Genome sequencing reveals insights into physiology and longevity of the naked mole rat

Abstract

The naked mole rat (Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal. Although it is the size of a mouse, its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed ageing, they are resistant to both spontaneous cancer and experimentally induced tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing, cancer and redox homeostasis. Although characterized by significant oxidative stress, the naked mole rat proteome does not show age-related susceptibility to oxidative damage or increased ubiquitination. Naked mole rats naturally reside in large colonies with a single breeding female, the 'queen', who suppresses the sexual maturity of her subordinates. They also live in full darkness, at low oxygen and high carbon dioxide concentrations, and are unable to sustain thermogenesis nor feel certain types of pain. Here we report the sequencing and analysis of the naked mole rat genome, which reveals unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness and insensitivity to low oxygen, and altered visual function, circadian rythms and taste sensing. This information provides insights into the naked mole rat's exceptional longevity and ability to live in hostile conditions, in the dark and at low oxygen. The extreme traits of the naked mole rat, together with the reported genome and transcriptome information, offer opportunities for understanding ageing and advancing other areas of biological and biomedical research.

Figure 1. Relationship of NMR to other mammals

a, Estimation of the time of divergence of NMR and 6 other mammals based on orthology relationship. Distances are shown in millions of years. b, Expansion and contraction in gene families. Numbers designate genes gained and lost since the split from the common ancestor.

Figure 2. Common and unique NMR gene families

This Venn diagram shows unique and overlapping gene families in NMR (H. gla), rat (R. nor), mouse (M. mus) and human (H. sap).

Figure 3. Unique changes in UCP1 and their roles in thermoregulation

a, Alignment of mammalian UCP1 sequences. Amino acids unique to NMR are highlighted in red, and conserved motifs in blue. b, Topology of UCP1. Regions affected in NMR are highlighted. c, Structural model of UCP1. Location of the channel and the nucleotide-binding loop with altered sequences in NMR are shown.