A better model of type 2 diabetes

Researchers have assembled the first reference genome of the Nile rat, a genetic template
for the species that can be used in laboratory and clinical studies.
Huishi Toh, a researcher at the University of California, Santa Barbara, said they hope the study will be useful
to those studying type 2 diabetes and neurological disorders linked to circadian rhythm disturbances.
Nile rats are susceptible to diet-induced diabetes and exhibit a pronounced diurnal pattern, which is uncommon
in rodents.

Toh, an assistant project scientist in the lab of cell biologist Dennis Clegg, who continues the work she began in the lab of UCSB professor emeritus of biology at UCSB, Dr.
Jamie Thomson, said: "It was a risk, and it took a long time
.
" "But when you assemble a new genome, you have to be aware of all sorts of sequencing errors
.
" Toh is the first author
of a paper published in BMC Biology.

"Highly complete genome" model organisms are one of our best assistants in understanding some of the more complex diseases, and one of the reasons people choose them is their similarity to humans in some physiological or genetic aspects
.
Such examples are house mice and brown rats, which are used to study the underlying genetics
of some human diseases.

But it's not a one-size-fits-all scenario, especially in the case of type 2 diabetes, which currently affects more than 35 million people in the United States
.
While researchers have been using common laboratory mice and rats to improve our understanding of the disease, tracking the development of diet-induced diabetes and its complications in more typical rodent models has not yielded much rewards
.

"One of the main problems with modeling type 2 diabetes is that lab rats and mice are not particularly susceptible to diet-induced diabetes
," Toh said.
"Obesity-induced mice are actually models of prediabetes and often require genetic or chemical manipulation to propel these traditional rodents to develop diabetes and its complications, and therefore cannot mimic the natural progression of
type 2 diabetes in humans.
"

However, over the past few decades, the Nile rat has become a potential model for
type 2 diabetes.
Hailing from the grasslands of sub-Saharan Africa, these rodents feed on high-fiber, low-carbohydrate food, unlike their urban-living cousins, who may have adapted to a high-carbohydrate diet
more like humans.
It was found that laboratory food was high-calorie for Nile rats, who spontaneously developed diet-induced diabetes
just like humans.

Previously, Thomson Laboratory demonstrated that Nile rats may develop diabetic retinopathy, whose main characteristics are similar to those of humans, but not in other rodent models, thus cementing Nile rats' position
as well-developed models of type 2 diabetes.
What's missing is a reference genome, a genetic sequence that represents the animal as a whole and can serve as a litmus test or starting point for finding genetic variants that may indicate susceptibility to certain diseases and other gene-related conditions
.
In collaboration with the Vertebrate Genome Project, the Morgan Ridge Institute, and the University of Southern California, international researchers collaborated to assemble a "highly complete and highly continuous" genome
.

When comparing the genome of Nile rats to that of laboratory mice, they noticed that Nile rats had fewer copies of a gene encoding the carbohydrate-processing enzyme amylase, which may reflect a lack of adaptability to a high-starch diet
.

"We think it makes sense that Nile rats are not adapted to eating high-carbohydrate foods because they usually graze
in Africa," Toh said.
"I think that's why
they're so prone to diabetes.
" Instead, lab mice — who have lived near and around humans — have more copies of this gene, a sign of
evolution for their adaptation to their environment.

In fact, Toh says, one of the benefits of having a reference genome is that it can witness the genetic consequences
of environmental impacts.
"Currently, we are using this reference genome to study the transcriptome changes associated with diet-induced initial development of diabetes," she said, "and we hope to eventually look at epigenetics
as well.
" ”

This research was supported by the Garland Initiative for Vision and funded
by the William K.
Bowes Jr.
Foundation.