The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health

By Ezran, Camille; Karanewsky, Caitlin J. et al. | Genetics, June 2017 | Go to article overview

The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health


Ezran, Camille, Karanewsky, Caitlin J., Pendleton, Jozeph L., Sholtz, Alex, Krasnow, Maya R., Willick, Jason, Razafindrakoto, Andriamahery, Zohdy, Sarah, Albertelli, Megan A., Krasnow, Mark A., Genetics


THE pantheon of genetic model organisms (including the bacterium Escherichia coli, yeast Saccharomyces cerevisiae, nematode Caenorhabditis elegans, fruit fly Drosophila melanogaster, zebrafish Danio rerio, mouse Mus musculus, and mustard weed Arabidopsis thaliana) has transformed our understanding of biology (Davis 2004; Fields and Johnston 2005). The focus on a small number of species has been important to this scientific success by providing the critical mass of investigators necessary to tackle complex biological systems, and by creating synergies and economies of scale that enabled systematic, genome-wide approaches. Central among these is the ability to achieve genetic saturation- identifying many or all of the genes involved in a biological process-and then to have elegant tools available to organize the genes into genetic pathways and localize their site of action.

Many of the genes, pathways, and principles elaborated in genetic model organisms have turned out to be broadly conserved, aiding understanding of organisms throughout the tree of life. However, the focus on a small number of organisms has impeded progress in areas of biology not represented in the pantheon. "Boutique" model organisms have sprung up to target some of the neglected areas, such as the flatworm Planaria torva for tissue regeneration (Newmark and Sanchez Alvarado 2002; Reddien et al. 2005), stickleback fish Gasterosteus aculeatus for vertebrate evolution (Peichel et al 2001; Jones et al. 2012), and killifish Nothobranchius furzeri for vertebrate aging (Harel et al. 2015; Kim et al. 2016). Remarkably, primate biology, which holds some of the most fascinating and important questions in all biology, has been left without its own model, relying on mouse and simpler model organisms and human genetic studies.

Mouse Fails to Mimic Many Aspects of Primate Biology, Behavior, and Disease

The laboratory mouse M. musculus is a nearly perfect mammalian model organism. It has a short generation time (2-3 months) and large litter size (8-12 pups), and is small and easy to maintain in a laboratory setting. Its rise to prominence followed the invention of the technology for introducing specific gene mutations into mice (Kuehn et al. 1987; Thomas and Capecchi 1987). Since that time, gene targeting has been used to elucidate the function of >3000 genes (http://www.mousephenotype.org/), and the nearly $1 billion International Mouse Phenotyping Consortium was established to generate and phenotype knockouts in all protein-coding genes during this decade (Collins et al. 2007; Abbott 2010; Skarnes et al. 2011). This mouse knockout strategy has revolutionized the study of mammalian biology and led to the establishment of thousands of mouse models to explore disease mechanisms and evaluate new diagnostics and therapeutics.

The strategy, however, does not always work. This became clear when Evans' Nobel Prize-winning knockout of the Lesch-Nyhan (HPRT) gene (Kuehn et al. 1987) was found to have the biochemical defect but not the behavioral manifestations (self-mutilation) of the human syndrome (Engle et al. 1996). Other examples followed, such as failure of mouse CFTR knockouts to model the devastating lung disease of cystic fibrosis patients (Grubb and Boucher 1999), along with similar setbacks for other lung diseases (Baron et al. 2012). Parkinson's, Huntington's, and other neurodegenerative diseases have been particularly difficult to model in mice (Schnabel 2008; Beal 2010), as have immune (Mestas and Hughes 2004; Zschaler et al. 2014), infectious (Rittirsch et al. 2007; Kim et al. 2014), and metabolic diseases (Panchal and Brown 2011; Perlman 2016). No organ system has escaped this problem, and reviews now appear with titles like "The mousetrap: what we can learn when the mouse model does not mimic the human disease" (Elsea and Lucas 2002). A systematic comparison of human and mouse genes and knockout phenotypes found that the mouse does not model the critical function, or have an assignable ortholog, of ~40% of the human genes required for viability (Liao and Zhang 2008); the authors speculate that the fraction is likely greater for nonessential genes, such as most human behavior and disease genes. …

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