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      Origin and Functional Diversification of an Amphibian Defense Peptide Arsenal

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          The skin secretion of many amphibians contains an arsenal of bioactive molecules, including hormone-like peptides (HLPs) acting as defense toxins against predators, and antimicrobial peptides (AMPs) providing protection against infectious microorganisms. Several amphibian taxa seem to have independently acquired the genes to produce skin-secreted peptide arsenals, but it remains unknown how these originated from a non-defensive ancestral gene and evolved diverse defense functions against predators and pathogens. We conducted transcriptome, genome, peptidome and phylogenetic analyses to chart the full gene repertoire underlying the defense peptide arsenal of the frog Silurana tropicalis and reconstruct its evolutionary history. Our study uncovers a cluster of 13 transcriptionally active genes, together encoding up to 19 peptides, including diverse HLP homologues and AMPs. This gene cluster arose from a duplicated gastrointestinal hormone gene that attained a HLP-like defense function after major remodeling of its promoter region. Instead, new defense functions, including antimicrobial activity, arose by mutation of the precursor proteins, resulting in the proteolytic processing of secondary peptides alongside the original ones.

          Although gene duplication did not trigger functional innovation, it may have subsequently facilitated the convergent loss of the original function in multiple gene lineages (subfunctionalization), completing their transformation from HLP gene to AMP gene. The processing of multiple peptides from a single precursor entails a mechanism through which peptide-encoding genes may establish new functions without the need for gene duplication to avoid adaptive conflicts with older ones.

          Author Summary

          Many amphibians defend themselves against predation and infections by secreting a mixture of gene-encoded toxins and antimicrobials. How does such an integrated defense weapon arise and how does it diversify to gain distinct antipredatory and antimicrobial functions? We took advantage of the availability of a sequenced genome for the African clawed frog Silurana tropicalis to provide the first comprehensive overview of an amphibian peptide defense arsenal, from its underlying genes to its bioactive components. A reconstruction of the evolutionary history of this gene repertoire allows us to elucidate the timing and mode of evolution of distinct defense functions. Our study shows that the basal transition from a gastrointestinal hormone function to a skin-secretory defense function was accompanied by major restructuring of regulatory sequences in the ancestral gene. Instead, subsequently diversifying defense genes underwent functional shifts by entering a bifunctional stage (by cleavage of two distinct defense peptides from a single precursor protein) and occasionally losing the original defense function (by loss of the original defense peptide). This pattern provides an evolutionary explanation for the processing of structurally or functionally unrelated toxins from the same or closely related precursor proteins in other poisonous and venomous animals.

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          MrBayes 3 performs Bayesian phylogenetic analysis combining information from different data partitions or subsets evolving under different stochastic evolutionary models. This allows the user to analyze heterogeneous data sets consisting of different data types-e.g. morphological, nucleotide, and protein-and to explore a wide variety of structured models mixing partition-unique and shared parameters. The program employs MPI to parallelize Metropolis coupling on Macintosh or UNIX clusters.
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            PAML 4: phylogenetic analysis by maximum likelihood.

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            PAML, currently in version 4, is a package of programs for phylogenetic analyses of DNA and protein sequences using maximum likelihood (ML). The programs may be used to compare and test phylogenetic trees, but their main strengths lie in the rich repertoire of evolutionary models implemented, which can be used to estimate parameters in models of sequence evolution and to test interesting biological hypotheses. Uses of the programs include estimation of synonymous and nonsynonymous rates (d(N) and d(S)) between two protein-coding DNA sequences, inference of positive Darwinian selection through phylogenetic comparison of protein-coding genes, reconstruction of ancestral genes and proteins for molecular restoration studies of extinct life forms, combined analysis of heterogeneous data sets from multiple gene loci, and estimation of species divergence times incorporating uncertainties in fossil calibrations. This note discusses some of the major applications of the package, which includes example data sets to demonstrate their use. The package is written in ANSI C, and runs under Windows, Mac OSX, and UNIX systems. It is available at -- (
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                Author and article information

                Role: Editor
                PLoS Genet
                PLoS Genet
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                August 2013
                August 2013
                1 August 2013
                : 9
                : 8
                [1 ]Amphibian Evolution Lab, Biology Department, Vrije Universiteit Brussel, Brussels, Belgium
                [2 ]Venom Evolution Laboratory, School of Biological Sciences, University of Queensland, St. Lucia, Queensland, Australia
                [3 ]Department of Bioengineering Sciences, Research Group of Microbiology and VIB, Vrije Universiteit Brussel, Brussels, Belgium
                [4 ]Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
                [5 ]Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium
                [6 ]Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
                [7 ]Functional Genomics and Proteomics, Department of Biology, KU Leuven, Leuven, Belgium
                Texas A&M University, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: KR FB. Performed the experiments: KR BGF LY BS LB EC LS PC. Analyzed the data: KR PK. Contributed reagents/materials/analysis tools: KR. Wrote the paper: KR BGF LY BS LB PK EC LS PC FB.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 16
                Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO-Vlaanderen) granted postdoctoral fellowships to KR, EC, and FB and research grant G.0133.08 to KR, EC, LS, and FB. BGF receives financial support from the Australian Research Council, and FB is supported by grant OZR1621 from Vrije Universiteit Brussel and grant 204509 (project TAPAS) from the European Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Evolutionary Biology



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