THE TETRANUCLEOTIDE REPEAT POLYMORPHISM D21S1245 DEMONSTRATES HYPERMUTABILITY IN GERMLINE AND SOMATIC-CELLS

Six novel polymorphic short sequence repeats were identified and local ized on the linkage map of human chromosome 21 by genotyping the CEPH reference pedigrees, One of these markers, the tetrameric (AAAG)(n) re peat D21S1245, was found to be hypermutable, In the DNAs from lymphobl astoid cell lines of members of the 40 CEPH families a total of 18 new alleles were detected, These new alleles, sometimes appearing in mosa ic forms, arose equally in paternal and maternal DNAs, and could be eq ually larger or smaller than the alleles from which they were derived, The larger alleles of D21S1245 are more prone to be converted to new alleles, None of the new alleles with mosaicism were present in the co rresponding genomic blood DNA, and therefore originated during or afte r the establishment of the lymphoblastoid cell lines; half of the new alleles without mosaicism were also found in genomic blood DNA of the appropriate CEPH individuals, The range of germline mutation rate obse rved in the 716 meioses examined was 0.56-1.4x10(-2); the range of som atic mutations observed in the 405 cell lines examined was 1.96-3.46x1 0(-2). This is one of the most hypermutable microsatellite repeat poly morphism in the human genome detected to date, D21S1245, is highly pol ymorphic (heterozygosity of 0.96) and maps between D21S231 and D21S198 .