25 Since their discovery and sequencing 40 years ago, the DENV genotypes have shown an extreme 26 coherence regarding the serotype class they code for. Considering the RNA virus mutation rate, 27 we used Timed Markov Model to explore the transmission possibilities of mutated viruses and the 28 statistical eventualities of new serotype emergence. We find that around 1 000 years are required 29 for a new serotype to emerge, in line with phylogenetic analysis of the Dengue serotypes. Our 30 work provides a mechanistic explanation of the strictness and low probability of a new Dengue 31 virus serotype occurrence. 32 33 Author summary 34 Recent Dengue virus global spread has drawn the attention of the Public Health Policy makers in 35 developing countries and developed countries as well. The infection gravity and the hemorrhagic 36 dengue syndromes have been related with the absence or presence of previous DENV immunity.37 Therefore, the emergence of a new DENV serotype and its spread constitute a matter of concern.38 Here, we constructed a mathematical model to determine the probability of such event, as well as 39 de-entangle the mechanistic reasons behind the low serotype emergence factor of the DENV. 40 41 Introduction 42 Dengue virus infection have showed a marked increase during the last two decades, imposing a 43 sizable burden on the health system and economy of the affected Latin-American countries (1). 44 Vaccine prospects have shown limited infection protection efficacy (42.3% to 77.7% of protection, 45 in function of the serotype), though drastically decreasing the appearance of hemorrhagic 46 symptoms in the infected population (2). 47 48 Part of the difficulty for Dengue vaccine design arises from the existence of 4 distinct DENV 49 serotypes with multiples genomic sequences. Nevertheless the existence of thousands of genotypes 50 for each serotype, the viruses have kept a great homology between the protein sequences of their 51 structural proteins (3). This phenomenon contrast with the one observed in the human 52 papillomavirus infection, which is caused by a DNA virus presenting over 170 serotypes (4). The 53 occurrence of viruses not belonging to the described 4 serotypes has been reported in Malaysia, 54 but this newcomer virus structure did not further propagate in the population (5). 55 56 Dengue virus are obliged to pass from one mammal host to one insect host to perpetuate the 57 infection. DENV infect several human tissues, encountering cells suitable for its amplification.58 Typically, endothelial cells of the liver; lung vascular endothelium cells, kidney tubules 59 multinucleated cells, spleen reactive lymphoid cells, macrophages, monocytes and lymphocytes 60 cells are the cells suitable for Virus infection (6). In the insect, the viral particle mainly infects 61 intestinal, circulatory and salivary gland cells (7). 62 63 In the mosquito environment, the virus mutation are dictated by the constraints of mosquito 64 interference RNA system evasion [8], [9]. The effect of immune defense protei...