Abstract:
The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal
exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of
their resistance to cancer and exceptional longevity has opened up new and important
avenues of research. Part of this resistance to cancer has been attributed to the fact that
NMRs produce a modified form of hyaluronan—a key constituent of the extracellular
matrix—that is thought to confer increased elasticity of the skin as an adaptation for
living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA)
stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme
(HAS2). To test whether other subterranean mammals with similar selection pressures
also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11
subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important
HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan
synthase function was uniquely shared by all African mole-rats. Interestingly, we also
identified multiple other amino acid substitutions in key domains of the HAS2 molecule,
although the biological consequences of these for hyaluronan synthesis remain to be
determined. Despite these results, we found evidence of strong purifying selection acting
on the HAS2 gene across all mammals, and the NMR remains unique in its particular
HAS2 sequence. Our results indicate that more work is needed to determine whether the
apparent cancer resistance seen in NMR is shared by other members of the African molerat
clade.
