Assembly of the high-quality reference genome of the Nile rat facilitates diabetes research

Model organisms are essential to biomedical research and have made possible many important scientific discoveries. The ability to sequence the genomes of these models is a powerful tool for studying genetic factors that affect human health.

house mouse (Musculoskeletal Muscles) and the norwegian rat (norwegian rat) are widely used in research because of their genetic similarity to humans. But there are other rodents rising through the ranks -; Arvicanthis niloticusNile rat.

New research published today in BMC Biology It provides a high-quality reference genome assembly of the Nile mouse, expanding its potential as an in vivo model.

We need research tools that enable us to do the same things with Nile rats that we used to do with lab mice. Obtaining the reference genome is progress toward that goal.”

Yuri Buchmann, a computational biologist with the Stewart Computational Biology Group in Morgridge and senior author on the project

In particular, the Nile rat serves as an alternative model in two research areas where there are limitations for laboratory mice and rats-; Type 2 diabetes and disorders associated with a disrupted circadian rhythm.

Mice and rats are nocturnal animals, so they are of less value in modeling human daily cycles. In addition, they can develop pre-diabetes symptoms with a high-fat diet but rarely develop long-term complications of diabetes like humans with the disease.

“You can alter their genes, give them too much fat, or use chemicals to speed up the process,” says the first author. “But there are a lot of additional confounding factors that drive the animal model to get what you want.” Huishi Toh, an assistant project scientist at the University of California, Santa Barbara, has worked with Jimmy Thompson, director emeritus of Regenerative Biology at Morgridge and a professor at UCSB.

The Nile rat is diurnal, and is active during the day like humans. However, it also has more photoreceptors in its eye than in nocturnal rodents, which makes it suitable for studying human retinal diseases -; Including diabetic retinopathy.

“There is still room for a lot of discoveries in type 2 diabetes, with questions that are difficult to answer,” Toh says. “That’s why we thought maybe it was time to risk a new animal model.” “Does that mean it’s more accurate or can you substitute other models? No, of course not. But you can find different information that can also be useful.”

Another benefit of the Nile mouse is that it acts as a mating model, which means that its genetics reflect a diverse population. Several strains of laboratory mice have been bred for generations, resulting in nearly genetically identical stable populations. This is useful for reducing experimental variance but less useful when studying complex genetic factors that contribute to disease.

“We also know that epigenetics is really important — the environment intersects with the genetic components — so we have to study both. That’s why we need a high-quality genome to allow the ability to do that,” Toh says.

The Nile rat genome is the product of an intense international collaboration involving the Vertebrate Genome Project, a consortium of researchers that aims to assemble reference-quality genomes of all vertebrate species.

The technology for producing highly accurate whole genome sequencing is relatively new. Typically, for a large genome sequence, the DNA sequences must be cut into shorter lengths, between 100-300 nucleotides, and then reassembled into longer contiguous sequences (contigs). But this approach tends to leave a lot of gaps.

“An important measure of genome quality is what is the average length of a contig. Essentially, the longer it is, the fewer gaps you have,” Buchmann says. “Our country is one of the longest.”

The research team applied long read sequencing technology to assemble longer constituents of reads ranging in length from 10,000 to 20,000 nucleotides. They also used multiple techniques to attach contigs into scaffolding that span the length of the chromosome. Finally, they can completely undo two copies of the genome – ; Who inherited the serial from his mother and the other from his father.

“These technologies are developing very quickly,” Buchmann says. “I think the holy grail would just be the ability to arrange an entire chromosome and do it precisely. However, that hasn’t happened yet.”

Another measure is to consider the completeness of the genome. The team analyzed the sequences of indigo mice through a database called BUSCO (Global Single Copy Orthologue Standards Measurement), which provides a set of genes commonly found in the phylogenetic population, in this case, rodents.

“We’re basically in the same league as the other organisms in the rodent model,” Buchmann says. “We found complete sequences of 99% of the BUSCO genes, so we’re not missing a lot of the protein coding sequences.”

With high-quality sequencing in hand, the researchers looked for patterns in the genome, such as genes that have a different number of copies in Nile rats than in house mice, which could be candidates for future study.

They also used Kinderminer and Serial KinderMiner (SKiM) -; Applications developed by Stewart Computational Biology Group at Morgridge -; To query PubMed summaries and identify genes associated with type 2 diabetes.

“We don’t have a ‘smoke gun’ at this point,” Buchmann says. “You can always get a list of genes. But then, how do you know they really matter in diabetes? This will take years and years of experimental work.”

Now that the Nile rat has a high-quality reference genome, Buchmann and Tuh hope the species will be used extensively in biomedical research.

“People are resistant to using new animal models, because it involves a lot of money, a lot of effort, and a lot of risk,” says Toh. “But we decided to go the unorthodox route. I think surviving the search is finding different flavors and different paths. And we’ve removed some of that risk.”

As an independent research organization, the Morgridge Institute for Research is exploring uncharted scientific territory to discover the cures of tomorrow. In partnership with the University of Wisconsin-Madison, we support researchers taking a fearless approach to promoting human health in emerging fields such as renewable biology, metabolism, virology, and biomedical imaging. Plus, through public programming, we work to inspire scientific curiosity in everyday life.


Journal reference:

Toh, H. et al. (2022) Haplotype-resolved genome assembly of the Nile mouse facilitates exploration of the genetic basis of diabetes. BMC Biology.

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