Contact UsLaboratory animals are an important model system for nutrigenomic research because the environment, including nutrient intake, can be rigorously controlled and experimentally manipulated. Outbred animals have often been used in nutritional experiments because they mimic the outbred human population. However, the limitation of using outbred laboratory animals is one of statistics: many more animals are needed for statistical signficance and only the average response can be obtained.
Inbred animals are better options because the genotype is consistent among all animals of a strain. Inbred strains are classically defined as resulting from at least 20 generations of brother X sister matings. The disadvantage of using inbred strains is that several to many different strains must be analyzed to get a more complete understanding of nutrient X genotype interactions. Although inbred strains aremore suitable models for nutrigenomic research, one must still plan experiments with care. (JK)
The Number of Inbred Laboratory Animals for Experiments
Why does each experimental and control group in a dietary/nutrigenomic research study require at least 5-10 laboratory mice or rats of a single inbred strain or F1 hybrid even though the individuals are genetically 99+% identical?
Genetic identity of two organisms, e.g. identical twins, does NOT imply that they will be physiologically or metabolically identical (5). Each gene is only a DNA template that dictates the structure of a messenger RNA (mRNA) utilized in the synthesis of a specific gene product (polypeptide/protein). Most importantly, all gene products are modified by a multiplicity of post-transcriptional and post-translational factors and their interactions in the intracellular microenvironments that likely differ even among inbred and F1 hybrid siblings.
The timing and duration of expression of any gene, i.e. the synthesis of the gene-specific protein/polypeptide, is directly determined by the activation/inactivation of transcription factors. This process is influenced by the complex interplay of a multitude of molecular factors and processes. In fact, the expression of a single gene can induce transcription of several or many other genes. In addition, a specific gene product may have multiple functions and thus affect diverse pathways (4).
Many gene products play active roles in different processes and pathways and, if any gene product has been modified during its maturation, these processes and pathways may be affected differently. Gene products enter a complex of metabolic and physiologic pathways that are continously modulated by external and internal environmental factors during development and adulthood. Internal environmental factors include, but are not limited to, a multiplicity of interacting hormones and immunologic factors that also respond to external factors such as temperature, atmospheric pressure, light, dark, relative humidity, dietary components, social interactions, etc.
Agouti Locus as a Model
The agouti locus is present in humans as well as in house mice although its expression differs between the two genera. The viable yellow Avy gene at the agouti locus on chromosome 2 of the house mouse provides an excellent model system for investigation of the complexities of gene expression and the resulting phenotypic diversity of genetically essentially identical mammals. Details of the molecular basis of the continuum of coat color patterns from obese clear yellow through various degrees of agouti/black mottling to lean pseudoagouti inbred siblings and of the variation in their physiologic and metabolic response patterns can be found in references 4 and 6. This model system is particularly well suited for nutrigenomic studies because genetically identical siblings differ in their metabolic responses to particular nutrients with respect to leanness, obesity, and development of hyperplastic/neoplastic lesions (1, 2, 3, 6, 7, 8, 9).
References
- Wolff, G. L., Morrissey, R. L. and Chen, J.J. 1986. Susceptible and resistant subgroups in genetically identical populations: Response of mouse liver neoplasia and body weight to phenobarbital. Carcinogenesis 7: 1935-1937. PMID 3769143
Contributed by George Wolff, Emeritus, National Center for Toxicological Research. Jefferson, AR, USA (July 2006)