McMahon Carrie, Neitz Jay, Neitz Maureen
Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
J Vis. 2004 Mar 25;4(3):203-8. doi: 10.1167/4.3.7.
Men with normal color vision vary widely in the ratio of long- (L) to middle-wavelength sensitive (M) cones. This variation provides opportunities to test models for the mechanism that produces L versus M cones during development. The L and M photopigment genes lie in a tandem array. Each gene has a promoter, and upstream of each array there is a genetic element, termed the locus control region (LCR), that is required for the expression of both L and M pigment genes. During development, for each cell that has been determined to be an L or M cone, it has been proposed that the LCR acts as a stochastic selector which chooses one gene from the array to be expressed. In this model, the L and M promoters compete for contact with the LCR in each photoreceptor. Theoretically, the promoter that, by chance, is the first to successfully form a stable and permanent complex with the LCR commits the cell to a lifetime of exclusive expression of its associated gene. Under this model, it has been suggested that nucleotide differences in the promoters influence their ability to compete in forming a complex with the LCR. Thus, normal variation in L:M cone ratio is predicted to be associated with nucleotide polymorphisms in the promoters. Here we tested this hypothesis by comparing the L and M promoter sequences for 73 males with normal color vision for whom L:M cone ratio estimates had been obtained previously. The M gene promoter sequences were found to be identical for all 73 males and the L gene promoters were identical for 71 out of the 73 males. Two males had mutations where in each case the L promoter differed by one nucleotide substitution compared to normal. Both of the males with promoter mutations had unusual cone ratios which is consistent with the growing body of evidence indicating that the relative ability of the promoters to form a complex with the LCR is a factor in determining cone ratio. However, the vast majority of cone ratio differences were not associated with any difference in the promoter sequence. To explain the high degree of cone ratio variation among normal males, the mechanism that determines whether a cone is L or M must involve genetic elements that have a high degree of genetic polymorphism in the normal population. The results presented here indicate that there are additional genetic components of the mechanism which remain to be identified and incorporated into the present hypotheses.
具有正常色觉的男性，其长波长敏感（L）视锥细胞与中波长敏感（M）视锥细胞的比例差异很大。这种差异为测试发育过程中产生L视锥细胞和M视锥细胞的机制模型提供了机会。L和M光色素基因呈串联排列。每个基因都有一个启动子，在每个基因阵列的上游有一个遗传元件，称为基因座控制区（LCR），它是L和M色素基因表达所必需的。在发育过程中，对于每个已被确定为L视锥细胞或M视锥细胞的细胞，有人提出LCR作为一个随机选择器，从阵列中选择一个基因进行表达。在这个模型中，L和M启动子在每个光感受器中竞争与LCR的接触。从理论上讲，偶然第一个成功与LCR形成稳定且永久复合物的启动子会使细胞终身专一表达其相关基因。在这个模型下，有人提出启动子中的核苷酸差异会影响它们与LCR形成复合物的竞争能力。因此，预计L:M视锥细胞比例的正常差异与启动子中的核苷酸多态性有关。在这里，我们通过比较73名具有正常色觉且之前已获得L:M视锥细胞比例估计值的男性的L和M启动子序列，来检验这一假设。发现所有73名男性的M基因启动子序列相同，73名男性中有71名的L基因启动子相同。两名男性有突变，在每种情况下，与正常情况相比，L启动子都有一个核苷酸替换。两名启动子有突变的男性都有不寻常的视锥细胞比例，这与越来越多的证据一致，这些证据表明启动子与LCR形成复合物相对能力是决定视锥细胞比例的一个因素。然而，绝大多数视锥细胞比例差异与启动子序列的任何差异都无关。为了解释正常男性中视锥细胞比例的高度差异，决定一个视锥细胞是L型还是M型的机制必须涉及在正常人群中具有高度遗传多态性的遗传元件。这里给出的结果表明，该机制还有其他遗传成分有待识别并纳入当前的假设中。
