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cleavage at the NS1/2A site, but the precise role of NS2A in processing is unclear(Falgout et al., 1989). In the case of YF, at least one additional cleavage site for theNS2B-3protease occurs in the NS2A region, and a mutation that block at this site islethal for virus replication.The NS2B protein (predicted M 27kd) contains a highly charged andconserved central region flanked by hydrophobic segments (Falgout et al., 1993).This protein together with NS3 serineprotease domain, have been shown to beessential for processing at all of the known structural and nonstructural dibasic sites(Amberg et al., 1994). Evidence of a stable complex between NS2B and NS3 hasbeen obtained (Arias et al., 1993; Chambers et al., 1993). Mutagenesis data suggestthat the charged central region participate in the formation of this complex and theactive protease (Chambers et al., 1993; Falgout et al., 1993). Besides its function inproteolysis, it has been suggested that the interaction between the hydrophobicNS2B protein and NS3 may be partially responsible for the localization of the RNAreplication machinery to cellular membranes.No data is available concerning the function of the hydrophobic NA4A and" NS4B proteins.2.2.6 PHYLOGENETIC RELATIONSHIPS OF FLAVIVIRUSESTHAT CORRELATE WITH THEIR EPIDEMIOLOGY,DISEASE ASSOCIATION AND BIOGEOGRAPHYMolecular sequenciug and phylogenetic re~onstructions have prov~dedimportant insights into the taxonomy (Heinz et al., 2000) and dispersal ofFlaviviruses (Gould et al., 1997). It was demonstrated previously (Marin et al.,1995; Kuno et al., 1998) that the Flavivirus genus was monophyletic and threedistinct groups of viruses, namely tick-borne, mosquito-borne and NKV viruses,diverged at the deepest nodes. Recently, it has been demonstrated that the mosquitoborneviruses are subdivided into culex and aedes clades (Gaunt et al., 2001).Moreover, the evolution of the culex clade appears to have occurred after theseparation of the mosquito-borne from the tick-borne and NKV viruses. Theseobservations were supported by the congruence between NS5 and E genephylogenies as well as by Monte Carlo simulation and quartet puzzling support.15