Development of Apolipoprotein E–Deficient Mice

Abstract

The first mouse carrying a deletion mutation in its apolipoprotein E (apoE) gene was born in our mouse colony in the summer of 1991. Our ongoing experiments to that point had indicated that this would happen, but the realization that the mouse in front of my eyes had inherited a mutation that we had designed and made in the laboratory filled me with awe. It did not occur to me immediately that this mouse would develop hypercholesterolemia and atherosclerosis and dictate the direction of my research for the next 20 years. I here briefly describe the background and my personal experience that led to the development of apoE-deficient mice as a model for human atherosclerosis. As a research scientist in the Department of Genetics at the University of Wisconsin, my main interest during the early 1980s was directed toward understanding how different types of DNA recombination contribute to the architecture and diversity of individual genomes within human populations and to DNA differences between humans and nonhuman primates. My studies clearly showed that new alleles and new genes are constantly being formed in the human genome by recombinational events, particularly between existing members of multigene families. There also appeared to be hot spots for recombination. By tracing a history of the human haptoglobin-gene cluster from the present-day structures in human populations and in other primates, I found that a single recombination event between related genes often produces much more drastic changes in the genome than those that result from simple point mutations.1 Whether this frequent yet natural occurrence of homologous recombination in the mammalian genome could be used to alter the genome of mammalian cells in culture in a preplanned fashion became a question of interest to several laboratories.2,3 An affirmative answer was first obtained in 1985, …