Aging & Genomic Changes: Role of Environment/Genetics

描述(申请人提供)：虽然获得性细胞遗传学改变与几种人类疾病(特别是癌症)有关，但其原因(S)尚不清楚。个体是否有发生基因组变化的遗传倾向，或者异常的频率受环境因素的影响最大吗？端粒缩短是否会增加人类获得性染色体异常的频率？为了回答这些主要问题，我们将确定(1)淋巴细胞和口腔粘膜细胞中获得性染色体变化的频率；以及(2)同卵双胞胎(MZ)和异卵双胞胎(DZ)的染色体特异端粒长度。我们开发的一种新的分析方法结合了光谱核型分析(SKY)、荧光原位杂交(FISH)和微核技术，将识别人类24条染色体中的每一条染色体的细胞遗传学异常。染色体特有的端粒长度将使用新开发的方法确定，该方法利用基于FISH和DMA梳理技术，后者允许在染色体长度测量中实现前所未有的分辨率(小至1-3kb)。这些端粒和染色体异常测量将获得220对同性双胞胎(110对MZ和110对DZ)。这对双胞胎的年龄会有所不同(从6岁到6岁不等。到至少80岁。)使我们能够量化衰老和获得染色体异常之间的联系。染色体不稳定性和端粒长度的个体差异在多大程度上由加性遗传、共同环境和特定环境效应决定，将使用稳健的方差分量估计方法(在Fisher定量遗传学包中实施)进行评估。总而言之，研究结果将使我们能够首次定量估计可归因于人类遗传和/或环境因素的染色体补体和染色体特定端粒长度的获得性变化的比例。这项研究的数据还将首次直接评估端粒长度在人类获得性染色体异常形成中所起的作用。这些信息是设计人类诱变剂和健康筛查测试以及开发药物遗传学策略以测试对人类基因组变化易感性的个体差异所必需的。

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.