Modeling diseases in multiple mouse strains for precision medicine studies

Abstract

The genetic basis of the phenotypic variability observed in patients can be studied in mice by generating disease models through genetic or chemical interventions in many genetic backgrounds where the clinical phenotypes can be assessed and used for genome-wide association studies (GWAS). This is particularly relevant for rare disorders, where patients sharing identical mutations can present with a wide variety of symptoms, but there are not enough number of patients to ensure statistical power of GWAS. Inbred strains are homozygous for each loci, and their single nucleotide polymorphisms catalogs are known and freely available, facilitating the bioinformatics and reducing the costs of the study, since it is not required to genotype every mouse. This kind of approach can be applied to pharmacogenomics studies as well.

Genomics and High-Consequence Infectious Diseases: A Scoping Review of Emerging Science and Potential Ethical Issues

“…20 However, the Collaborative Cross (CC) mouse ''panel,'' which consists of 8 lines of recombinant inbred mice together serving as a next-generation platform for investigating the genetics of complex diseases, is attracting research interest for more closely approximating diverse outcomes in human disease, and host genetics of bacterial and viral infections has been a focal area for CC studies. 21,22 Researchers hope CC findings will serve as a means to target and improve human genome-wide association studies by identifying promising candidate genes, biomarkers, and pathways for directed investigation; illuminating environmental factors and genetic subpopulations contributing to the variability observed in genome-wide association studies; and providing helpful information for evaluating therapeu-tic strategies. 23 CC mouse models have been developed for 3 high-consequence pathogens-Ebola, 12 SARS, and H1N1 24 -successfully producing a range of disease phenotypes reflecting important human aspects of disease.…”

Genetic Background Matters: Population-Based Studies in Model Organisms for Translational Research

“…The advantages of using mouse models in biomedicine have been discussed extensively [ 3 ]. Some benefits are the following: (i) the availability of genetic tools for creating disease models by transgenic, knockout, and knock-in technologies [ 4 , 5 , 6 ] ( (accessed on 22 May 2022)); (ii) inbred mouse strains are nearly isogenic, enabling to study how the same genetic mutation modifies a phenotype of interest in different genetic backgrounds [ 7 , 8 , 9 , 10 , 11 ]; (iii) mouse tissues are available for omics studies which can be challenging to obtain from humans [ 12 ]. Some limitations include different evolutive pressures for mice and humans; therefore, some systems, such as the immune system, do not function similarly in both species [ 13 ].…”

“…Advantages of using the HMDP panel are the following: (i) their genomes are known (http://mouse.cs.ucla.edu/mouseHapMap/ (accessed on 22 May 2022)); thus, it is unnecessary to spend funds performing this step; (ii) HMDP possesses ~4 million common single-nucleotide variants (SNVs), which is similar to the number present in humans [15]; (iii) high-resolution association mapping [14], which is at least an order of magnitude higher than in linkage analysis; (iv) it is possible to integrate gene mapping with other omics (transcriptomics, proteomics, and metabolomics data) [12]; (v) commercially available (from The Jackson Laboratory, Harlan, and others); (vi) sufficient bioinformatics tools for data mining of complex mouse and human disease traits, such as the Systems Genetics Resource (SGR) (http://systems.genetics.ucla.edu (accessed on 22 May 2022)); (vii) servers to perform association mapping and statistical power simulation, which are also available in R to run them in house [16].…”

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

“…One attractive approach to identify new therapeutic targets to modulate GCase is to use the natural genetic diversity present in populations of individuals (i.e., model organisms) to identify genetic modifiers that control a given trait [ 8 ]. By integrating gene mapping with other sets of -omics, it is possible to find regulatory elements underlying the variation in a given trait [ 9 ]. This holistic population-based approach is called systems genetics [ 10 ].…”