18 November 2022

Replacement for mice and rats

The genome of the Nilotic grass mouse has been read. Will it become a new model organism?

XX2 century


Nilotic Grass Mouse (Arvicanthis niloticus) — a species of mammals from the genus of grass mice of the mouse family. Herbivorous, diurnal, in nature widespread in the African savanna from Senegal to Sudan and Ethiopia, from where the range extends south, including Uganda and Kenya. In addition, it lives in the Nile Valley, where the range is limited by a narrow strip of flooded plain. It is found on the Arabian Peninsula, where, apparently, it was introduced by man. It is also found in three isolated mountain ranges of the Sahara. In Egypt, it is considered a pest of agriculture.

Recently, a large group of scientists from the USA, China, Great Britain, Germany and Denmark presented in the journal BMC Biology a high-quality reference annotated genome assembly of this African rodent (Toh et al., A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes). According to the authors of the work, the availability of these data at the disposal of scientists will allow them to use the Nilotic grass mouse more often and more effectively in biomedical research as a model organism.

The study of the genome of any living being is useful, because it brings us closer to full biological knowledge. And the scientific work published on November 8 on the study of the grass mouse genome — as part of the large international project "Vertebrate Genome" — is also part of the movement towards this full knowledge. However, in addition to the fundamental, this study has, according to its authors, a direct practical significance. The fact is that the most familiar model vertebrates today, the house mouse (Mus musculus) and the Norwegian rat (Rattus norvegicus), lead a predominantly nocturnal lifestyle and in this sense are not particularly valuable when modeling human circadian rhythms. This is important, because recently there is more and more information about the connection of various disorders and pathologies (for example, obesity and type II diabetes) with circadian rhythm disorders.

The Nilotic grass mouse leads a diurnal lifestyle and is active during the daytime, like humans, while it lives and reproduces well in captivity. Thus, it is much more suitable for modeling our circadian rhythms than ordinary rats and mice. When the Nilotic mouse is fed with the food that laboratory rats and mice usually receive, it quickly develops obesity, hyperglycemia and hypertension, which makes it, apparently, a good model for type 2 diabetes research. It also has more photoreceptors in the eye than nocturnal rodents, which means that it is also more suitable for studying human retinal diseases, including diabetic retinopathy.

Another advantage of the Nilotic mouse is that today it is a mongrel model, which means that its genetics reflect the diversity of the population. Many strains of laboratory mice have been inbreeding for many generations, creating stable populations that are genetically almost identical. This is useful for reducing experimental variability, but less useful when studying complex genetic factors contributing to the disease.

Actually, from time to time the grass mouse has already been used in scientific research. What it still lacked to become a full-fledged model organism was, first of all, a properly read genome.

"We need research tools," he says Yuri Bukhman, bioinformatician from the Morgridge Institute for Research and senior author of the project, which will allow us to do with the Nile rat the same thing that we used to do with a laboratory mouse. Having a reference genome is a step towards this goal."

The technology of obtaining a complete and highly accurate genomic sequence is relatively new. As a rule, in order to sequence a large genome, the DNA sequence must be divided into shorter segments, from 100 to 300 nucleotides, and then reassembled into longer adjacent (or rather even overlapping) contigue sequences. Unfortunately, this approach often leaves a lot of gaps.

"An important indicator of genome quality is the average contigue length. In fact, the bigger it is, the fewer gaps you have," explains Yuri Bukhman. "Our contigues are among the longest."

The research team applied long—read sequencing technology to collect longer - from 10,000 to 20,000 nucleotides. Then they combined the contigues into scaffolds, the length of which is equal to the length of the chromosome. Finally, they were able to fully decode two copies of the genome.

As a result, having obtained a high-quality genomic sequence of a grass mouse, the authors searched for genes in it that could be candidates for future research. In particular, they used a PubMed search application developed at Morgridge in order to obtain a list of genes associated with type 2 diabetes from the works published there. And some of these were found in the genome of Arvicanthis niloticus. However, there is no certainty yet that these genes are indeed associated with diabetes.

"At the moment, we don't have 'irrefutable proof,'" explains Buchman. — You can always get a list of genes. But then how do you know that they are really important for diabetes? This will require many years of experimental work."

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