A unified approach to the study of mutation, from bacteria to humans: some potentialities of the new DNA technologies.

Abstract

Let me at the outset express my deep appreciation at the receipt of the Annual Award of the Environmental Mutagen Society. In the 27 years since this Award was established, it has recognized many persons for seminal contributions to the field of mutagenesis, and I am honored to join those previous recipients. I was impressed by how many different facets of the subject of mutagenesis they represented. Today, in the course of my brief remarks, I hope to direct attention to still another aspect of our complex field. As many of you know, for more than 50 years I have been involved in studies of spontaneous and radiation-induced mutation rates in humans. This work has been in collaboration with quite a number of American and Japanese colleagues, to whom I am very grateful and whose contributions will be recognized in the citations that follow. Now, my genetic roots were formed in the course of studies with two eminent Drosophilists, Warren P. Spencer and Curt Stern, and you can be certain that after my transition into human genetics and my involvement with the genetic effects of the atomic bombs, I have kept a close eye on developments in experimental radiation genetics, especially those involving the fruit fly and the mouse. Some 17 years ago, in the Wilhemina E. Key Lecture of the American Genetic Association [Neel, 1983], I attempted to compare spontaneous mutation rates in the fruit fly, the house mouse, and humans. It was a pretty unsatisfactory business, but what emerged was, to me, an apparent surprising similarity in the spontaneous mutation rates per gene per generation of these three species, considering the great differences in their life cycles. Then, some 9 years ago, Susan Lewis and I [Neel and Lewis, 1990] attempted to compare radiationinduced rates in humans and mice, and again it was a frustrating undertaking. Now the issue was to what extent did the genetic findings on radiation effects in humans agree with those on mice. This is a whole other story I do not propose to get into today, other than to comment that recent developments regarding mosaic mutation in mice [Russell and Russell, 1996] and the prevalence of cluster mutations in mice [Selby, 1998] seem to be bringing the estimates of the genetic doubling dose based on mice closer to the higher estimate based on the findings in Japan [Neel, 1999]. But today, rather than dwelling on the past, I propose to engage in a fantasy for the future. The fantasy emerges out of the truly amazing developments in molecular genetics and genomics over the past several decades. The fantasy involves the concept that we may soon be able to study comparative mutagenesis, both spontaneous and induced, at the DNA level, thus providing the ultimate basis for acrossspecies comparisons. As I say this, I realize that many EMS members have already been engaged in analyzing at the molecular level a variety of mutations detected through some phenotypic effect. I want to talk about a method of screening for mutations that begins at the molecular level.