Expression and Function of Cone Pigment Genes

描述（来自申请人的摘要）：三种视觉色素介导 人类、旧大陆猴子和猿的三色色觉。的基因 几乎相同的编码中波长和长波长敏感色素， 分别缩写为M和L。M和L基因位于一个头对尾的位置， X染色体上的串联阵列，并通过基因复制事件产生 据估计，在灵长类谱系中发生了大约3500万至6000万起 年前短波长敏感性色素（S）由一个 常染色体，并估计已偏离祖先M/L基因约 在8 - 11亿年前。人类和灵长类动物的绝大多数视锥细胞 视网膜是M或L视锥，只有大约7%的视锥是S。 在L和M视锥细胞中，每个细胞仅表达一种色素基因 从X染色体阵列上有两个根本性的重要问题没有解决 关于X染色体连锁的视色素基因表达的谜团， 这是这次赠款的重点。首先，M和L视锥是否代表两个不同的 细胞类型，因此M视锥细胞特异性机制指导M 色素，和L锥特异性机制指导L色素的表达？在 在这种情况下，M视锥细胞和L视锥细胞是独特的不同，事实上它们 表达不同的色素是次要的这些其他差异。或者， M和L视锥细胞是一种细胞类型，其中有一个随机过程， X染色体色素基因的互斥表达在这 在这种情况下，选择用于表达的基因的身份决定了该基因是否被表达。 圆锥体将是M或L圆锥体。第二个谜团是，是什么决定了 来自单个阵列的基因被表达？最近的证据表明 在具有3个基因的阵列中，阵列中的最后一个基因（最3 ′）不表达。 但如果是4个基因的阵列，第三个基因表达了吗？ 解开这两个谜团将对我们理解 基本的生物学过程，决定了组织的 光感受器镶嵌，以及神经回路如何连接以提取颜色 第一个突触的信息。为了解开这些谜团我们建议 具体目的如下：1）表征 2）为了测试产生高表达的机制的模型， 人类L和M基因序列多态性的程度， 观察下游基因的表达模式，3）进行发育 和比较研究，以检验随机模型; 4）开发创新的 用于直接测试随机模型的模型。

DESCRIPTION (From the Applicant's Abstract): Three visual pigments mediate trichromatic color vision in humans, Old World monkeys and apes. Genes that are nearly identical encode the middle- and long-wavelength sensitive pigments, abbreviated M and L, respectively. The M and L genes lie in a head-to-tail tandem array on the X-chromosome and were produced by a gene duplication event that is estimated to have occurred in the primate lineage about 35-60 million years ago. The short-wavelength sensitive pigment (S) is encoded by an autosome, and is estimated to have diverged from the ancestral M/L gene about 800-1 100 million years ago. The vast majority of cones in human and primate retina are either M or L cones, with only about 7 percent of cones being S. Among the L and M cones, each cell exclusively expresses only one pigment gene from the X-chromosome array. There are two fundamentally important unsolved mysteries regarding expression of the X-linked visual pigment genes that are the focus of this grant. First, do the M and L cones represent two distinct cell types, so that an M cone specific mechanism directs expression of M pigment, and an L cone specific mechanism directs expression of L pigment? In this scenario, the M and L cones are uniquely different, and the fact that they express different pigments is secondary to these other differences. Or, are the M and L cones one cell type in which there is a stochastic process that directs mutually exclusive expression of one of the X-chromosome pigment genes? In this scenario, the identity of the gene chosen for expression determines whether the cone will be an M or an L cone. The second mystery is, what determines which of the genes from an individual array are expressed? Recent evidence suggests that in arrays with 3 genes, the last gene in the array (3' most) is not expressed. But what about arrays with 4 genes, is the third gene expressed? Solving these two mysteries will have profound impact on our understanding of the fundamental biological processes that determine the organization of the photoreceptor mosaic, and of how neural circuits are wired to extract color information at the first synapse. Towards solving these mysteries we propose the following 4 specific aims: 1) To characterize the expression pattern of downstream genes, 2) To test the model for the mechanism that produces the high degree of L and M gene sequence polymorphism in humans implied from the observed expression pattern of downstream genes, 3) To conduct developmental and comparative studies to test the stochastic model; 4) To develop innovative models for directly testing the stochastic model.