gms | German Medical Science

The SARS coronavirus is the etiologic agent for the epidemic of the Severe Acute Respiratory Syndrome. The recent emergence of this new pathogen, the careful tracing of its transmission patterns, and the ability to propagate in culture allows the exploration of the mutational dynamics of the SARS-CoV in human populations. Close examination of whole genome sequence of 54 SARS-CoV isolates, including 22 from patients in Singapore revealed the mutations engendered during human-to-Vero and Vero-to-human transmission as well as in multiple Vero cell passages in order to refine our analysis of human-to-human transmission. Though co-infection by different strains in individual tissue samples is observed, the in vitro mutation rate of the SARS-CoV in Vero cell passage is negligible. The in vivo mutation rate, however, is consistent with estimates of other RNA viruses at approximately 5.7×10^-6 nucleotide substitutions per site per day (0.1722 mutations per genome per day), or two mutations per human passage (adjusted R-square=0.4014). Using the immediate Hotel M contact isolates as roots, we observed that the SARS epidemic has generated four major genetic strains that are geographically associated: two Singapore strains, one Taiwan strain, and one North China strain which appears most closely related to the putative SARS-CoV isolated from a palm civet. Our results show that the SARS-CoV is well adapted to growth in culture and did not appear to undergo specific selection in human populations. We further assessed that the putative origin of the SARS epidemic was in late October 2002 which is consistent with a recent estimate using cases from China. The greater sequence divergence in the structural and antigenic proteins and consistent deletions in the 3' - most portion of the viral genome suggest that certain selection pressures are interacting with the functional nature of these validated and putative ORFs. Non-synonymous mutations are centered in non-essential ORFs especially in structural and antigenic genes such as the S and M proteins, but these mutations did not distinguish the geographical strains. The absence of coding mutations in the 3CLpro and the polymerase genes suggest that these enzymes are reasonable targets for small molecule therapeutics.