The naked mole rat (Heterocephalus glaber) is a subterranean-dwelling rodent native to East Africa. This organism is often subject to research due to its many unique characteristics, over 90% of its genome has been sequenced along with its mitochondrial genome (Kim et. al. 2012). Its lifespan of over thirty years and abnormal phenotype has resulted in researchers sequencing the genome in order to find the underlying genes behind these features. Naked mole rats experience minimal biological aging, cancer resistance, adaptive circulatory functions, and many other defining characteristics.
The naked mole rat’s genome is most often compared to that of mice, humans, and other rodents which allowed multiple synteny blocks to be identified in the genomes of these organisms. However, since the split from their most common ancestor over 73 million years ago, there has been a low rate of genome rearrangement. The phylogeny of these organisms can be found in figure 1a. Also, studies over time have revealed a moderate growth and shrinkage of specific gene families. Of the genes gained, 75.5% were able to be transcribed and many of the genes lost were converted for other specific functions. The changes in gene families of the naked mole rat and other organisms are shown in figures 1b and 2. (Kim et. al. 2012). Although the genome of the naked mole rat was sequenced, researchers have put more emphasis on studying the specific genes that encode the abnormal phenotype and its comparison to those of similar organisms.
Cancer resistance in naked mole rats is perhaps the most profound characteristic seen in this organism. Numerous studies revealed different ways in which the naked mole rat expresses its resistance. Kim, et. al., studied the products of the CYP46A1 and SMAD3 genes. These genes are responsible for cholesterol mediation and the rate of cell proliferation. The products act by slowing down the rate of cell proliferation which helps to protect from cancer by keeping a balance between cell divisions and cell deaths (2012). The CYP46A1 and SMAD3 genes were found to have elevated expression in the naked mole rat brain over time, whereas the opposite was found in humans. Tian, et. al., studied the cancer resistance as a result of high-molecular-mass hyaluronan (HMM-HA) and early contact inhibition. HMM-HA represses mitogenic signaling and is an anti-inflammatory agent. Its effects are the opposite of low-molecular-mass HA (LMM-HA) which is seen in mice and guinea pigs. The effects of HMM-HA aids in cancer resistance because the repression of mitogenic signaling prevents cell growth similar to early contact inhibition (ECI). ECI stops cell growth when a cell makes contact with another cell. This mechanism is not found in cancerous cells, but in naked mole rats, ECI occurs at a much lower density than those of mouse cells, resulting in an enhanced resistance of cancer (2013). The HMM-HA was found to be the extracellular signal of ECI and as stated before, the naked mole rat secretes HMM-HA rather than LMM-HA (Keane et.al. 2014). Cancer resistance is one of a few natural phenomena that is seen in the naked mole rat.
Another interesting feature of the naked mole rat genome is its longevity compared to other rodents. While it may live for over thirty years, a mouse of the same size only has the life expectancy of around four years. Researchers were interested to find the genetic reasoning behind the senescence of naked mole rats. Sequenced data from RNA was used from varying ages of naked mole rats and compared to that of other mammals. Unlike other animals, the naked mole rat had few genes that exhibited varying expression throughout different periods of life. In fact, of fifty-three differentially expressed genes found in humans, thirty of the same genes in naked mole rats had stable expression and two had the opposite change in expression (Kim et. al. 2012). Such results have led to questions over whether or not naked mole rats have different regulatory mechanisms. Furthermore, the genes GSTA1, DERL1, and GNS, all contributors to the degradation of macromolecules, did not have enhanced expression with age. Similarly, the genes NDUFB11, ATP5G3, and UQCRQ which encode mitochondrial proteins were still expressed consistently throughout life, resulting in healthy mitochondrial function at all ages (Kim et. al. 2012). Specific analyses of genes have helped to identify why naked mole rats have such long life-spans compared to those of its relatives.
Due to its subterranean habitat, the naked mole rat exhibits unique adaptations in order to increase its chances of survival. While its genes for melatonin synthesis, which is affected by light presence, were present, the expression was very low in comparison to other mammals. It was found that the receptors MTNR1A and MTNR1B were inactivated by stop codons. Therefore, the naked mole rat maintained circadian rhythms through other processes when exposed to brief light changes (Kim et. al. 2012). The gene UCP1 which is crucial for thermogenesis in mammals is changed for naked mole rats as well. In the regulatory site, Arg-Trp replaces Gly-Pro which results in structural and functional changes in this gene that prevents thermogenesis from being sustained (Kim et. al. 2012). Living underground, naked mole rats are exposed to extremely low oxygen levels and high carbon dioxide levels. Due to this, they have adapted and developed metabolic functions that reduce metabolic rate and development. The naked mole rat has a different affinity for hemoglobin oxygen than land-dwelling organisms, which enhances their survival in their low oxygen environment (Kim et. al. 2012). Lastly, also acting as an adaptation, the naked mole rate has deficiencies in its eyesight. Mice, rats, and guinea pigs all have four opsin genes (RHO, OPN1LW, OPN1MW, and OPN1SW). Living in a primarily dark habitat without the need for much visual function, naked mole rats only have the RHO and OPN1SW genes, resulting in poor eyesight. Also, of the 200 genes in humans and mice that are responsible for visual perception, about ten percent are either inactivated or lost in naked mole rats. Furthermore, abnormal eye size is seen as well, which is due to the result of the inactivation of the CRYBA4 gene (Kim et. al. 2012). Numerous factors play into the poor visual function in naked mole rats, much of which has to do with the inactivation or loss of specific visual genes.
Naked mole rats are researched in depth due to their many unique phenotypic characteristics. Researchers have been studying these specific features that are seen in this organism in order to see if there is a way for implementation of similar functions and processes into other organisms. The longevity and lack of biological aging, cancer resistance, and genetic accommodations to an extreme environment are all features found within the naked mole rat genome that provide many opportunities for research and open up many questions. Much of what is studied in this genome could provide answers to and contribute to solving the current challenges in medicine and science as a whole.