SOMATIC INTRAGENIC RECOMBINATION WITHIN THE MUTATED LOCUS BLM CAN CORRECT THE HIGH SISTER-CHROMATID EXCHANGE PHENOTYPE OF BLOOM-SYNDROME CELLS

Cells from persons with Bloom syndrome feature an elevated rate of sis ter-chromatid exchange (SCE). However, in some affected persons a mino rity of blood lymphocytes have a normal SCE rate. Persons who inherit the Bloom syndrome gene BLM identical by descent from a common ancesto r very rarely exhibit this high-SCE/low-SCE mosaicism; conversely, mos aicism arises predominantly in persons who do not share a common ances tor. These population data suggested that most persons with Bloom synd rome in whom the exceptional low-SCE cells arise are not homozygous fo r a mutation at BLM but instead are compound heterozygotes. Following this clue, we carried out a genotype analysis of loci syntenic with BL M in 11 persons who exhibited mosaicism. In five of them, polymorphic loci distal to BLM that were heterozygous in their high-SCE cells had become homozygous in their low-SCE cells, whereas heterozygous loci pr oximal to BLM remained heterozygous. These observations are interprete d to mean that intragenic recombination between paternally derived and maternally derived mutated sites within BLM can generate a functional ly wild-type gene and that low-SCE lymphocytes are progeny of a somati c cell in which such intragenic recombination had occurred.