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The abundant larval transcript (ALT-2) protein is present in all members of the  Filarioidea , and has been reported as a potential candidate antigen for a subunit vaccine against lymphatic filariasis. To assess the potential for vaccine escape or heterologous protection, we examined the evolutionary selection acting on ALT-2. The ratios of nonsynonymous (K(a)) to synonymous (K(s)) mutation frequencies (ω) were calculated for the  alt-2  genes of the lymphatic filariasis agents  Brugia malayi  and  Wuchereria bancrofti  and the agents of river blindness and African eyeworm disease  Onchocerca volvulus  and  Loa loa . Two distinct Bayesian models of sequence evolution showed that ALT-2 of  W .  bancrofti  and  L .  loa  were under significant ( P <0.05;  P  < 0.001) diversifying selection, while ALT-2 of  B .  malayi  and  O .  volvulus  were under neutral to stabilizing selection. Diversifying selection as measured by ω values was notably strongest on the region of ALT-2 encoding the signal peptide of  L .  loa  and was elevated in the variable acidic domain of  L .  loa  and  W .  bancrofti . Phylogenetic analysis indicated that the ALT-2 consensus sequences formed three clades: the first consisting of  B .  malayi , the second consisting of  W .  bancrofti , and the third containing both  O .  volvulus  and  L .  loa . ALT-2 selection was therefore not predictable by phylogeny or pathology, as the two species parasitizing the eye were selected differently, as were the two species parasitizing the lymphatic system. The most immunogenic regions of  L .  loa  and  W .  bancrofti  ALT-2 sequence as modeled by antigenicity prediction analysis did not correspond with elevated levels of diversifying selection, and were not selected differently than predicted antigenic epitopes in  B .  malayi  and  O .  volvulus . Measurements of ALT-2 evolvability made by χ 2  analysis between alleles that were stable ( O .  volvulus  and  B .  malayi ) and those that were under diversifying selection ( W .  bancrofti  and  L .  loa ) indicated significant ( P <0.01) deviations from a normal distribution for both  W .  bancrofti  and  L .  loa . The relationship between evolvability and selection in  L .  loa  followed a second order polynomial distribution (R 2  = 0.89), indicating that the two factors relate to one another in accordance with an additional unknown factor. Taken together, these findings indicate discrete evolutionary drivers acting on ALT-2 of the four organisms examined, and the described variation has implications for design of novel vaccines and diagnostic reagents. Additionally, this represents the first mathematical description of evolvability in a naturally occurring setting.

Differential Evolutionary Selection and Natural Evolvability Observed in ALT Proteins of Human Filarial Parasites