Molecular organization and haplotype analysis of centromeric DNA from human chromosome 17: implications for linkage in neurofibromatosis.

The alpha satellite DNA subset located at the centromere of human chromosome 17 has been shown to be tightly linked genetically to the gene for von Recklinghausen neurofibromatosis (NF1). The centromeric DNA polymorphisms used for linkage analyses in NF1 are complex and involve a "locus" (D17Z1) that spans over one million base pairs of satellite DNA. To understand more completely the basis for these polymorphisms and how they might be best scored and used in the analysis of NF1, we have examined the molecular composition of the alpha satellite array on individual copies of chromosome 17 by two complementary approaches. First, we have analyzed segregation of chromosome 17 alpha satellite haplotypes in large, three-generation families that provide information on the different types of alpha satellite segregating in a block fashion. Second, we have analyzed directly the extent of variation in different D17Z1 arrays by genomic blotting analysis of haploid copies of chromosome 17 isolated in rodent/human somatic cell hybrids. The data indicate the existence of a wide range of different alpha satellite variants on individual copies of chromosome 17, each haplotype differing in the size, restriction map, and relative proportion of particular polymorphic repeat forms. Despite this complexity, the D17Z1 markers provide a potentially useful and genetically close starting point for the molecular and clinical analysis of NF1.