Aging & Genomic Changes: Role of Environment/Genetics

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DESCRIPTION (provided by applicant): Although acquired cytogenetic changes have been implicated in several human conditions (especially cancer), their cause(s) are poorly understood. Do individuals have a genetic predisposition to develop genomic changes or is the frequency of abnormalities most heavily influenced by environmental factors? Does telomere shortening contribute to an increased frequency of acquired chromosomal abnormalities in humans? To answer these primary questions, we will determine (1) the frequency of acquired chromosomal changes in lymphocytes and buccal mucosa cells; and (2) chromosome-specific telomere lengths in identical (MZ) and fraternal (DZ) twins. The cytogenetic abnormalities will be identified for each of the 24 human chromosomes using a novel assay we developed which combines spectral karyotyping (SKY), fluorescence in situ hybridization (FISH), and micronuclei technologies. The chromosome-specific telomere lengths will be determined using newly developed methods that exploit FISH-based and DMA combing technology, the latter of which allows for unprecedented resolution (as small as 1-3 kb) in measures of chromosome length. These telomere and chromosome abnormality measures will be obtained for 220 same-sex twin pairs (110 MZ and 110 DZ pairs). The twins will vary in age (ranging from 6 y.o. to at least 80 y.o.) to allow us to quantify the association between aging and the acquisition of chromosomal aberrations. The extent to which individual differences in chromosomal instability and telomere lengths are determined by additive genetic, common environmental, and specific environmental effects will be assessed using a method of robust variance component estimation (implemented in the FISHER quantitative genetics package). Collectively, the study results will enable us to make the first quantitative estimate of the proportion of acquired changes in chromosomal complements and chromosome-specific telomere length that is attributable to genetic and/or environmental factors in humans. The data from this investigation will also lead to the first direct estimate of the contribution that telomere lengths play in the formation of acquired chromosome abnormalities in humans. This information is needed for designing human mutagen and health screening tests, as well as the development of pharmacogenetic strategies to test for individual differences in susceptibility to changes in the human genome.