Telomere integrity of de novo terminal deletions

Baylor College Of Medicine, Houston TX

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Abstract

Although about 3% of the World's population are mentally retarded, the etiology of mental retardation of the majority of patients is unknown. Of the known causes, chromosomal abnormalities account for about 20% of cases. An under-recognized cytogenetic abnormality, which contributes to the mentally retarded population, is deletion of the terminal band of the short arm of chromosome 1. Preliminary mapping of the subtelomeric- region of distal 1p has revealed diversity in the ends of the chromosomes with some apparent terminal deletions, some patients of this proposal is to understand the mechanisms involved in generating terminal deletions. We will use deletions of the short arm of chromosome 1 as a model system to explore the following specific aims. Aim 1: To distinguish the various types of rearrangements that comprise a group of cytogenetically terminal deletions. Deletions of 1p36 will be screened with a commercially available set of telomere region-specific fluorescence in situ hybridization (FISH) probes to identify those that are terminal deletions. Deletions of 1p36 will be screened with a commercially available set of telomere region-specific fluorescence in situ hybridization (FISH) probes to identify those that are terminal deletions, interstitial deletions, or derivative chromosomes (products of an unbalanced translocation). Aim 2: To determine the structure of the subtelomeric region of distal 1p. This will define the end of the physical and genetic map of 1p will enable the identification of deletion breakpoints and identify genomic regions that may recombine with 1pter to produce deletion and derivative chromosomes. Aim 3: Identify the mechanisms by which terminal deletions are formed and stabilized. Using reagents from Aim 2, subtelomeric sequences will be defined and deletions screened for retention of the subtelomeric region. Those without subtelomeric regions will be investigated for the de novo synthesis of the telomeric repeat using a variety of techniques. Aim 4: Delineate a DNA sequence that is susceptible to chromosome breakage or recombination that results in terminal deletions of 1p36. Breakpoints will be identified and sequenced for 1p36 deletions. Sequence comparison of breakpoints is likely to identify a common sequence susceptible to breakage or rearrangement. Aim 5: Determine the evolution and organization of orthologous sequences to human 1p36 in higher primates and determine the fidelity of the breakpoint susceptibility locus in the karyotypic evolution of higher primates. Reagents from Aim 2 will be used to interrogate the genomic structure in higher primates. Breakpoint susceptibility sequences will be analyzed in the primate species to understand their organization and role in karyotypic evolution.