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Molecular genetic analysis of human 8p inversion duplication chromosomes

University of British Columbia

Inversion duplications of the short arm of chromosome 8 (8p) with common morphology have been described in over 60 mentally retarded individuals. These aberrant chromosomes contain material derived from both maternal chromosomes, separated by a single copy region at a common center of symmetry, with deletion of distal subtelomeric sequences. A mechanism mediated by inverted repetitive elements may explain the recurrence of these similar aberrant chromosomes in unrelated patients. A megasatellite repeated sequence, localized to chromosome 8p23, was investigated as a candidate for the proposed repetitive elements. Cosmid clones isolated from a single chromosome 8 library contained three classes of megasatellite. Megasatellite-containing YAC clones map to two locations on chromosome 8p consistent with the flanking positions predicted by the known extent of the single copy region. Although the megasatellite sequences span 16 kb, all cosmids containing the megasatellite cross hybridize outside of this region. A BAC clone, that lacks the megasatellite but contains these crosshybridizing sequences within which the megasatellite is embedded, was used as a FISH probe to metaphase chromosomes. Hybridization occurred at multiple locations throughout the genome, including 8p23. Therefore, the 8p copies of the megasatellite are each embedded within a region of at least 160 kb that is itself reiterated throughout the genome. These results suggest that the megasatellite, embedded within a large reiterated region of the genome, may be involved in the generation of inversion duplication (8p) chromosomes by providing a site for anomalous interchromosomal recombination. Investigation of a patient where the single copy region could not be detected suggests that, in rare cases, other mechanisms may be involved.

Thesis/Dissertation

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2009-05-28

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http://hdl.handle.net/2429/8432

Genetics

University of British Columbia

UBCV

DSpace