Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

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 mole-rat clade.

From humans to hydra: patterns of cancer across the tree of life

“…Faulkes et al . () found that high‐molecular‐mass hyaluronan is generated from two different mutations in the hyaluronan synthase 2 gene ( HAS2 ), one of which is shared among all African mole‐rats.…”

“…The mole‐rats of the genus Spalax , also known as blind mole‐rats, can avoid not only spontaneous tumours, but induced tumours as well (Manov et al, ). They, too, produce high‐molecular‐mass hyaluronan, but they have neither of the two mutations in the HAS2 gene previously identified as key for the production of the modified molecule, which means they may have other mechanisms of producing this molecule (Faulkes et al, ). Additionally, blind mole‐rats resist cancer by at least one other mechanism: the release of interferon‐β (IFN‐β) in the face of excessive proliferation, which then activates tumour‐suppressor pathways (Gorbunova et al, ).…”

Evolution of the β-adrenoreceptors in vertebrates

“…They also are useful in providing significant information to guide genetic experiments, especially in model species where genetic manipulations can be made. Comparative studies have taken a new perspective since the discovery that some non-model species are resistant to age related diseases (Yu et al, 2011;Edrey et al, 2012;Gorbunova et al, 2012;Manov et al, 2013;Novikov and Burda, 2013;Henning et al, 2014;Faulkes et al, 2015), and by the fact that some mammals develop pathologies in a similar way to humans (Castro-Fuentes and Socas-Pérez, 2013;Tarragon et al, 2013;Braidy et al, 2015;Inestrosa et al, 2015).…”

Evolutionary history of the reprimo tumor suppressor gene family in vertebrates with a description of a new reprimo gene lineage

“…Heterocephalus glaber, Fukomys anselli, Spalax sp.) are resistant to the aging processes and age-related diseases, such as cancer (Yu et al, 2011;Edrey et al, 2012;Gorbunova et al, 2012;Manov et al, 2013;Novikov and Burda, 2013;Henning et al, 2014;Faulkes et al, 2015), or the finding that some wild animals (e.g. Octodon degus) develop pathologies (such as Alzheimer and diabetes) in a similar way as humans (Castro-Fuentes and Socas-Pérez, 2013;Tarragon et al, 2013;Braidy et al, 2015;Inestrosa et al, 2015), making them promising biomedical models.…”