The high spontaneous mutation rate: Is it a health risk?*

James F. Crow

Proc. Natl. Acad. Sci. USA
Vol. 94, pp. 8380-8386, August 1997


Genetics Laboratory, University of Wisconsin, Madison, WI 53706



My topic is mutation. Mutation is the ultimate source of variability on which natural selection acts; for neutral changes it is the driving force. Without mutation, evolution would be impossible. My concern, however, is not with mutation as a cause of evolution, but rather as a factor in current and future human welfare. Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious. And it is this deleterious effect that I want to discuss.

The ideas that I am presenting are not new. Some go back to early in the century, but the evidence has been strengthened in recent times. In this review, I shall draw on the work of many who have contributed to this history.

This lecture is dedicated to three heroes. The first is Wilhelm Weinberg, a busy German physician and obstetrician42 years of practice and more than 3,500 birthswho somehow found time to invent all manner of clever tricks for studying heredity in that recalcitrant species, Homo sapiens. He was the first to suggest that the mutation rate might be a function of paternal age (1). The second hero is J. B. S. Haldane, an eccentric polymath with an enormous number and an incredible diversity of accomplishments. He was one of the first to measure a human mutation rate and was the first to notice a sex difference in the rate (2). The third is H. J. Muller, who made mutation an experimental subject by devising an objective way of measuring it and showing that ionizing radiation is mutagenic. In the later years of his life, Muller spent much of his energy, physical and emotional, in a crusade against unnecessary human exposure to radiation. Interestingly, he gave little attention to what is surely much more important, chemical mutagens. The main reason is that when he was still active there were no known mutagens that were not highly toxic; mustard gas is an example. Had he known of relatively harmless compounds that are highly mutagenic, he would surely have extended his crusade to environmental chemicals. Curiously, although Muller emphasized the high rate of spontaneous mutation, he did not include it in his crusade, mainly, I think, because he saw no feasible way to reduce it (3).

The Nature of Mutations