Bioprospecting for Hypoxia Tolerance: Applied Genomics of the Blind Subterranean Mole Rat (Spalax)

The blind subterranean mole rat (Spalax ehrenbergi) is a model for survival under extreme environments due to its ability to survive in underground habitats under severe hypoxic stress. Adaptation to hypoxia is of great biological and medical interest with implications in development, wound healing, ischemic disease and cancer. Throughout our studies of hypoxia-tolerance we have identified a growing list of genes that have evolved structural changes and/or different expression responses following hypoxic-insult in Spalax as compared to rat. Among these, many affect heart, brain and muscle function as well as mechanisms identified for tumor survival. Early cloning and sequencing experiments showed that vascular endothelial growth factor a major neoangiogenic factor, is constitutively expressed at high levels in Spalax muscles with no increased transcription under hypoxia. Among structural changes, the binding domain of Spalax p53 harbors two amino acid substitutions identical to those identified in human tumor cells, resulting in increased activation of DNA repair elements and reduction of apoptosis.  Through transcriptome sequencing of Spalax brain and muscle tissues from animals exposed to normoxic and hypoxic environments a database of over 51,000 contigs with homology to 12,000 mammalian genes was assembled. Based on these results, it was possible to detect large numbers of splice variants, SNPs, and novel transcribed regions. In addition, multiple differential expression patterns were detected between tissues and treatments. The results presented here will serve as a valuable resource for understanding the mechanisms of adaptation to hypoxia which appear to parallel survival pathways which evolve in solid tumors.