Chimerism in humans after intragenic recombination at the haptoglobin locus during early embryogenesis.
The human haptoglobin (HP) HP*2 allele contains a 1.7-kilobase (kb) intragenic duplication that arose after a unique nonhomologous recombination between the prototype HP*1 alleles. During a genetic screening of 13,000 children of survivors exposed to atomic-bomb radiation and 10,000 children of unexposed persons, two children suspected of carrying de novo mutations at the haptoglobin locus were identified (one in each group). DNA analyses of single-cell-derived colonies of Epstein-Barr virus-transformed B cells revealed that the two children were mosaics comprising HP*2/HP*2 and HP*2/HP*1 cells at a ratio of approximately 3:1. We infer that the latter cells are caused by reversion of one HP*2 allele to HP*1 through an intramolecular homologous recombination between the duplicated segments of the Hp*2 allele that excised one of the segments. Because the mosaicism is substantial (approximately 25%), this recombination must have occurred in early embryogenesis. The frequency of finding these children and the extent of their mosaicisms corresponds to an HP*2 to HP*1 reversion rate of 8 x 10(-6) per cell during development. This leads to the prediction that the HP*1 allele also will be represented, although usually at a very low frequency, in any HP2-2 person. We tested this prediction by using PCR for a single individual and found the HP*1 allele at frequencies of 4 x 10(-6) and 3 x 10(-6) in somatic and sperm cells. The HP*1 allele was detected by PCR in all four other HP2-2 individuals, which supports the regular but rare occurrence somatically of homologous recombination within duplicated regions in humans, in agreement with previous observations in mouse and Drosophila.
Asakawa
J
J
Department of Genetics, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima 732-0815, Japan. asakawa@rerf.or.jp
Kodaira
M
M
Nakamura
N
N
Satoh
C
C
Fujita
M
M
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes; D002648:Child; D002678:Chimera; D003434:Crossing Over, Genetic; D005314:Embryonic and Fetal Development; D005260:Female; D014644:Genetic Variation; D006242:Haptoglobins / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D051379:Mice; D009030:Mosaicism; D009154:Mutation; D009689:Nuclear Warfare; D011995:Recombination, Genetic / Q000528:radiation effects; D017741:Survivors
D006242:Haptoglobins