Role of a locus control region in the mutually exclusive expression of human red and green cone pigment genes

Abstract

Trichromacy in humans and other Old World primates evolved from a dichromatic color vision system Ϸ30 -40 million years ago. One essential part of this evolution was the duplication and divergence of sequences on the X chromosome to create the present-day red and green cone pigment genes. Earlier work demonstrated that a locus control region (LCR) located upstream of these genes is essential for their expression. In the present work, we have generated a variety of modified human red and green pigment gene arrays that direct the expression of distinguishable histochemical reporters from each gene promoter. Transgenic mice carrying a single copy of each modified array were studied to define the role of three variables in producing mutually exclusive expression of red and green pigment transgenes: the distance between the promoter and the LCR, the identity of the visual pigment promoter, and LCR copy number. The results support a model in which the mutually exclusive expression of these genes in their respective cone types is controlled by competition between visual pigment promoters for pairing with the LCR, and they suggest a facile mechanism for the evolution of trichromacy after visual pigment gene duplication.T he evolution of a new dimension of chromatic discrimination requires (i) the production of a visual pigment with a novel absorbance spectrum, (ii) the expression of the new visual pigment in a distinct class of photoreceptors, and (iii) patterns of neural connectivity that can extract chromatic information by comparing the degree of excitation of the new and preexisting classes of photoreceptors. The present work addresses the second of these three requirements as it relates to the most recent step in the evolution of human color vision.The human red and green pigment genes reside on the X chromosome in a head-to-tail tandem array in which a single red pigment gene lies 5Ј to one or more nearly identical green pigment genes (1-3). A locus control region (LCR) resides between 3.1 and 3.7 kb 5Ј of the start site of red pigment gene transcription (4, 5). The LCR is highly conserved among diverse mammals and, unlike the visual pigment gene transcription units, seems not to have been duplicated in the human genome. As a result of X-inactivation in females and X chromosome hemizygosity in males, the X chromosomal location of these genes implies that, for any given cone photoreceptor, the decision to express either a red or a green pigment gene needs to be made on only one allele.Two contrasting models, which we shall refer to as ''standard'' and ''stochastic'', might account for the mutually exclusive expression of the red and green pigment genes in their respective cone types. The standard model envisions red and͞or green cone-specific transcriptional activators or repressors acting to coordinate cell type-specific gene expression. By contrast, the stochastic model posits that differential expression of the red and green pigment genes ref lects a choice between two stable and mutually exclusive configuration...

Neural mechanisms underlying the evolvability of behaviour

“…Transgenic mice that expressed modified human photopigments showed a remarkable segregation of those opsin genes to different photoreceptors [50]. Subsequent work suggested that there is a developmental mechanism that causes mutually exclusive expression of opsin genes in cones [51]. This leads to chromatic sensitivity in retinal ganglion cells [52].…”

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

“…The expression of the opsin is selected from a tandem repeat of M and L opsin genes. The decision is governed by an upstream locus control region, although understanding of the mechanism is still outstanding (Smallwood et al, 2002;Deeb, 2005).…”

Nucleotide polymorphisms upstream of the X-chromosome opsin gene array tune L:M cone ratio

“…Differences among the haplotypes may tip the balance more or less in favor of expressing L opsin, and thus are likely candidates for producing subtle differences such as the difference between the intermediate versus the high and low % L cones phenotypes. Recently, evidence has accumulated indicating that the difference between L versus M cones is decided simply by which of the X-chromosome cone opsin genes is chosen for expression (Smallwood et al, 2002, Knoblauch et al, 2006. DNA polymorphisms in the region of the opsin genes containing elements involved in controlling gene expression and silencing can influence the transcriptional output of each of the X-chromosome opsin genes.…”

“…L and M photoreceptors represent a cell type distinct from S cones (Bumsted et al, 1997), and evidence has accumulated recently indicating that L and M cones represent essentially a single cell type differentiated only by which X-chromosome opsin gene is selected for expression (Smallwood et al, 2002). In humans and other Old World primates the selection mechanism has been proposed to involve a competition between activation and silencing of adjacent cone opsin genes (Knoblauch et al, 2006).…”

“…The relative numbers of long-wavelength (L) to middle wavelength sensitive cones is highly variable among men with normal color vision (DeVries, 1946;Rushton & Baker, 1964;Dartnall et al, 1983;Pokorny et al, 1991;Roorda & Williams, 1999;Carroll et al, 2002;Hofer et al, 2005), and it has long been suspected that variation in L:M cone ratio is Xlinked (DeVries, 1946;Smallwood et al, 2002, McMahon, 2004. L and M photoreceptors represent a cell type distinct from S cones (Bumsted et al, 1997), and evidence has accumulated recently indicating that L and M cones represent essentially a single cell type differentiated only by which X-chromosome opsin gene is selected for expression (Smallwood et al, 2002).…”