Abstract
The Hedgehog (Hh) gene family codes for a class of secreted proteins composed of two active domains that act as signalling molecules during embryo development, namely for the development of the nervous and skeletal systems and the formation of the testis cord. While only one Hh gene is found typically in invertebrate genomes, most vertebrates species have three (Sonic hedgehog – Shh; Indian hedgehog – Ihh; and Desert hedgehog – Dhh), each with different expression patterns and functions, which likely helped promote the increasing complexity of vertebrates and their successful diversification. In this study, we used comparative genomic and adaptive evolutionary analyses to characterize the evolution of the Hh genes in vertebrates following the two major whole genome duplication (WGD) events. To overcome the lack of Hh-coding sequences on avian publicly available databases, we used an extensive dataset of 45 avian and three non-avian reptilian genomes to show that birds have all three Hh paralogs. We find suggestions that following the WGD events, vertebrate Hh paralogous genes evolved independently within similar linkage groups and under different evolutionary rates, especially within the catalytic domain. The structural regions around the ion-binding site were identified to be under positive selection in the signaling domain. These findings contrast with those observed in invertebrates, where different lineages that experienced gene duplication retained similar selective constraints in the Hh 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.
Highlights
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]
To evaluate why the Dhh paralog is missing in the current publically available avian genomic databases, we determined the synteny of the Dhh gene in the genomes of several species that represent major groups of vertebrates using the GENOMICUS v64.01 database browser [37] and 45 avian and three non-avian reptilian species provided by the BGI-G10K avian Phylogenomics Project (Zhang et al.; Jarvis et al manuscripts in preparation) (Fig. 2)
We observed that the Dhh gene formed a conserved linkage group with the LMBR1L, RHEBL1 and MLL2 genes in all the tetrapods in the database
Summary
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]. 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 doi:10.1371/journal.pone.0074132.g001
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