Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes

Abstract

The rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades. The availability of these resources has stimulated numerous studies aimed at discovering disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout (KO) mutations]. Furthermore, even when the human gene causing a disease is identified, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, about 300 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases. This article provides the reader with an inventory of these genes.

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

“…In contrast, in rats, DNA microinjection and ES cells began in the early 1990s and 2010, respectively (Mullins et al, 1990;Kawamata and Ochiya, 2010). In the meantime, researchers used classical breeding approaches to develop a variety of rat strains that model human diseases (Szpirer, 2020). The need for genetic engineering tools for the rat and the continuous use of zygote pronuclei microinjection of DNA in the rat, explain why genespecific nucleases were applied in rats in 2009, earlier than in mice (2010) (Geurts et al, 2009;Carbery et al, 2010).…”

“…These rat strains have been used to introduce genetic modifications to analyze the role of genes (Aitman et al, 2010(Aitman et al, , 2016. For example, Wistar Kyoto, Dahl/SS, and spontaneously hypertensive strains develop hypertension and have extensively used to analyze the role of many genes (Moreno et al, 2011;Rudemiller et al, 2014;Nayak et al, 2015;Aitman et al, 2016;Lerman et al, 2019;Szpirer, 2020). The diabetes-prone biobreeding rat strain is another model that has been used to genetically modify genes involved in diabetes FIGURE 1 | Timeline showing the major technical advances in genome editing and delivery in mice and rats from the 1980s to today.…”