NBS1 founder mutation and Darwinian fitness
The chromosomal instability disorder, Nijmegen breakage syndrome (NBS), is characterized by microcephaly, growth retardation, immunodeficiency, hypersensitivity to X-irradiation, and predisposition to lymphoid malignancy. Nibrin, the product of the NBS1 gene, is part of the MRE11/RAD50 complex, which is involved in the repair of DNA double strand breaks (DSBs). The majority of NBS patients carry the common founder mutation in the NBS1 gene, 657del5. This is not a null mutation but rather a hypomorphic mutation, since a truncated, functionally active protein is produced. We found an unexpectedly high carrier frequency of the founder mutation in newborn of five different slavic populations: Czech Republic, Poland, Ukraine, Bulgaria, and the sorbs. Thus, the original mutational event occurred while the slavic people were still together in their homeland, the Pripet swamp, more than 1,500 years ago. If one excludes that this independent increase in allelic frequency is simply due to chance, it must result from a different reproduction rate under gene carriers. This has been confirmed in a cohort study on the reproductive history of persons from the Czech Republic. We found that in consecutive generations, female gene carriers gave birth to more children than the non-carriers and had less miscarriages. Since in man, oogenesis is an error prone process, perhaps due to a checkpoint defect, leading to a high rate of aneuploidy and consequently spontaneous abortions, we assume that the NBS heterozygotes exhibit a lower non-disjunction rate compared to normal homozygous females. This effect is, perhaps, related to the truncated protein found in NBS heterozygotes which is obviously expressed during oogenesis and might, directly or indirectly, improve the defective checkpoint control during meiosis.