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University of Copenhagen, Copenhagen, Denmark, Citation: Pereira J, Johnson WE, O’Brien SJ, 8 Evolutionary genomics and adaptive evolution of the hedgehog gene family (Shh, Ihh and Dhh) in vertebrates Pereira, Joana; Johnson, Warren E.; O'Brien, Stephen J.; Jarvis, Erich D; Zhang, Guojie; Gilbert, M. Thomas P.; Vasconcelos, Vitor; Antunes, Agostinho Published in: PloS one DOI: 10.1371/journal.pone.0074132 Publication date: 2014 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Pereira, J., Johnson, W. E., O'Brien, S. J., Jarvis, E. D., Zhang, G., Gilbert, M. T. P., Vasconcelos, V., & Antunes, A. (2014). Evolutionary genomics and adaptive evolution of the hedgehog gene family (Shh, Ihh and Dhh) in vertebrates. PloS one, 9(12), [e74132]. https://doi.org/10.1371/journal.pone.0074132 Download date: 24. sep.. 2021 RESEARCH ARTICLE Evolutionary Genomics and Adaptive Evolution of the Hedgehog Gene Family (Shh, Ihh and Dhh) in Vertebrates Joana Pereira1¤, Warren E. Johnson2, Stephen J. O’Brien3,4, Erich D. Jarvis5, Guojie Zhang6, M. Thomas P. Gilbert7, Vitor Vasconcelos1,8, Agostinho Antunes1,8* 1. CIIMAR/CIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Porto, Portugal, 2. Smithsonian Conservation Biology Institute, National Zoological Park, Front Royal, Virginia, United States of America, 3. Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russia, 4. Oceanographic Center, N. Ocean Drive, Nova Southeastern University, Ft. Lauderdale, Florida, United States of America, 5. Howard Hughes Medical Institute, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, United States of America, 6. BGI-Shenzhen, Beishan Industrial Zoon, Yantian District, Shenzhen, China, 7. Centre for OPEN ACCESS GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark, Citation: Pereira J, Johnson WE, O’Brien SJ, 8. Department of Biology, Faculty of Sciences, University of Porto, Porto, Portugal Jarvis ED, Zhang G, et al. (2014) Evolutionary Genomics and Adaptive Evolution of the Hedgehog *[email protected] Gene Family (Shh, Ihh and Dhh)in ¤ Current address: European Molecular Biology Laboratory (EMBL) Hamburg Outstation, c/o DESY, Vertebrates. PLoS ONE 9(12): e74132. doi:10. Hamburg, Germany 1371/journal.pone.0074132 Editor: Hector Escriva, Laboratoire Arago, France Received: March 15, 2013 Accepted: July 29, 2013 Abstract Published: December 30, 2014 The Hedgehog (Hh) gene family codes for a class of secreted proteins composed of Copyright: ß 2014 Pereira et al. This is an open- two active domains that act as signalling molecules during embryo development, access article distributed under the terms of the Creative Commons Attribution License, which namely for the development of the nervous and skeletal systems and the formation permits unrestricted use, distribution, and repro- of the testis cord. While only one Hh gene is found typically in invertebrate duction in any medium, provided the original author and source are credited. genomes, most vertebrates species have three (Sonic hedgehog – Shh; Indian Funding: Joana Pereira was funded by a BII grant hedgehog – Ihh; and Desert hedgehog – Dhh), each with different expression (CIIMAR/C2008/BII/01-25) from the Portuguese Foundation for Science and Technology (FCT). patterns and functions, which likely helped promote the increasing complexity of SJO was supported as Principal Investigator by vertebrates and their successful diversification. In this study, we used comparative Russian Ministry of Science Mega-grant no.11.G34.31.0068. Erich D. Jarvis was funded by genomic and adaptive evolutionary analyses to characterize the evolution of the Hh HHMI. Agostinho Antunes was partially supported genes in vertebrates following the two major whole genome duplication (WGD) by the European Regional Development Fund (ERDF) through the COMPETE - Operational events. To overcome the lack of Hh-coding sequences on avian publicly available Competitiveness Programme and national funds through FCT under the projects PEst-C/MAR/ databases, we used an extensive dataset of 45 avian and three non-avian reptilian LA0015/2013 and PTDC/BIA-BDE/69144/2006 genomes to show that birds have all three Hh paralogs. We find suggestions that (FCOMP-01-0124-FEDER-007065), PTDC/AAC- AMB/104983/2008 (FCOMP-01-0124-FEDER- following the WGD events, vertebrate Hh paralogous genes evolved independently 008610) and PTDC/AAC-AMB/121301/2010 within similar linkage groups and under different evolutionary rates, especially (FCOMP-01-0124-FEDER-019490). The funders had no role in study design, data collection and within the catalytic domain. The structural regions around the ion-binding site were analysis, decision to publish, or preparation of the identified to be