Somatic hypermutation targeting is influenced by location within the immunoglobulin V region.

The observed mutation pattern in immunoglobulin (Ig) V genes from peripheral B cells is influenced by several mechanisms, including the targeting of AID to specific DNA motifs, negative selection of B cells unable to express Ig receptor, and positive selection of B cells that carry affinity-increasing mutations. These influences, combined with biased codon usage, produce the well-known pattern of increased replacement mutation frequency in the CDR regions, and decreased replacement frequency in the framework regions. Through the analysis of over 12,000 mutated sequences, we show that the specific location in the V gene also significantly influences mutation accumulation. While this position-specific effect is partially explained by selection, it appears independently of the CDR/FWR structure. To further explore the specific targeting of SHM, we propose a statistical formalism describing the mutation probability of a sequence through the multiplication of independent probabilities. Using this model, we show that C→G (or G→C) mutations are almost as frequent as C→T and G→A mutations, in contrast with C→A (or G→T) mutations, which are as any other mutation. The proposed statistical framework allows us to precisely quantify the effect of V gene position, mutation substitution type, and micro-sequence specificity on the observed mutation pattern.

The association of winds with the spread of EHDV in dairy cattle in Israel during an outbreak in 2006.

Winds may play a major role in spread of arthropod-borne viruses (arboviruses). Arboviruses like epizootic hemorrhagic disease virus (EHDV), bluetongue virus and bovine ephemeral fever virus (BEFV) frequently cause major outbreaks in Israel with a unique pattern of spread. Most of these outbreaks begin in the Jordan valley, near the Sea of Galilee and then spread to the north, south and west through the major valleys of Israel. The aim of this study was to describe the spread pattern in such an outbreak and to find if this pattern can be explained by winds. Herein, we compared the spread rate to each direction and used Cox proportional hazards model to test factors associated with the spread of EHDV, which emerged in diary cattle in Israel during the summer of 2006. Documented, clinical and serological data on spread of the outbreak were then compared with wind data collected by meteorological stations along the trail of virus spread and with modeled winds at high altitude (>500 m). The analysis revealed that both the hazard and the rate of outbreak spread to the south and to the north were significantly higher than to the west. Average rate of outbreak spread during periods in which at least 3 h of winds to spread direction were recorded was 20,880 m/week (SD=13,230) vs. 7486 m/week (SD=4936) in periods during which no such winds were recorded. Serological evidence demonstrated exposure to the virus up to 166 km away from the location of the initial outbreak center. Modeled wind data showed that this spread may be explained by winds at high altitudes. Animal movements due to shipments of feedlot calves and slaughters could not explain the spread pattern observed during the outbreak. This study therefore shows that winds are probably a major contributory factor for long and medium distance spread of Culicoides borne viruses in this region.