Research Highlight April 02, 2019

The how and why of research with diversity mouse strains and populations

Modeling human diversity... in mice!

How can scientific research get answers when there's so much human diversity? Mice, of course!

First developed about a century ago, inbred mice have contributed an immense amount to our knowledge of mammalian biology as well as clinical insight. For some research applications, however, inbred strains may not be the right choice. Human populations are genetically diverse, so in considering the genetic contributions to disease, inbred strains provide only a small part of the picture. Recently developed diversity mouse strains and outbred mouse populations, such as the diversity outbred (DO) mice at The Jackson Laboratory (JAX), have created research options that parallel or even exceed human genetic diversity. And now there’s a resource for research using diversity mice: The JAX Genetic Diversity Initiative website.

Inbred mice have been specifically bred so that individuals within large populations have nearly identical genetics. They have allowed researchers to minimize variables and characterize genetic contributions to the trait of interest with relative accuracy. With the technologies in past years, reductionism was a necessity, and inbred mice have provided invaluable knowledge, gene by gene.

Nonetheless, work with a single inbred strain has had relatively limited utility for some of humankind’s most common diseases. The genetic complexity of diabetes, heart disease, Alzheimer's, obesity, addiction, autoimmune disorders and cancer makes research more challenging and has limited clinical translation. Now, with the advent of greatly increased capabilities, including genomic sequencing and genetic engineering, we possess the ability to more fully understand the origin, progression and treatment of complex human diseases and conditions.

Genetically diverse mouse strains and outbred populations offer important advantages. They feature stable, well-characterized, segregated genetic variation that more accurately reflects the genetic structure of human populations. Research with them makes possible powerful new approaches to studying genetically complex traits such as disease susceptibility, drug resistance, and behavioral conditions by enabling high resolution genetic mapping. So while inbred strains remain vital when precise genotypic standardization is needed and for disease modeling on known, defined genetic backgrounds, there is growing interest in the use of genetically diverse mouse strains and outbred populations for a wider variety of applications. In recent years, diversity mouse strains and populations have been effectively used for research into type 2 diabetes, Alzheimer’s disease, cancer and more.

The JAX Genetic Diversity Initiative (GDI) is a strategic effort to increase the awareness and availability of genetically diverse mouse populations and associated tools across the research community. The GDI website provides information, tools, references, case studies and more for working with two sets of recombinant inbred mouse lines and an outbred mouse population. The founder inbred strains, BXD and Collaborative Cross (CC), provide advantages of inbred mouse research with known genetic diversity across panels. The outbred mouse population, known as Diversity Outbred (DO), was derived from 160 incipient CC strains. DO mice provide an effectively unlimited source of novel allelic combinations and sub-megabase mapping resolution across most regions of the genome.