Microsatellite DNA mutations and human embryonic mortality

In the analysis of tetranucleotide DNA repeats inheritance carried out in 5 5 families with a history of spontaneous miscarriages and normal karyotypes in respect to 21 loci located on seven autosomes, 8 embryos (14.5%) demons trating 12 cases of the presence of alleles absent in both parents were des cribed. The study of chromosome segregation using other DNA markers permitt ed highly probable exclusion of false paternity as well as uniparental diso my as the reasons for parent/child allele mismatches. A high probability of paternity, together with the presence of a "new" allele at any offspring l ocus, points to the mutation having occurred during gametogenesis in one of the parents. Examination of mutation in spontaneous abortuses revealed an increased number of tandem repeat units at microsatellite loci in three cas es and an decreased number of these repeats in six cases. In two abortuses, a third allele absent in both parents, which resulted from a somatic mutat ion that occurred during embryonic development, was observed. The prevalenc e of the male germline mutations, revealed during investigation of the muta tion origin, was probably associated with an increased number of DNA replic ation cycles in sperm compared to the oocytes. In spontaneous abortuses, th e mean mutation rate of the tetranucleotide repeat complexes analyzed was 9 .8 x 10(-3) per locus per gamete per generation. This was about five times higher than the spontaneous mutation rate of these STR loci. It can be sugg ested that genome instability detected at the level of repeated DNA sequenc es can involve not only genetically neutral loci but also active genomic re gions crucial for embryonic viability. This results in cell death and termi nation of embryonic development. Our findings indicate that the death of em bryos with normal karyotypes in most cases is associated with an increased frequency of germline and somatic microsatellite mutations. The data of the present study also provide a practical tool for the quantitative evaluatio n of this phenomenon and for the analysis of the reasons for miscarriages a nd embryonic death in certain families.