under positive selection in the signaling domain. These findings manuscript. contrast with those observed in invertebrates, where different lineages that Competing Interests: The authors have declared that no competing interests exist. experienced gene duplication retained similar selective constraints in the Hh PLOS ONE | DOI:10.1371/journal.pone.0074132 December 30, 2014 1/35 Evolutionary Genomics of the Hedgehog Gene Family orthologs. Our results provide new insights on the evolutionary history of the Hh gene family, the functional roles of these paralogs in vertebrate species, and on the location of mutational hotspots. Introduction Cell-to-cell signaling is a process crucial to the development and survival of multicellular organisms, and is controlled by only a few signaling pathways that interact with molecules that are responsible for many of the diverse and complex functions observed in modern vertebrates [1]. Metazoans use numerous signaling proteins for cell-to-cell communication, all of which are encoded by a small number of gene families, among which the Hedgehog (Hh) signaling pathway is ‘‘one of the most enigmatic’’ [1, 2]. The Hedgehog (Hh) gene family codes for a class of secreted proteins that act as key modulators during embryogenesis and homeostasis of adult tissues in vertebrates and invertebrates [3]. Hh proteins are synthesized as pro-proteins that undergo auto-cleavage [4] and lipid modifica- tions [5, 6] in the endoplasmic reticulum (ER) to produce a mature signaling peptide [7] that leaves the cell and can be incorporated into lipoprotein particles [8] or diffuse freely to target cells [2]. This is possible because Hh proteins are composed of two distinct domains: a N-terminal ‘‘Hedge’’ domain and a C- terminal ‘‘Hog’’ domain [9], separated during an auto-cleavage reaction to generate two similar-sized globular fragments [4, 9], HhN and HhC (Fig. 1). The Hog domain is highly conserved [10] and promotes the auto-cleavage reaction and the addition of a cholesterol moiety to the signaling peptide HhN on the endoplasmic reticulum (ER) [9, 11](Fig. 1). The Hog reaction is similar to the protein-splicing activity of Inteins and requires the ‘‘Hint’’ region and a sterol recognition region. The Hint region forms the N-terminal part of the Hog domain [12] and encompasses a highly conserved glycine-cysteine-phenylalanine (GCF) motif, and the sterol recognition region (SRR) on the Hog domain C-terminal end recruits cholesterol that acts as an electron donor on the auto-cleavage reaction and becomes incorporated into the signaling HhN peptide [5]. The Hedge domain is also highly conserved [10] and, together with a signaling sequence (SS), forms the HhN peptide after cleavage [9]. Before leaving the ER and separating from the SS, the HhN peptide undergoes further palmitoylation at its N-terminal [6, 13] and leaves the cell to act as a long- and short-range signal molecule recognized by transmembrane co-receptors, including the Interference hedgehog (IHog), Brother of interference hedgehog (BOI) and their homologs [14]. These co-receptors present the signaling HhN peptide to the transmembrane receptor Patched (Ptc), subsequently activating the Ci/Gli transcription factors [15]. This signaling activity has important roles in differentiation, survival and cell cycle progression [3, 16], which links the Hedgehog signaling pathway to several congenital and hereditary diseases, including holoprosencephaly and cyclopia PLOS ONE | DOI:10.1371/journal.pone.0074132 December 30, 2014 2/35 Evolutionary Genomics of the Hedgehog Gene Family Fig. 1. Structural features of the Hh proteins. The hedgehog proteins are composed by two main domains: the Hedge (N-terminal) and Hog (C-terminal) domains. The Hedge domain forms the HhN portion of the Hh proteins (together with the signaling sequence, SS) that is separated from the rest of protein by an auto-cleavage reaction preformed by the Hog domain [4]. The Hog domain forms the HhC portion of the Hh proteins and shares similarity with self- splicing Inteins on the Hint module [22]. The auto-cleavage reaction occurs on a GCF (glycine-cysteine-phenylalanine) motif that forms the boundary between the two main parts of the Hh proteins, with the cysteine residue initiating a nucleophilic attack on the carbonyl carbon of the preceding residue, the glycine [5]. The sterol-recognition region (SRR) forms the C-terminal region of the Hog domain and binds a cholesterol moiety that acts as an electron donor on a second nucleophilic attack that results in the cleavage of the bound between the glycine and cystein residues and in the attachment of the cholesterol moiety to the glycine residue [5]. After auto-cleavage,
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