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Characterization of the Antimicrobial Peptide Family Defensins In View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Sydney eScholarship Immunogenetics (2017) 69:133–143 DOI 10.1007/s00251-016-0959-1 ORIGINAL ARTICLE Characterization of the antimicrobial peptide family defensins in the Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos cinereus), and tammar wallaby (Macropus eugenii) Elizabeth A. Jones1 & Yuanyuan Cheng1 & Denis O’Meally1,2 & Katherine Belov1 Received: 19 August 2016 /Accepted: 5 November 2016 /Published online: 12 November 2016 # Springer-Verlag Berlin Heidelberg 2016 Abstract Defensins comprise a family of cysteine-rich anti- Keywords Tasmanian devil . Koala . Tammar wallaby . microbial peptides with important roles in innate and adaptive Defensin . Evolution immune defense in vertebrates. We characterized alpha and beta defensin genes in three Australian marsupials: the Tasmanian devil (Sarcophilus harrisii), koala (Phascolarctos Introduction cinereus), and tammar wallaby (Macropus eugenii) and iden- tified 48, 34, and 39 defensins, respectively. One hundred and Defensins are a family of cysteine-rich polypeptides that play twelve have the classical antimicrobial peptides characteristics critical roles in innate and adaptive immune defense (Yang et al. required for pathogen membrane targeting, including cationic 1999) in vertebrates (Lehrer and Ganz 2002;Ganz2004), in- charge (between 1+ and 15+) and a high proportion of hydro- vertebrates (Hoffmann and Hetru 1992;LehrerandGanz1999; phobic residues (>30%). Phylogenetic analysis shows that de la Vega and Possani 2005), and plants (Broekaert et al. gene duplication has driven unique and species-specific ex- 1995). These include defense against bacterial (Lehrer et al. pansions of devil, koala, and tammar wallaby beta defensins 1989; Schibli et al. 2002), fungal (Edgerton et al. 2000;Feng and devil alpha defensins. Defensin genes are arranged in et al. 2005) and viral pathogens (Daher et al. 1986), immuno- three genomic clusters in marsupials, whereas further duplica- modulatory functions (Bowdish et al. 2006;Grigatetal.2007; tions and translocations have occurred in eutherians resulting Steinstraesser et al. 2011), roles in reproduction and fertility in four and five gene clusters in mice and humans, respective- (Zhou et al. 2004; Patil et al. 2005; Narciandi et al. 2011; ly. Marsupial defensins are generally under purifying selec- Tollner et al. 2011), and natural flora control (Salzman et al. tion, particularly residues essential for defensin structural sta- 2007). Defensin characterization is critical in defining a species’ bility. Certain hydrophobic or positively charged sites, pre- host-defense peptide repertoire and understanding its immune dominantly found in the defensin loop, are positively selected, system. Defensins are also ideal for studying adaptive molecu- which may have functional significance in defensin-target in- lar evolution because of their intrinsic link with rapidly evolv- teraction and membrane insertion. ing pathogens (Hughes 1999;Sempleetal.2003; Tennessen 2005; Cheng et al. 2015). The antimicrobial affinity of defensins makes them promising templates for future classes Electronic supplementary material The online version of this article of novel antibiotics and in vivo gene therapy (Huang et al. (doi:10.1007/s00251-016-0959-1) contains supplementary material, 2002; Thevissen et al. 2007;Eastonetal.2009), which are which is available to authorized users. urgently required to combat multidrug-resistant pathogens. α β * Katherine Belov Three defensin subfamilies, alpha ( ), beta ( ), and theta [email protected] (θ), have been described in mammals, with alpha and beta genes found in all lineages (Ganz 2004). Defensins typically 1 Faculty of Veterinary Science, School of Life and Environmental consist of a conserved signal sequence and a propeptide se- Sciences, University of Sydney, Camperdown, NSW 2006, Australia quence encoded by the first one to two exons, and a mature 2 Centre for Animal Health Innovation, University of the Sunshine peptide domain encoded by the terminal exon (Ouellette and Coast, Sippy Downs, QLD 4556, Australia Selsted 1996;Ghoshetal.2002). They are initially synthesized 134 Immunogenetics (2017) 69:133–143 as precursor molecules which are post translationally processed defensin sequences were used to create the initial HMMs, to form an active mature peptide (Valore and Ganz 1992). whichwerethenupdatedtoincludenovelAustralianmarsupial Intramolecular disulfide bridges form between three cysteine defensin sequences with HMMER searches repeated. All pairs in mature peptides, defining the subfamilies: disulfide HMMER searches were performed on a six frame translation bond bridge cysteines 1–6, 2–4, and 