In vivo somatic microsatellite mutations identified in non-malignant human tissue

Microsatellite instability (MSI) has been described in cancer cells and in vitro cell lines, and meiotic changes in repeat length have also been documented. We report the novel observation of somatic microsatellite mutation (SMM) in normal human somatic cells in vivo, detected while genotyping 5767 prenatal samples (4640 amniotic fluid samples and 1127 chorionic villus biopsies) as a diagnostic test for exclusion of trisomy 13, 18 or 21. Quantitative fluorescence-PCR using a multiplex of 12 primer pairs, for four loci on each of the three chromosomes, was followed by fragment analysis on a capillary-based genetic analyser. Forty-seven (4.2%) chorionic villus samples and six (0.1%) amniotic fluid samples showed allelic mosaicism, interpreted as SMM. In four cases, analysis of parental blood samples confirmed the presence of a de novo allele. SMM was detected at all but two of the 12 loci tested, and the incidence of mutation increased with repeat length. Detection of SMM in chorionic villus samples may imply less rigorous correction of replication errors in these extra-embryonic tissues, and is likely to have been facilitated by clonal expansion in the small samples of tissue tested. The presence of the same phenomenon in six amniotic fluid samples would imply that in these pregnancies, the instability event had occurred early in embryogenesis. The results suggest that defective proof reading during DNA replication may be more common in non-malignant human somatic tissue than previously recognised.