MOLECULAR GENETICS OF COLOR VISION

该建议的中心目标是通过将X连锁的色素基因的分子遗传学与其在视网膜中的表达和色觉表型相关联来定义红/绿色色觉的分子遗传学。红色和绿色色素基因在X染色体上排列成阵列，由单个红色和一个或多个绿色色素基因组成。由于该基因座的不合理重组而导致的基因缺失或杂合基因（红绿和绿红）的形成导致色觉缺陷。然而，并不是所有其他基因的红色/绿色阵列中表达的视网膜，在预测色觉表型从基因型的不确定性。理解这些基因选择性表达的机制是确定基因型-表型关系的基础。我们已经划定了红-绿基因位点的关键调控区域，并检测了与之结合的蛋白质。本研究的主要目的是克隆和鉴定在调节视色素基因表达中起主要作用的转录因子。我们将绘制人类和小鼠染色体上编码这些因子的基因。图谱位置将与视网膜疾病相关的已知基因座相关联。我们开发了一种快速的方法来确定基因顺序的男性谁有多达三个色素基因在他们的阵列，并发现证据的基因表达和色觉的基因顺序的作用。我们建议改进他们的方法，以确定大多数个体的基因顺序。了解序列和基因顺序将允许更精确地预测克隆的光谱敏感性和色觉表型。红、绿色视锥细胞的比例是通过测量死后人视网膜中mRNA的相对水平间接确定的。我们建议通过原位分子技术直接确定视网膜中视锥细胞的比例和分布。这些发现对视觉科学具有根本的重要性。我们在非洲人中观察到非常高频率的绿红杂交基因。我们将研究这些杂交体的序列并确定它们在阵列中的位置。阐明该位点影响感觉知觉的表达的分子机制是其他复杂位点基因表达的模型。这些研究可能会导致快速和准确的色觉缺陷的血液测试。我们建议克隆的新型感光细胞特异性基因可能是某些遗传性视网膜疾病的良好候选基因。

The central objective of this proposal is to define the molecular genetics of red/green color vision by relating the molecular genetics of the X- linked photopigment genes to their expression in the retina and to the color vision phenotype. The red and green pigment genes are arranged in an array on the X-chromosome consisting of a single red and one or more green pigment genes. Deletion of genes or formation of hybrid genes (red-green and green-red) due to illegitimate recombination at this locus causes color vision defects. However, not all other gens of the red/green array are expressed in the retina, creating uncertainties in predicting color vision phenotype from genotype. Understanding the mechanism by which selective expression of these genes is accomplished is fundamental to defining genotype-phenotype relationships. We have delineated critical regulatory regions of the red-green gene locus and detected proteins that bind to them. A major aim of this proposal is to clone and character the transcription factors that play major roles in regulating expression of the visual pigment genes. We will map the genes encoding these factors on human and mouse chromosomes. Map positions will be correlated with known loci associated with retinal diseases. We developed a rapid method for determining gene order in males who have up to three pigment genes in their arrays and found evidence for a role of gene order in gene expression and color vision. We propose to advance their method in order to determine gene order in the majority of individuals. Knowing the sequence and gene order will allow more precise prediction of the spectral sensitivities of clones and the color vision phenotype. The ratio of red to green cones was determined indirectly by measuring relative levels of mRNA in postmortem human retinae. We propose to determine the ratio and distribution of cones in the retina directly by in situ molecular techniques. The findings will be of fundamental importance for the visual sciences. We observed a very high frequency of green-red hybrid genes among Africans. We will investigate the sequence of these hybrids and determine their position in the array. Elucidation of the molecular mechanism of expression of this locus affecting sensory perception is a model for expression of genes in other complex loci. These studies may lead to rapid and accurate blood tests for color vision defects. The novel photoreceptor-specific genes we propose to clone may be good candidates for some of the inherited retinal diseases.