A total of 289,868 locus tests, based on 28 different protein phenotypes and using one-dimensional electrophoresis to detect variant proteins, has yielded one probable mutation in the offspring of "proximally exposed" parents, who received an estimated average gonadal exposure of 31 to 39 rem in the atomic bombings of Hiroshima and Nagak. There were no mutations in 208,196 locus tests involving children of "distally exposed" parents, who had essentially no radiation exposure. Studies of the genetic effects of atomic bombs have been in progress in Hiroshima and Nagasaki since 1946 (1-5). The first generation of studies was essentially morphological in nature. More recently, profiting from technological developments, studies have been undertaken at the cytogenetic (6, 7) and biochemical (8) levels. We present here a progress report on the results of the biochemical approach at approximately the midpoint of the study. No statistically significant difference between the children of exposed and control parents can be demonstrated at this time (nor was it expected at this juncture in the study). In addition to the timeliness of a progress report, however, the present publication is dictated by three other considerations. (i) The current intense interest in the genetic effects of low-level ionizing radiation has prompted a complete re-evaluation of 30 years of genetic studies on the effects of the atomic bombs; the present data can be integrated into that treatment. (fi) The control aspects of the data of this study can be combined with similar data from other studies to yield a direct estimate of the rate at which spontaneous mutation results in electrophoretic variants of proteins; this should be useful in planning the feasibility and magnitude of any other genetic studies of this type. (Wi) A wealth of data on biochemical variants in Japanese has accumulated during the past 7 years; this description should clear the way for the presentation of this information.
Studies of a Japanese population, involving a total of 539,170 locus tests distributed over 36 polypeptides, yielded three presumptive spontaneous mutations altering the electrophoretic mobility of the polypeptide. This corresponds to a mutation rate of 0.6 x 10-5 per locus per generation. The apriori probability that undetected discrepancies between legal and biological parentage might in our test system result in an apparent electrophoretic mutation in this population is calculated to be only 0.3 x 10-7 per locus per generation. Since electrophoresis only detects about half of the amino acid substitutions due to mutations of nucleotides, the corrected rate for mutations causing amino acid substitutions in polypeptides is 1.2 x i0-5 per locus per generation. With allowance for synonymous mutations and those resulting in stop codons, the total mutation rate for nucleotide changes in the exons encoding a polypeptide becomes =1.8 x 10-5 per locus per generation. When the present observations are combined with all of the other available data concerning mutation resulting in electrophoretic variants, the electrophoretic rate drops to 0.3 x 10-5 per locus per generation, the total locus rate drops to roughly 1.0 x 10-5, and the nucleotide rate drops to 1 x 10-8. Even with this lower estimate, given -2 x 109 nucleotides in the haploid genome and an average of 103 exon nucleotides per polypeptide encoded, the implication, if these exon rates can be generalized, is of -20 nucleotide mutations per gamete per generation. This estimate of the frequency of "point" mutations does not include small duplications, rearrangements, or deletions resulting from unequal crossing-over, transcription errors, etc.In a previous report in these PROCEEDINGS we have described the protocol and the preliminary results of a search for mutations altering the electrophoretic behavior of a series of proteins, in children of atomic bomb survivors and a suitable group of control children (1). This study has now been completed. In the present report we describe the spontaneous mutation rate observed in the so-called control children of that study-i.e., children both of whose parents were more than 2500 meters from the hypocenter at the time of the bombings or one ofwhose parents was at this distance and the other was not in the city. These parents, referred to as the distally exposed, are presumed to have received either no radiation, or very negligible amounts (<1 rad; 1 rad = 0.01 gray), at the time of the bombings (ATB). In a few instances, neither of the parents in the control group was in the city ATB. These data are combined with other similar data available from the world literature to obtain a best estimate of the rate with which mutation results in electrophoretic variants and to infer both the total rate with which mutation results in an amino acid substitution in proteins and the nucleotide mutation rate to which this corresponds. Whenever a rare variant was encountered, an effort was made to obtain a blood sample from both the f...
SummaryA total of 17,126 individuals, of whom 1t,833 are unrelated, living in Hiroshima and Nagasaki were examined for erythrocyte phosphoglucomutase-2 (PGM2) by starch gel electrophoresis using TEMM buffer, pH 7.4. Four kinds of hereditary rare variants were encountered, three detected in single families and the one remaining in 9 unrelated families. In addition, a fresh mutant whose main band migrated slightly cathodal to the d-band was detected in a male child in Nagasaki, whose parents were proximally exposed to the atomic bomb in that city. The results described here confirm our previous data that PGM2 variation is quite low among the Japanese.
The frequency of inherited variations in thermostability was investigated in a series of seven enzymes in a Japanese population. Among a total of 5930 determinations, nine variants were encountered. In each instance one parent exhibited a similar finding. It is suggested that this procedure should detect a high proportion of the variants of these enzymes characterized by amino acid substitutions not altering molecular charge. Failure to detect more such thermostability variants is interpreted to mean that electrophoresis not only detects amino acid substitutions altering molecular charge but also a considerable proportion of those that do not alter charge.
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