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变化 与几种人类疾病（尤其是癌症）有关，其原因 我们对此知之甚少。个体是否有遗传倾向， 基因组变化或异常的频率最严重的影响 环境因素？端粒缩短是否有助于增加 人类获得性染色体异常的频率？回答这些 主要问题，我们将确定（1）获得性染色体 淋巴细胞和颊粘膜细胞的变化;（2）染色体特异性 端粒长度在同卵（MZ）和异卵（DZ）双胞胎。的细胞遗传学 将使用一种方法对24条人类染色体中的每一条染色体进行异常鉴定。 我们开发了一种新的分析方法，它结合了光谱核型分析（SKY）， 荧光原位杂交（FISH）和微核技术。的 染色体特异性端粒长度将使用新开发的 利用比较基因组杂交（CGH）和DNA梳理 方法，后者允许前所未有的分辨率（如小 如1-3 kb）。这些端粒和染色体 将获得200对同性双胞胎（100 MZ和 100 DZ对）。双胞胎的年龄各不相同（从6岁到10岁不等）。到至少80 y.o），以使我们能够量化衰老和获得之间的关联 染色体畸变个体差异的程度 染色体异常水平和端粒长度是由加性 遗传、共同环境和特定环境的影响， 使用稳健方差分量估计方法（在FISHER定量遗传学软件包中实施）进行评估。总的来说，研究结果将 使我们能够对获得的比例进行第一次定量估计， 染色体补体和染色体特异性端粒长度的变化， 这是由遗传和/或环境因素造成的。从这个数据 调查还将导致第一次直接估计的贡献 端粒长度在后天染色体形成中的作用 人类的异常这些信息是设计人类诱变剂所必需的 和健康筛查测试，以及药物遗传学的发展， 策略来测试个体差异的敏感性变化， 人类基因组

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 techniques that exploit comparative genomic hybridization (CGH) and DNA combing methodology, 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 200 same-sex twin pairs (100 MZ and 100 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 chromosome aberrations. The extent to which individual differences in chromosome abnormality levels 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. 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.