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Why is the Fat Sand Rat Diabetes-Prone? New Research Reveals Mechanisms

July 4 , 2017
Why is the Fat Sand Rat Diabetes-Prone? New Research Elucidates the Truth

Researchers published their discoveries in PNAS concerning the genome of psammomys obesus, or fat sand rat as it is commonly known. From Oxford University, CNGB, and Novo Nordisk, scientists teamed up to undertake research studying the genome of the fat sand rat, analyze its genome, and try to identify the genetic mechanisms contributing to the development of diabetes.

The fat sand rat derives from the gerbil subfamily and has been shown to be a unique animal model for studying type two diabetes (T2D). Mostly found in barren deserts, the rat adapts to the acute shortage of water and food at the expense of its sugar metabolism capacity. Obesity develops in these rats when they are fed with sugar-rich food, alongside symptoms of type two diabetes, which can result in pancreatic failure and death in some cases. PDX1 is a transcription factor present in pancreatic cells that regulates insulin production and function. PDX1 has not yet been identified in the fat sand rat or other members of the gerbil subfamily, although it has been found in the Cairo spiny mouse (acomys cahirinus), identified as the closest subfamily. Therefore, researchers postulated that the gerbil subfamily may have lost the PDX1 during evolution and have thus become vulnerable to acquiring T2D. Further research contradicts this claim and hypothesizes the possibility of losing PDX1 due to its role in pancreatic development during embryogenesis. Accordingly, it is thought that the absence of PDX1 in rats could cause death from underdevelopment of the pancreas.

To elucidate the mechanisms of acquiring diabetes in the Fat Sand Rat, scientists undertook RNA sequencing of liver, pancreatic and duodenal tissues to identify important gene sequences. Of note, their research showed that there was a loss of PDX1, as well as 88 neighboring gene sequences in the initial gnomon. Subsequently, they identified homologous sequences in RNA and observed high amounts of GC nucleotides, suggesting a possible reason behind the loss of PDX1 in the fat sand rat. Researchers isolated the genome area high in GC and re-constructed the genome using MiSeq sequencing. Using this data, the PDX1 gene locus and its neighboring genes were identified.

Comparing 60 amino acids from the PDX1 gene locus in the rat with other vertebrates revealed evolutionary changes in PDX1 resulting in 15 unique amino acid points and several missing sequences. The protein disulfide isomerase (PDI) shows similar overall gene sequences of fat sand rat is with humans and mouse, although it was observed that PDX1is dissimilar. Among the top ten gene sequences by PDI, seven are located in the GC hot spot, implying mutation of GC may influence coding and sequencing within this area. It is hypothesized that such mutations contribute to the high level of GC nucleotides that are found within the PDX1 gene locus in the fat sand rat, thus influencing insulin production and pancreatic gene transcription. Further research has shown that mutations can promote sugar metabolism efficiency in the fat sand rat and its wider gerbil subfamily. Ultimately, this research explains why the fat sand rat can easily acquire diabetes when fed calorie-intensive food.

Further reading
Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster