title: Differential Evolutionary Selection and Natural Evolvability Observed in ALT Proteins of Human Filarial Parasites.
abstract: 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 χ2 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 (R2 = 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.
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Devoe
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Corbett
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Linsey
authors.initials: L
authors.lastname: Barker
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Chang
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Gudis
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mullen
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Kailey
authors.initials: K
authors.lastname: Perez
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Hugo
authors.initials: H
authors.lastname: Raposo
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Scholz
authors.affiliation: University of New England College of Osteopathic Medicine, Biddeford, Maine, 04005, United States of America.
authors.forename: Meghan
authors.initials: M
authors.lastname: May
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D010802:Phylogeny; D012641:Selection, Genetic; D017174:Spirurida / Q000145:classification / Q000235:genetics*; D017205:Spirurida Infections / Q000276:immunology / Q000469:parasitology*
chemical_list: D015801:Helminth Proteins