most mouse experiments, the parental animals were used at a rather uniform age (usually about 12 weeks), and the question of paternal age effects has not been specifically addressed.

Since most spontaneous mutations arise as a result of errors in DNA replication, one would expect that the mutation rate in human males would be higher than that in females and that there would be an increase in the likelihood of spontaneous germinal mutations with the age of the male (so-called paternal age effect). By and large, these expectations have been fulfilled. The literature on this subject and the recent evidence from molecular studies have been reviewed (Crow and Denniston 1985; Crow 1993, 1997, 1999; Vogel and Motulsky 1997; Sankaranarayanan 1998; Green and others 1999).

When one considers the large differences in life span between humans and mice and the paternal age effect for spontaneous mutations in humans, it is clear that extrapolation from short-lived mice to humans is unlikely to provide a reliable average spontaneous rate in a heterogeneous human population of all ages. This is one reason to abandon the use of the mouse data on spontaneous mutation rates in DD calculations and to use human spontaneous mutation rates instead. The following arguments support this: (1) estimates of spontaneous mutation rates in humans are unweighted averages of the rates in the two sexes (and therefore automatically incorporate sex differences and paternal age effects), and (2) the sex-averaged rate is relevant in the context of DD calculations (Sankaranarayanan 1998).

A second reason for not using the mouse spontaneous mutation rates for DD calculations is that the whole question of spontaneous mutation rates in mice has now assumed an unexpected complexity due to the noninclusion, until recently, of mutations that originated as germinal mosaics (resulting in progeny carrying the same mutation [“clusters”] in the following generation) in estimates of spontaneous mutation rates in the specific locus experiments (Russell and Russell 1996; Selby 1998a, 1998b; Russell 1999). According to Russell and Russell (1996), if mosaic data are included, the total spontaneous rate becomes twice that of 6.6 × 10−6 per gene based on mutations that arose singly. However, Selby (1998a, 1998b) has argued that (1) the data on clusters should be included in calculating the total spontaneous mutation rate; (2) his computer simulation studies (which incorporate clusters in his model) suggest an increase of the rate by a factor of about 5 compared to that based on mutations that arose singly; (3) the fivefold higher total spontaneous rate is the appropriate numerator in DD calculations; and (4) if paternal age effects are extrapolated from humans to mice, the estimate of spontaneous rate is even higher. In the view of this committee, the above argument cannot be sustained for humans for the following reasons:

First, while there is no doubt that a proportion of spontaneous mutations in human genes arise as germinal mosaics (and can potentially result in clusters in the following generation), the limited data available on mosaics and clusters at present preclude a quantitative assessment of their contribution to spontaneous mutation rates. The main relevance of germinal mosaicism in the human context is this: the parent who carries a mosaic mutation for an autosomal dominant or X-linked trait does not have a mutant phenotype and therefore would not be considered as having a risk of producing affected children. However, because his or her gonads contain mutant and normal cells, he or she may run the risk of having more than one progeny who carries the mutant gene (mutational “clusters”).

Second, if a substantial proportion of human mutations arise as germinal mosaics in one generation and result in clusters in the following generation, the frequencies of at least autosomal dominant and X-linked diseases also have to be corrected upwards to account for this possibility; there is no reliable way of doing this at present. The published estimates of human spontaneous mutation rates do not provide sufficient grounds for assuming that substantial proportions of mutations in the germ cells first arose as mosaics and subsequently resulted in clusters of mutations; if this had been the case, major increases in the frequencies of affected individuals from one generation to the next would have been observed, but this does not appear to be true. Further, family sizes in present-day human populations are limited (in fact, they are so small that there is almost never more than one affected offspring from a mating, in contrast to the situation in mice where large numbers of progeny are obtained from a single male). Both of these arguments support the view that mutational clusters are much less relevant in humans than in mice.

The advantages of using human spontaneous mutation rates for DD calculations are (1) they pertain to human disease-causing genes; (2) as mentioned earlier, the mutation rate estimates in humans, because they are averaged over both sexes, automatically include sex differences and paternal age effects; and (3) in mutation rate calculations, human geneticists count all mutants that arise anew irrespective of whether they were part of a cluster or not; if clusters had occurred, they would have been included. The committee therefore accepts the view that the use of human spontaneous rates and mouse induced rates for DD calculations (i.e., the procedure used in BEIR I; NRC 1972) is more logical, and it has assessed published data on spontaneous mutation rate in humans and induced rates of mutations in mice.

Doubling Dose Estimation Using Spontaneous Mutation Rates of Human Genes and Induced Rates of Mouse Genes

Estimation of the Average Spontaneous Mutation Rate of Human Genes

To calculate a representative average spontaneous mutation rate of human genes, the available estimates for indi-



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