Aging & Genomic Changes: Role of Environment/Genetics

描述（由申请人提供）：尽管获得性细胞遗传学改变与几种人类疾病（尤其是癌症）有关，但其原因尚不清楚。个体是否有遗传易感性来发展基因组变化，还是异常的频率受环境因素的影响最大？端粒缩短是否导致人类获得性染色体异常的频率增加？为了回答这些主要问题，我们将确定(1)淋巴细胞和颊粘膜细胞获得性染色体改变的频率；(2)同卵双胞胎（MZ）和异卵双胞胎（DZ）染色体特异性端粒长度。我们将利用一种结合了光谱核型（SKY）、荧光原位杂交（FISH）和微核技术的新检测方法，对24条人类染色体中的每一条进行细胞遗传学异常鉴定。染色体特异性端粒长度将使用新开发的方法来确定，该方法利用基于fish和DMA的梳理技术，后者允许前所未有的分辨率（小至1-3 kb）来测量染色体长度。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）。这些双胞胎的年龄各不相同（从6岁到至少80岁），这样我们就可以量化衰老和染色体畸变之间的关系。染色体不稳定性和端粒长度的个体差异在多大程度上是由加性遗传、共同环境和特定环境影响决定的，将使用稳健方差分量估计方法进行评估（在FISHER定量遗传学软件包中实施）。总的来说，研究结果将使我们能够首次定量估计人类遗传和/或环境因素导致的染色体补体和染色体特异性端粒长度获得性变化的比例。这项研究的数据也将导致第一次直接估计端粒长度在人类获得性染色体异常形成中的作用。这些信息对于设计人类诱变原和健康筛查试验，以及制定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都是必要的。

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.