Defining the Extent of Genetic Variability

Peter Nelson, M.D., Fred Hutchinson Cancer Research Center

Phenotypes exhibited by biological entities such as entire organisms or individual cells are primarily driven by ordered steps of gene utilization that regulate discrete developmental stages, responses to nutrients and other environmental cues, and reactions to internal and external insults. The major contributor to phenotype is the genome, which places boundaries or constraints on phenotypic possibilities. However, within these genome-defined limits, there remain latitudes of variability that profoundly affect many aspects of biology. In the context of mammalian systems, it is readily apparent that individuals sharing identical genomes (e.g., inbred mouse strains, monozygotic twins) may have strikingly different characteristics. This phenotypic variability underlies much of human pathology and disease.

This discussion will center on efforts designed to establish the extent of gene expression variability in the most widely used model system in biomedical research: the mouse. Comparative studies between individuals within genetically identical inbred strains and between different strains reveals a remarkable variability that is superimposed upon genome-level differences. The potential implications of these findings will be explored in terms of experimental design, experimental interpretation, and biological significance.