Instability of interstitial telomeric sequences in the human genome

The length variability of four human interstitial telomeric sequences (ITs) is described. Three of the ITs contain short telomeric stretches ranging b etween 53 and 84 bp and are localized in 21q22, 2q31, and 7q36; the fourth IT derives from the subtelomeric domain of chromosome 6p and contains a tra ct of a few hundred basepairs of exact and degenerate repeats. Using primer s flanking the repeats, we amplified the genomic DNA from unrelated individ uals and from family members, and we found that all the loci are polymorphi c. At the 21q22 IT locus, two equally frequent alleles were found, while th e number of alleles at the 2q31, 7q36, and 6pter IT loci was 8, 6, and 4, r espectively. Sequence analysis revealed that in the three loci containing s hort ITs the alleles differ from one another for multiples of the hexanucle otide; it is likely that the mechanism leading to the polymorphism is DNA p olymerase slippage. These loci we:re also unstable in gastric tumor cells c haracterized by microsatellite instability. At the 6pter IT locus, the four alleles range in length from about 500 to about 700 bp; this variability i s probably due to unequal exchange or gene conversion. Our data indicate th at stretches of exact internal telomeric repeats can be highly unstable, li ke microsatellites with shorter units, and that they can be useful polymorp hic mailers for linkage analysis, for forensic applications, and for the de tection of genetic instability in tumors. (C) 2000 Academic Press.