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

Abstract

The laboratory 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 causal 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 mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.

Creation of X-linked Alport syndrome rat model with Col4a5 deficiency

“…Although there are several advantages comparing with mice, production of genetically engineered rat models has not yet been extensively proceeded during the past decades. The recent CRISPR/Cas9 system is the simplest for generating rats carrying a modified genome 24 , 25 , however, the standard method for genome-editing in mammals involves 3 major steps: isolation of zygotes from females, micromanipulation ex vivo, and transfer into pseudopregnant females. These 3 steps require extremely high level of technical expertise and its proficiency of the researchers as well as technicians.…”

Genome-to-phenome research in rats: progress and perspectives

“…These rat strains have been used to detect QTLs 48 - 61 for 1) cardiovascular conditions, such as blood pressure, electrocardiographic parameters, basal mean arterial pressure (MAP), delta MAP and delta heart rate, left ventricular hypertrophy and heart size; 2) metabolic complexity, such as alcohol consumption and propensity for alcohol-induced organ damage, glucose oxidation and its incorporation into brown adipose tissue lipids, insulin resistance, dyslipidemia and glucose handling; 3) behavioral traits, such as shuttle box, automated novel cage activity and elevated zero maze, startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion; 4) physiologic and hormonal quantitative traits, such as serum adiponectin and thyroid stimulating hormone activity, dopamine beta-hydroxylase enzyme activity, catecholamine biosynthesis and catecholamine secretion; 5) bone fragility, bone mineral density, bone structure and bone strength; 6) hematology, such as full blood count; 7) immunology, such as FACScan analysis of white blood cells; 8) neuroinflammation, such as myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis and TNF alpha in serum; and 9) tissue weight, such as adrenal glands, bone, blood, brain, ears, heart, kidney, liver, spinal cord, spleen, and thymus. In addition, Szpirer 62 recently reviewed the use of rats for knockout investigations of QTLs and gene functions.…”

High-Fat Diets-Induced Metabolic Disorders to Study Molecular Mechanism of Hyperlipidemia in Rats

“…Metabolism disorders due to HFD feeding are considered more relevant than monogenic animal models (germline defect leptin production/signaling) because in humans, it rarely occurs. A widely used animal model for studying physiology, behavior, metabolic disorders, toxicology, and cardiovascular disease is the rat, especially the white rat (Rattus norvegicus) (6,7). Rats are an animal model of human disease that is more convenient and beneficial than other organisms (8).…”