Enhanced Negative Regulation of the DHH Signaling Pathway as a Potential Mechanism of Ascrotal Testes in Laurasiatherians

Unsuccessful descent of testes in humans and other scrotal mammals can result in cryptorchidism, consequent abnormalities and a high risk of malignancy. However, many male adult mammals possessing natural ascrotal testes are as viable and healthy as other scrotal mammals. This study performed an evolutionary analysis on the desert hedgehog (DHH) signaling pathway, an important regulator for testicular development, mainly in laurasiatherians. Significant positive selection, accelerated evolutionary rates, and specific amino acid substitutions were identified in ascrotal species, some of which caused radical changes in physicochemical and biological properties. Considering that most signs of positive selection were identified in genes responsible for or related to negative regulation, we suggest that the enhanced negative regulation of the DHH signaling pathway drives, at least in part, the evolution of ascrotal testes in laurasiatherians and other mammals. This study could provide some novel insights into the evolution of natural healthy ‘cryptorchidism’ in mammals and into the convergent molecular evolution of the complex trait.