ESTIMATION OF THE AGE OF THE ANCESTRAL ARGININE(3500)-]GLUTAMINE MUTATION IN HUMAN APO-B-100

Familial defective apoB-100 (R3500Q) [FDB (R3500Q)] is caused by a mut ation in the apoB gene (2p23.24). Almost all individuals with this dis order are of European descent, and in almost all cases the mutation is on a chromosome with a rare haplotype (194) at the apoB locus, sugges ting that all FDB (R3500Q) probands are descended from a common ancest or in whom the original mutation occurred. The distribution of the mut ation is consistent with an origin in Europe 6000-7000 years ago. We h ave estimated the amount of recombination between the apoB gene and ma rkers on chromosome 2 in 34 FDB (R3500Q) probands in whom the mutation is on a 194 haplotype. Significant linkage disequilibrium was found b etween the apoB gene and marker D2S220. We have identified three YACs that contain the apoB gene and D2S220. The shortest restriction fragme nt common to the three YACs that contained both loci was 240 kb long. No shorter fragments with both loci were identified. On the assumption that 1000 kb corresponds to 1 cM, we deduce that the recombination di stance between D2S220 and the apoB gene is about 0.24 cM. Combining th is value with the linkage disequilibrium observed between the two loci in the probands, we estimate that the ancestral mutation occurred abo ut 270 generations ago. We postulate that the original mutation occurr ed in the common ancestor of living FDB (R3500Q) probands, who lived i n Europe about 6750 years ago. The errors in this estimate are discuss ed. (C) 1997 Academic Press.