3–5 in alpha defensins of each marsupial genome. Based on previously defined and cysteines 1–5, 2–4, and 3–6inbetadefensins(Ganzetal. defensin intron lengths (Patil et al. 2005), signal sequences 1985; Selsted et al. 1985). within 15 Kbp upstream of a mature peptide motif were pre- The gray short-tailed opossum (Monodelphis domestica)is dicted to be the matching signal sequence. Defensins were the only marsupial in which defensins have been characterized named sequentially as they were identified using an abbreviated (Belov et al. 2007). Australian marsupials diverged from species name, a subfamily suffix, and a gene number. American marsupials 80 million years ago (MYA) (Meredith et al. 2008). The Tasmanian devil (Sarcophilus harrisii), koala Phylogenetic analysis (Phascolarctos cinereus), and tammar wallaby (Macropus eugenii) last shared a common ancestor 60 MYA,representing Alpha and beta defensin peptide sequences were each aligned three distinct lineages within the Australasian radiation using CLUSTALW. A beta defensin tree was constructed (Phillips et al. 2006;Meredithetal.2008). The Tasmanian using 41 devil, 32 koala, 36 wallaby, 46 opossum, 36 human, devil and koala have both been severely affected by conta- and 46 mouse sequences, and the alpha defensin tree consisted gious diseases in recent years (McCallum et al. 2007; of seven devil, two koala, three wallaby, two opossum, five Rhodes et al. 2011). The devil faces extinction due to devil human, six chimpanzee, 13 mouse, and 11 rat sequences facial tumor disease (Lachish et al. 2007), while the koala (Supplementary Tables 2 & 3). Phylogenetic trees were con- faces an ongoing battle with chlamydiosis and the koala ret- structed using the neighbor-joining method based on p- rovirus (KoRV) (Polkinghorne et al. 2013). Characterization distance of aligned amino acids in MEGA 5 (Tamura et al. of defensins in these species is the first step in defining their 2011). A thousand bootstrap replicates were used to test phy- role in host health and will inform our understanding of the logeny reliability (Felsenstein 1985). evolution of this important peptide family. Here, we decribe alpha and beta defensins in the Tasmanian devil, tammar wal- Synteny analysis laby, and koala and discuss their evolution. Synteny groups were based on genomic organization and phy- logenetic analysis of orthologs between species. The Methods ENSEMBL genome browser (Release 84) (Cunningham et al. 2015) was used to determine the position and orientation Computational search for defensin genes of human and mouse defensin genes according to the latest human (Genbank assembly ID GCA_000001405.20 released Known opossum, platypus, human, and mouse defensin se- 2014) and mouse (GenBank Assembly ID GCA_000 quences were used to perform BLASTN and BLASTP 001635.6 released 2012) genome assemblies. Human and (Altschul et al. 1997) searches against the devil (Murchison mouse defensin cluster flanking genes were used as query et al. 2012), tammar wallaby (Renfree et al. 2011), and koala sequences to BLAST the Tasmanian devil, koala, wallaby, (KGC, unpublished data) genomes. For evidence of transcrip- and opossum genomes to determine their location and orien- tion and to refine genome annotations, BLASTP and tation (Supplementary Table 2). Wallaby was excluded from TBLASTN searches were performed on published tran- synteny analysis due to the fragmented nature of the genome scriptome data from devil (Murchison et al. 2012) assembly. (Hewavisenti et al. 2016), tammar wallaby (Wong et al. 2011), and koala (Hobbs et al. 2014) (Supplementary Selection tests Table 1). Significant BLAST hits (e-value <10−5; identity over 60%) were retrieved and aligned with CLUSTALW The data monkey web server (Pond and Frost 2005a; Delport (Thompson et al. 1994) and examined for the defensin cysteine et al. 2010) was used to assess individual residues under pos- motif or the conserved signal sequence in Bioedit 7.0.0 (Hall itive and negative selection. Fixed Effect Likelihood (FEL) 1999). Novel defensin sequences were then used as the query (Pond and Frost 2005b) and Fast Unconstrained Bayesian sequences for additional BLASTN and BLASTP searches. Approximation for Inferring Selection (FUBAR) (Murrell Seven hidden Markov models (HMMs) were generated using et al. 2013) were used to detect both negatively and positively HMMER 3.0 (Finn et al. 2011): four targeted the six cysteine selected sites. Mixed Effects Models of Evolution (MEME) mature peptide motif and three targeted the first exon signal (Murrell et al. 2012) was also used to test positively selected sequence. Representative opossum, human, mouse, and dog sites. Significance value for FEL and MEME were set at Immunogenetics (2017) 69:133–143 135 p < 0.05, and posterior probability
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