Molecular Genetics of Color Vision

描述(申请人提供)：本提案的长期目标是全面定义人类色觉的分子遗传学及其常见缺陷，并阐明X连锁的红绿色觉基因表达的调控机制。由于长波敏感色素(L)和中波敏感色素(M)存在共同的光谱变异，导致各种色觉缺陷，该基因座存在显著的基因型和表型的异质性。初步研究表明，一些携带L和M三种色素基因的女性具有额外的颜色辨别能力。我们将调查这种扩展的颜色辨别能力的遗传基础。 长波敏感(L)或红色素基因和中波敏感(M)或绿色素基因在X染色体上相邻定位，但视网膜圆锥只表达L或M色素基因-这一发现是红/绿色视觉的基础。我们发现，人视网膜母细胞瘤细胞系WERI以互斥的方式表达红色和绿色色素基因，细胞分裂重置在子细胞中表达的基因类型，这为阐明调控机制提供了独特的机会。这个系统提供了一个优雅的模型来研究基本的调控过程，该过程控制着特定细胞中一系列密切相关基因的开关。 最近的技术进步促进了跨基因调控模块的高分辨率作图，并使识别与这些模块结合的调控蛋白成为可能。我们将把这些高效、快速的方法应用到红/绿颜色轨迹的研究中。此外，我们还将利用最近发展起来的、功能强大的RNA抑制方法在WERI细胞中从功能上剖析其中一些蛋白质在L和M色素基因表达中的作用。 阐明该基因调控影响感觉知觉的分子机制是相似复杂基因座基因表达的模型。我们建议鉴定的新的光感受器基因可能是一些遗传性视网膜疾病的很好的候选基因。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to fully define the molecular genetics of human color vision and its common defects, and to elucidate the mechanisms of regulation of expression of the X-linked red-green color vision locus. A remarkable heterogeneity of genotypes and phenotypes exist at this locus due to the existence of common spectral variants of the long wave sensitive (L) and middle wave sensitive (M) pigments causing various color vision defects. Preliminary studies have shown that some women who carry three forms of the L and M pigment genes have additional color discrimination capacity. We will investigate the genetic basis for this extended color discrimination capacity. The long wave sensitive (L) or red pigment gene and the middle wave sensitive (M) or green pigment gene are located next to each other on the X chromosome but a retinal cone only expresses either the L or the M pigment gene - a finding that is fundamental for red/green color vision. Our discovery that the human retinoblastoma cell line WERI expresses the red and green pigment genes in a mutually exclusive manner and that cell division resets the type of gene expressed in daughter cells provides a unique opportunity to elucidate regulatory mechanisms. This system furnishes an elegant model to study a basic regulatory process that controls the on and off switch of an array of closely related genes in a specialized cell. Recent technological advances have facilitated high resolution mapping of regulatory modules across genes, and allowed identification of regulatory proteins that bind to these modules. We will apply these efficient and rapid approaches to our studies on the red/green color locus. In addition, we will functionally dissect the role of some of these proteins in expression of the L and M pigment genes by the recently developed and powerful method of RNA inhibition (RNAi) in WERI cells. Elucidation of the molecular mechanisms of regulation of the genes of this locus affecting sensory perception is a model for expression of genes in analogous complex loci. The novel photoreceptor genes we propose to identify may be good candidates for some inherited retinal diseases.