Chowers Itay, Liu Dongmei, Farkas Ronald H, Gunatilaka Tushara L, Hackam Abigail S, Bernstein Steven L, Campochiaro Peter A, Parmigiani Giovanni, Zack Donald J
Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Hum Mol Genet. 2003 Nov 15;12(22):2881-93. doi: 10.1093/hmg/ddg326. Epub 2003 Sep 30.
Despite evidence that differences in gene expression levels contribute significantly to phenotypic variation across individuals, there has been only limited effort to study gene expression variation in human tissue. To characterize expression variation in the normal human retina, we utilized a custom retinal microarray to analyze 33 normal retinas from 19 donors, aged 29-90 years. Statistical models were designed to separate and quantify biological and technical sources of variation, including age, gender, eye laterality, gene function and age-by-gender interaction. Although the majority of the 9406 genes analyzed showed relatively stable expression levels across different donors (for an average gene the expression level value of 95 out of a 100 individuals fell within a 1.23-fold range), 2.6% of genes showed significant donor-to-donor variation, with a false discovery rate of 10%. The mean expression ratio standard deviation was 0.15+/-0.8, log2, with a range of 0.09-0.99. Genes selectively expressed in photoreceptors showed higher expression variation than other gene classes. Gender, age and other donor-specific factors contributed significantly to the expression variation of multiple genes, and groups of genes with an age- and gender-associated expression pattern were identified. Our findings show that a significant fraction of gene expression variation in the normal human retina is attributable to identifiable biological factors. The greater expression variability of many genes central to retinal function (including photoreceptor-specific genes) may be partially explained by the dynamics of the vision process, and raises the possibility that photoreceptor gene expression levels may contribute to phenotypic diversity across normal adult retinas. In addition, as such diversity may result in different levels of disease susceptibility, exploring its sources may provide insights into the pathogenesis of retinal disease.
尽管有证据表明基因表达水平的差异对个体间的表型变异有显著贡献，但对人体组织中基因表达变异的研究却非常有限。为了表征正常人视网膜中的表达变异，我们使用定制的视网膜微阵列分析了来自19名年龄在29 - 90岁供体的33个正常视网膜。设计统计模型以分离和量化变异的生物学和技术来源，包括年龄、性别、眼别、基因功能以及年龄与性别的相互作用。虽然所分析的9406个基因中的大多数在不同供体中显示出相对稳定的表达水平（对于一个平均基因，100个个体中有95个个体的表达水平值落在1.23倍范围内），但2.6%的基因显示出显著的供体间变异，错误发现率为10%。平均表达比标准偏差为0.15±0.8（log2），范围为0.09 - 0.99。在光感受器中选择性表达的基因比其他基因类别显示出更高的表达变异。性别、年龄和其他供体特异性因素对多个基因的表达变异有显著贡献，并鉴定出具有年龄和性别相关表达模式的基因群。我们的研究结果表明，正常人视网膜中相当一部分基因表达变异可归因于可识别的生物学因素。许多视网膜功能核心基因（包括光感受器特异性基因）的更大表达变异性可能部分由视觉过程的动态变化来解释，并增加了光感受器基因表达水平可能导致正常成人视网膜表型多样性的可能性。此外，由于这种多样性可能导致不同程度的疾病易感性，探索其来源可能为视网膜疾病的发病机制提供见解。
