Specifically, a number of hypotheses have been proposed to explain the variation in testicular position among mammals, although none fully explains the observed variation. For example, the ascrotal testis is accompanied with streamlined body shape in many aquatic taxa (e.g., true seals, cetaceans and manatees). These findings provide general insights into cryptorchidism and have implications for health and infertility both in humans and domestic mammals.įrom an adaptive evolution perspective, the diverse testicular positions in different groups of mammals benefits the adaptation to their unique environments and lifestyles. Further, we identified cancer resistance and DNA repair as potential protective mechanisms in natural cryptorchids. Our results revealed that alterations in gubernaculum development contributed to the evolution of testicular position in mammals and provided the first support for two hypotheses for variation in testicular position in mammals, the “cooling hypothesis”, which proposes that the scrotum provides a cool environment for acutely heat-sensitive sperm and the “training hypothesis”, which proposes that the scrotum develops the sperm by exposing them to an exterior environment. Genes associated with testicular position were significantly enriched in functions and pathways related to cancer, DNA repair, DNA replication, and autophagy. These genes showed rapid evolution and the signature of positive selection, with specific substitutions in ascrotal mammals. Moreover, genes related to testicular position were significantly associated with spermatogenesis and sperm fertility. In the present study, comparative genomics and evolutionary analyses revealed that genes associated with the extracellular matrix and muscle, contributing to the development of the gubernaculum, were involved in the evolution of testicular position in mammals. However, the evolution of testicular position and the molecular mechanisms underlying the maintenance of health, including reproductive health, in ascrotal mammals are not clear. Although cryptorchidism is hazardous to human health, some mammalian taxa are natural cryptorchids. We anticipated THANATOS can be a useful resource for further studies.Mammals have wide variations in testicular position, with scrotal testes in some species and ascrotal testes in others. In addition, we observed multiple types of PTM regulators such as protein kinases and ubiquitin E3 ligases or adaptors were significantly associated with human autophagy, and again the results emphasized the importance of PTM regulations in autophagy. In total, we mapped 65,015 known sites of 11 types of PTMs to collected proteins, and revealed that all types of PTM substrates were enriched in human autophagy. By reconstructing a human kinase-substrate phosphorylation network for ATG proteins, our results confirmed that phosphorylation play a critical role in regulating autophagy. Further analyses revealed that known cancer genes and drug targets were overrepresented in human autophagy proteins, which were significantly associated in a number of signaling pathways and human diseases. We performed an evolutionary analysis of ATG genes, and observed that ATGs required for the autophagosome formation are highly conserved across eukaryotes. Then we computationally identified potential orthologs of known proteins, and developed a comprehensive database of The Autophagy, Necrosis, ApopTosis OrchestratorS (THANATOS, ), containing 191,543 proteins potentially associated with autophagy cell death pathways in 164 eukaryotes. In this work, we collected 4,237 experimentally identified proteins regulated in autophagy and cell death pathways from the literature. Besides ATG proteins, numerous regulators together with various post-translational modifications (PTMs) are also involved in autophagy. Macroautophagy/autophagy is a highly conserved process for degrading cytoplasmic contents, determines cell survival or death, and regulates the cellular homeostasis.
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