations allow viruses from avian origin to spread successfully in the human population is of great importance in predicting and controlling influenza pandemics. Here we describe a novel approach to identify such mutations. We use a sitewise non-homogeneous phylogenetic model that explicitly takes into account differences in the equilibrium frequencies of amino acids in different hosts and locations. We identify 172 amino acid sites with strong support and 518 sites with moderate support of different selection constraints in human and avian viruses. The sites that we identify provide an invaluable resource to experimental virologists studying adaptation of avian flu viruses to the human host. Identification of the sequence changes necessary for host shifts would help us predict the pandemic potential of various strains. The method is of broad applicability to investigating changes in selective constraints when the timing of the changes is known. Influenza A's natural reservoir is waterfowl. Sometimes avian virus genomic segments are able to shift to a human host, either in toto or by combining with those that underwent a previous host shift event. Such host shift events can cause worldwide pandemics in their immunologically naive hosts. In order for these host shifts to establish a stable lineage, the virus has to adapt to the new host. Identifying the changes that have occurred in the past can provide important clues about how this process happens, and how surveillance for new influenza threats should be targeted. Unfortunately, it is difficult to determine whether an amino acid has changed due to adaptation to the new host or whether the change occurred through random drift. Here we describe a novel phylogenetic approach to identifying locations where the nature of the selective pressure exerted on the location has changed corresponding to the host shift event. We identify a set of locations on a number of the genomic segments. The approach we describe is of wide applicability when the timing of the change of selective constraints is known in advance.