Bench Talk

Why does genetic background matter? (Pt. 1)

Posted by Nate Nowak on Nov 27, 2018 11:00:00 AM

how-science-goes-wrongLaboratory mice have played a long-standing and critical role in life sciences research. Small, easily housed and cared for, mice are inexpensive, breed quickly and have a short lifespan. All of the above, combined with genetic, biological and behavioral similarities to humans, have made mice indispensable to modern biomedical research. Add in the ease with which they can be genetically modified, and mice have become a powerful tool in research.

 

Inbred vs. Outbred

Laboratory mice can be broadly categorized into two groups: inbred and outbred. Inbred mice are genetically homogenous, having very little variation as a result brother/sister mating for at least 20 generations. Inbred strains are used to reduce variability in experimental design and to increase the reproducibility of studies.

Outbred mice are created to maximize genetic diversity within a population. By rotating breeding stock and preventing inbreeding one can, in theory, ensure that no two mice in a population are genetically identical. Outbred mice tend to be stronger and better breeders than inbred mice and are used in studies that require a population of heterogeneous individuals.

Inbred Populations and Genetic Drift

While inbred mice are created to be genetically identical, mutations that occur and are transmitted to the germline will inevitably create genetic variation within an inbred strain. This increase in variation within a population is referred to as genetic drift. Any inbred strain maintained for more than 20 generations will have become genetically distinct from the parental strain and can be referred to as a substrain. Breeding and maintaining inbred strains at many different sites over the years had led to the development of many substrains of each of the major inbred strains.

Inbred Strains and Genetically Engineered Models

Choosing a particular inbred strain background should be based on the research being done and the suitability of that strain as an experimental model. It is important to note that each inbred strain has a unique phenotype and characteristics that will impact their use in experiments. This is also true for the different substrains of an inbred strain.

The impact of the genetic background is magnified when genetically modified models (GEMs) are part of a research program. Since a gene functions in the context of the genome as a whole, the phenotype of a single genetic modification or mutation is modulated by a large number of background genes. This means that the same transgene or knockout can have divergent phenotypes when present in different inbred strains or substrains.

Even more concerning is the number of GEM mice that occur on mixed-backgrounds rather than pure congenic strains. Congenic strains are derived by backcrossing to a parental inbred strain for at least ten generations while selecting for the genetic modification of interest. This results in a line that is identical to the inbred strain except for the mutated gene of interest and the surrounding region. Data from studies done on mixed backgrounds are not reproducible nor reliable as the inherent genetic variability in the models has not been controlled. 

Tags: Genetic Monitoring, Genetic Background