with which spontaneous mutation results in a variety of dominantly inherited phenotypes and (2) the more recent data on the rate with which spontaneous mutation results in “recessively” inherited protein abnormalities. An absolutely lower bound to the impact of “point” mutation is provided by studies of the cumulative rate with which mutation results in the genetic syndromes exhibiting dominant or sex-linked inheritance. Thus, considering the results of a variety of specific studies as well as population surveys, the successive Committees on the Biological Effects of Ionizing Radiation of the U.S. National Academy of Sciences (see Committee on the Biological Effects of Ionizing Radiations, National Research Council 1980) and the various United Nations Scientific Committees on the Effects of Atomic Radiation (see the 1986 Report) have in their various publications tended to converge on the estimate that, in each generation, about 0.2% of all newborns will to some extent be handicapped (and sometimes will die prematurely) from spontaneous dominant or sex-linked mutation in their parents that results in identifiable diseases/syndromes.
This figure does not appear to include some of the growing list of syndromes due to chromosomal microdeletions (reviewed in Dallapiccola and Forabosco 1987), syndromes for which early death or sterility prevent a demonstration of genetic transmission. This figure also does not appear to include either any fraction of the cytogenetically normal children with major congenital defect not corresponding to a known genetic entity or the dysplastic children with impaired survival and mental retardation (with whom all pediatricians are familiar and who are so often encountered in institutions), some proportion of which must be due to dominant mutation, chromosomal or “point.” The figure also does not include children with “failure to thrive,” a category comparable to that of mouse “runts,” whose frequency is increased by radiation (Searle and Beechey 1986).
With respect to autosomal recessively inherited disease, we note our own recent estimates, arrived at by electrophoretic studies (see Neel et al. 1986), that spontaneous mutations characterized by amino acid substitutions in the proteins under study occur with a frequency of about 1×10-5/gene/generation, or 1× 10-8/nucleotide/generation. If this rate can be extrapolated to the entire genome, then with 3×109 nucleotides/gamete, or perhaps 50,000 functional genes, the implication is that each zygote might receive on average one mutation of this type in the introns of a functional gene, or some 60 nucleotide substitution-type mutations scattered throughout the genome. The ultimate potential for phenotypic ill effects of some of these mutations is best documented by the extensive studies of the hemoglobin loci, with the demonstration that nucleotide substitutions may result in abnormal hemoglobins (e.g., S or C) or in thalassemia.
In addition, enzyme variants characterized by total loss of activity (the basis ranging, at the DNA level, from key nucleotide substitutions or abnormally situated stop codons to insertion/deletion/inversion events) have about the same frequency in populations as do the rare protein variants presumably maintained by the pressure of mutation resulting in nucleotide substitutions (see Satoh et al. 1983). This similarity suggests that these may arise through the mutation of functional genes with at least the same rate (1×10-5/locus/ generation) as nucleotide substitutions. The ill effects of these null variants is documented by the many recessively inherited inborn errors of metabolism. If, again, there were 50,000 genes in the haploid genome, the average zygote might carry one newly arisen mutation resulting in either loss of the activity or nonsynthesis of a gene product. We suggest that the high level of child care exercised by humans reduces dramatically the heterozygote effects in our species prior to age 20 years— to perhaps 10%–20% of those observed in experimental animals. It follows that the heterozygous effects of spontaneous point mutation might result in the prereproductive death of approximately 0.2%–0.4% of all children.
In the light of all these considerations concerning point mutations, we will suggest that in this series at least 0.20% of the infants reaching the twentieth week of gestation who do not exhibit gross chromosomal abnormality will be characterized by an untoward pregnancy outcome/prereproductive death because of so-called point mutation of all types in the parents —and the total may well be 0.40%. In view of the total frequency of congenital defect/genetic disease documented for Japanese and other populations (Schull and Neel 1965; Baird et al. 1988; Czeizel et al. 1988), and in view of the data on heterozygote disadvantage, this seems a conservative figure —conservative in the sense that, the lower this estimate, the lower the estimates of the minimal and probable doubling doses.
When the results of the considerations of these three sections are totaled, we arrive at the following estimate of the impact of spontaneous mutation on untoward pregnancy outcomes/early deaths: approximately 0.10% +0.03% + (0.20%–0.40%), or 0.33%–0.53%. We assign half of this to UPOs and half to F1 mortality exclusive of cancer (see table 5). Inasmuch as UPOs