**4. Genetic evolution and disease severity in SEA**

The micro evolutionary change within dengue serotypes has resulted in substantial genetic diversity with emergence of endemic and epidemic genotypes. With current advances in the field of genetic and molecular techniques scientists are now trying to decipher relation of changing clades with disease severity and epidemic potential. With the availability of complete genomic sequence of the Dengue virus different genetic loci have been investigated to find this relationship. Envelope –gene (E-gene) sequence is the most frequently investigated locus, (Wittke,V.et al., 2002;-Thu, H.M. et al.,2004;Islam, M.A.et al., 2006,27) followed by capsuler C-prM gene (Kukreti, H. 2008;,Dash, P.K. 2006;,Kanakaratne, N. 2009;Jamil B,2007). In addition non-structural (NS) viral proteins such as NS1 and untranslated genomic region 3'-UTR, 5' UTR along with complete genomic sequences have been investigated to relate the genetic changes with the disease severity (Mangada, M.N. et al., 1997;Zhou,Y.et al.,2006;Islam, M.A.et al.,2006. Despite the wealth of genomic data available the exact cause and effect of viral virulence and clade changes is yet to be proven, however, viral linage is continually changing with local extinction and emergence of new clade. The introduction of new clade in the region translates in form of outbreaks of DHF and DSS. In order to analyze if there is a selection of specific clade in South East Asia that is circulating in the region and causing DHF outbreaks we conducted a meta-analysis. Studies conducted from 1950 to 2009 in South East Asian region that have investigated association of disease severity with specific sequence mutations in the dengue virus genome were retrieved. The objective was to analyze association of disease severity with the specific genomic mutation in the clade circulating and causing periodic epidemics in South East Asia. Since DENV-2 and DENV-3 are more common in this region our study was focused on these two genotypes only. Objectives of the metaanalysis were to identify association of specific genetic mutation in DENV-2 and DENV-3 with clinical severity seen during periodic epidemics in South East Asia. The specific review question was:Is clinical severity of dengue in the South East Asian region associated with emergence of specific mutations in genomes of DENV-2 and DENV-3 genotypes? We hypothesized that there is changing pattern of dengue virus genotypes in South East Asia and these mutations are associated with clinical severity of the disease.
