Evolutionary Genomics and Adaptive Evolution of the Hedgehog Gene Family (<i>Shh, Ihh and Dhh</i>) in Vertebrates

<div><p>The Hedgehog (<i>Hh</i>) 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 <i>Hh</i> gene is found typically in invertebrate genomes, most vertebrates species have three (Sonic hedgehog – <i>Shh</i>; Indian hedgehog – <i>Ihh</i>; and Desert hedgehog – <i>Dhh</i>), 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 <i>Hh</i> genes in vertebrates following the two major whole genome duplication (WGD) events. To overcome the lack of <i>Hh</i>-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 <i>Hh</i> paralogs. We find suggestions that following the WGD events, vertebrate <i>Hh</i> 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 <i>Hh</i> orthologs. Our results provide new insights on the evolutionary history of the <i>Hh</i> gene family, the functional roles of these paralogs in vertebrate species, and on the location of mutational hotspots.</p>