Abstract
It is widely known that there are many copy number polymorphisms in the human genome and several are related to certain kinds of disease or individual differences. While most are transmitted from parent to child, a few arise de novo. We have investigated whether atomic-bomb radiation causes de novo copy number mutations in the germ cells of atomic-bomb survivors by examining the genome of offspring of atomic-bomb survivors. In case only one of the parents was exposed to radiation, it was necessary to discriminate whether mutation occurred on which one of homologous chromosome of offspring derived from their parents. In order to examine the whole human genome, we conducted the examination using BAC-array CGH on which about 2,500 BAC clones were printed. The study used genomic DNA from 265 offspring of atomic-bomb survivors and 40 offspring of an unexposed control group. Three mutations were identified in three offspring, that were not in their parents. One mutation was a deletion type involving a 1.4 Mb length of chromosome 1q41 and two mutations were an amplification type involving 131,290 bp of 5p15.2 and 431,737 bp of 17p13.3, respectively. In the breakpoints of the deletion mutation, precise breakpoints could not be determined, segmental duplications were involved in both termini. There were microhomologies in the each breakpoint of both two amplification mutations. Because only one of the parents was the atomic-bomb survivor in all three families, we needed to determine parental origin of the de novo mutations. We used an Affymetrix SNP array 6.0 to examine Mendelian inconsistency of SNP information in the genome region involving the mutations. We examined 422 SNPs in the genome region involving the deletion mutation, of which 43 SNPs were informative for discrimination of parental origin. There were 54 and 85 SNPs in the genome regions involving the two amplification mutations, of which 15 SNPs were informative for each. Informative SNPs for each case showed that all three mutations occurred on a chromosome derived from the radiation-exposed father. The SNP array was valuable for determination of the parental origin of de novo copy number mutations. This number of de novo mutations (three) is too small to reach a solid conclusion as to whether the mutation rate of the children of atomic-bomb survivors is significantly higher than in those from control group. We will continue and expand our study to increase the statistical power.
