NUCLEOTIDE-SEQUENCE ANALYSIS OF THE APOLIPOPROTEIN-B 3' VNTR

Variable number of tandem repeat (VNTR) loci typically exhibit high ra tes of germline mutations that alter allele length and thus are ideal models for examining processes governing repeat sequence instability, We have characterized by nucleotide sequencing the internal structure of the apolipoprotein B (Ape B) 3' VNTR in a sample of same- and diffe rent-sized alleles previously associated with flanking marker haplotyp es, Significant linkage disequilibrium between flanking polymorphisms and minisatellite alleles excludes unequal recombination as the predom inant mechanism of mutation at the Apo B VNTR and is consistent with i ntra-allelic mutational processes such as replication slippage and/or unequal sister chromatid exchange, Diversity among different length al leles was distinctly polar and was usually attributable to changes in copy number at one particular repeat sequence. Analysis of predicted s econdary structures for the dimeric repeats demonstrated a relationshi p between variability and the potential to form self-complementary int ermediates. Preferential instability of the variable repeat: (i) was a function of its location within the tandem array; (ii) was not solely dependent on copy number; and (iii) may be related to the base compos ition of the VNTR and the degree of self-complementarity between the d imeric repeat sequences. The data suggest that polarized variability m ay be independent of the mutational process(es) generating length vari ation at minisatellite loci and suggest a possible alternative mechani sm of mutation that involves the formation of secondary structures.