Diversity Outbred (DO) mice are a significant advancement in biomedical research, a powerful tool for studying complex biological processes and diseases. They better reflect the genetic diversity of human populations, improving upon traditional laboratory models. Their development enhances the relevance and applicability of mouse study findings to human health. This approach bridges the gap between preclinical research and clinical outcomes, accelerating scientific discovery.
Understanding Diversity Outbred Mice
Diversity Outbred mice are developed from eight distinct inbred founder strains. These include A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ, each contributing unique genetic characteristics and disease susceptibilities. For instance, the NOD/ShiLtJ strain is prone to type 1 diabetes, while A/J is susceptible to cancer, and NZO/HlLtJ tends to develop obesity. Through systematic, randomized breeding over many generations, these eight strains were intercrossed to produce a highly heterogeneous population where each mouse possesses a unique genetic combination. This results in mice with over 50 million segregating genetic variants, making them the most genetically diverse mouse population available and a more accurate representation of the human genome.
Limitations of Traditional Mouse Models
Traditional mouse models, particularly inbred strains, have been instrumental in biomedical research but have limitations. Inbred mice are genetically uniform; individuals within a strain are virtually identical. While this homogeneity offers advantages for specific studies, such as controlling variables and ensuring reproducibility, it restricts their ability to model the genetic complexity of human diseases. Many human conditions, like heart disease, diabetes, and Alzheimer’s, arise from the interplay of multiple genes and environmental factors, a complexity a single inbred strain cannot fully capture. This uniformity can lead to findings specific to a particular strain that may not translate well to the genetically diverse human population, contributing to reproducibility issues.
Advantages for Scientific Discovery
Diversity Outbred mice offer advantages over traditional models due to their extensive genetic diversity. Their rich genetic variation allows researchers to investigate complex traits and diseases influenced by multiple genes and environmental factors. This enables the identification of novel genes and biological pathways linked to disease susceptibility or varying responses to drugs. For example, DO mice can reveal how genetic background affects sensitivity to chemical toxicities, such as benzene, or responses to certain chemotherapies. The broad genetic spectrum in DO mice improves the translational relevance of research outcomes, making findings more applicable and robust for human medicine.
Applications in Health Research
Diversity Outbred mice are applied across various health research fields, providing insights into complex human conditions. In cancer research, DO mice help study how genetic differences influence tumor development and response to treatments. For metabolic diseases like type 2 diabetes and obesity, these models allow researchers to identify genetic modifiers that impact disease progression and explore potential therapeutic targets. Their genetic diversity also proves useful in infectious disease studies, investigating varied immune responses to pathogens and environmental exposures, such as cigarette smoke. DO mice are also employed in toxicology studies to assess varying susceptibility to chemical exposures and in drug discovery to evaluate drug efficacy and safety across diverse genetic backgrounds, supporting personalized medicine approaches.