Understanding the extent and limitation of viral genome evolution can provide insight about potential drug and vaccine targets. Influenza B Viruses (IBVs) infect humans in a seasonal manner and causes significant morbidity and mortality. IBVs are negative-sense single-stranded RNA viruses with a segmented genome and can be divided into two antigenically distinct lineages. The two lineages have been circulating and further evolving for almost four decades. The immune response to IBV infection can lead to antibodies that target the strain causing the infection. Some antibodies are cross-reactive and are able to bind strains from both lineages but, because of antigenic drift and immunodominance, both lineages continue to evolve and challenge human health. Here we investigate changes in the genomes of an IBVs from each lineage after passage in tissue culture in the presence of human sera containing polyclonal antibodies directed toward antigenically and temporally distinct viruses. Our previous analysis of the fourth segment, which encodes the major surface protein HA, revealed a pattern of change in which signature sequences from one lineage mutated to the signature sequences of the other lineage. Here we analyze genes from the other genomic segments and observe that most of the quasispecies' heterogeneity occurs at the same loci in each lineage. The nature of the variants at these loci are investigated and possible reasons for this pattern are discussed. This work expands our understanding of the extent and limitations of genomic change in IBV.