In general, interactions are transferred between different species based on the sequence similarity between the corresponding proteins. In addition, one might expect interactions among orthologous proteins with high sequence similarity to have a higher likelihood of being conserved. Yu and colleagues found that interactions could be confidently transferred from one species to another if the joint sequence identity of the interacting orthologs was .80% [47] . However, since none of the herpesviral core proteins shares such a high degree of sequence similarity across subfamilies, these criteria cannot be applied to herpesviruses. Furthermore, no correlation was observed between sequence similarity and the number of species in which an interaction was observed in the Y2H experiments. Thus, our results show that sequence similarity alone seems to be insufficient for predicting herpesviral interactions from one species onto another. Our analysis of cross-species interactions indicates an enrichment of interactions involving core proteins (either core-core or core-noncore). The detailed cross-species analysis of the interaction between the major capsid protein (MCP) and the smallest capsid protein (SCP) (HSV-1 UL19-UL35, Figure S10B ) only yielded 1 intraspecies interaction by Y2H, however 4 by LUMIER, indicating that this interaction is conserved despite being observed in only one species by Y2H. While capsid proteins and interactions are thought to be highly conserved, most of them were indeed only observed in one species in our genome-wide Y2H screens. However, three of the four observed capsid interactions (HSV-1 UL19-UL35, UL18-UL38, UL18-18 and UL35-UL35) have been published previously (Tables S3 and S14) , and, in addition, the LUMIER analysis resulted in an increased number of cross-species interactions. The cross-species interactions between the two tegument proteins HSV-1 UL11 and UL16 (and their orthologs), as well as between the two capsid proteins HSV-1 UL19 and UL35 (and their orthologs), were mainly observed between species within the same herpesviral subfamily. A similar observation has recently been reported by Schnee and colleagues [35] , and may indicate that some binding sites are more conserved within herpesvirus subfamilies. The other two interactions could be detected in a larger number of cross-species interactions by both Y2H and LUMIER. HSV-1 UL14, for example, was observed to interact with all orthologs of HSV-1 UL33 by LUMIER. Previous reports suggested that HSV-2 UL14 shares certain similarities with cellular chaperones which may account for its promiscuous binding pattern [48] .