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Tupaia (Tupaia belangeri) is a small mammal belonging to the family Tupaiidae, which consists of four genera and 19 extant species. The members of the genus Tupaia, which are colloquially referred to as the tree shrews, were first recorded in a sketch by William Ellis on a voyage with Captain Cook in 1780. Tree shrews are similar in appearance to squirrels, and their body weight ranges between 120-200 g. The natural habitat of the tree shrews consists of the tropical rainforests in South East Asia, where they feed on fruits, insects, and small vertebrates.

The similarities in the brain anatomy of tree shrews and primates were first reported by Le Gros Clark in the 1920s. However, recent molecular studies have separated the tupaias from the primates, and placed them in the order Scandentia and grandorder Euarchonta that also contains the primates and the animals belonging to the order Dermoptera. Evolutionary characterization of the 7S RNA-derived short interspersed elements (SINEs) revealed that 7S RNA is a component of the cytoplasmic signal recognition particle found in primates, tupaia, and rodents, i.e. it is found in all the members of the placental mammalian order Supraprimates and the superorder Euarchontoglires. The fossil Alu monomer was previously considered to be the oldest common ancestor of all the 7S RNA-derived SINEs, and was thought to be restricted to the primates. Tupaia possesses specific, chimeric Tu-type II SINEs, which may share a common ancestry with the rodent B1 SINEs (1). Phylogenetic analysis of the 7SL RNA-derived SINEs has shown that tupaias can be grouped with the primates and the dermopterans under the grandorder Euarchonta, while animals in the orders Rodentia and Lagomorpha can be grouped under the clade Glires.

Whole-genome analysis involving several groups revealed a genetic relationship between the tupaias and humans (2,3). Similarly, phylogenetic analysis based on whole genome sequences showed that humans are closer to the tupaias than they are to mice.

Tupaias have also been used in studies on viral infection, especially with hepatitis B virus and hepatitis C virus (HCV) (4-7). Chimpanzee is the only existing naturally occurring animal model for studies on human infections with these viruses. However, because chimpanzees are long-lived (>50 years), very expensive, and subject to stringent animal welfare regulations, development of an alternate natural infection model is crucial for the development of vaccine and therapeutic strategies. HCV can successfully establish infection in the humanized chimeric mice liver (8), but these liver cells lack immune response; therefore, the pathogenicity of HCV could not be characterized using humanized chimeric mice liver cells .

The high degree of genetic homology between several neuromodulator receptor proteins in tree shrews and primates enabled the extensive utilization of Tupaia in preclinical research, particularly in the areas of toxicology and virology. Although adult male tupaias exhibit strong territoriality in their natural habitat, the coexistence of two males in visual and olfactory contact in the laboratory leads to the establishment of a stable dominant-subordinate relationship, with the subordinates showing distinct stress-induced alterations in their behavior, physiology, and central nervous system activity. These alterations exhibited by the subordinate male tupaias are similar to those observed in depressed human patients, and can be used in preclinical research on antidepressant drugs (9). Various aspects of human behavior, infant development, communication, and social structure can also potentially be studied using tupaias.

Taken together, the tupaia shows high potential as an animal model, and this tupaia genome database constructed using both the whole genome and comprehensive RNA sequencing is expected to contribute towards the development of a tupaia animal model.

References

  1. Kriegs, J.O., et al. 2007. Evolutionary history of 7SL RNA-derived SINEs in Supraprimates. Trends Genet 23: 158-61.
  2. Fan, Y., et al., 2013. Genome of the Chinese tree shrew. Nat Commun 4: 1426.
  3. Tsukiyama-Kohara K, Kohara M. 2014. Tupaia belangeri as an experimental animal model for viral infection. Experimental Animal Oct 30; 63(4):367-74..
  4. Amako Y. et al., 2010. Pathogenesis of hepatitis C virus infection in Tupaia belangeri. J. Virology 84(1):303-311. Selected in “Spot light”
  5. Sanada T., et al., 2016. Property of hepatitis B virus replication in Tupaia belangeri hepatocytes. Biochem Biophys Res Commun. Jan8;469(2):229-235.
  6. Kayesh MEH et al., 2017. Interferon-β response is impaired by hepatitis B virus infection in Tupaia belangeri. Virus Res. Jun 2;237:47-57.
  7. Kayesh MEH et al., 2017. Oxidative stress and immune responses during Hepatitis C virus infection in Tupaia belangeri. Scientific Reports Aug 29;7(1):9848.
  8. Mercer DF, et al. 2001. Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7: 927–933.
  9. Hai-Ying C, et al. Establishment of an intermittent cold stress model using Tupaia belangeri and evaluation of compound C737 targeting neuron-restrictive silencer factor. Exp Anim. Jul 29;65(3):285-292, 2016.