( A) R7 and R8 subtypes are determined by the on/off expression of Spineless (Ss). yR7s expressing Ss do not send this signal, resulting in expression of green-detecting Rhodopsin6 (Rh6) in yR8s ( Figure 1A) ( Franceschini et al., 1981 Montell et al., 1987 Zuker et al., 1987 Chou et al., 1996 Huber et al., 1997 Chou et al., 1999a Mikeladze-Dvali et al., 2005 Mazzoni et al., 2008 Vasiliauskas et al., 2009 Jukam and Desplan, 2011 Hsiao et al., 2013 Johnston, 2013 Jukam et al., 2013 Jukam et al., 2016 Yan et al., 2017). pR7s lacking Ss signal to pR8s to activate expression of blue-detecting Rhodopsin5 (Rh5). The on/off state of Ss in a given R7 also indirectly determines the subtype fate of the neighboring R8 photoreceptor. Ss expression in a random subset of R7s induces ‘yellow’ ( yR7) fate and expression of Rhodopsin4 (Rh4), whereas the absence of Ss in the complementary subset of R7s allows for ‘pale’ ( pR7) fate and Rhodopsin3 (Rh3) expression ( Figure 1A) ( Wernet et al., 2006 Johnston et al., 2011 Thanawala et al., 2013 Johnston and Desplan, 2014). In flies, the stochastic on/off expression of Spineless (Ss), a PAS-bHLH transcription factor, determines R7 photoreceptor subtypes. The fly eye, like the human eye, contains a random mosaic of photoreceptors defined by expression of light-detecting Rhodopsin proteins ( Montell et al., 1987 Bell et al., 2007 Johnston and Desplan, 2010 Viets et al., 2016). To address this question, we investigated natural variation in stochastic color photoreceptor specification in the Drosophila retina. How naturally occurring changes in the genome affect stochastic mechanisms to alter sensory system development and perception is poorly understood. Stochastic fate specification diversifies sensory neuron subtypes in a wide array of species including worms, flies, mice, and humans ( Ressler et al., 1993 Roorda and Williams, 1999 Troemel et al., 1999 Hofer et al., 2005 Johnston and Desplan, 2010 Magklara and Lomvardas, 2013 Alqadah et al., 2016 Viets et al., 2016). Differentiation of sensory neurons often requires stochastic mechanisms whereby individual neurons randomly choose between different fates. Organisms require a diverse repertoire of sensory receptor neurons to perceive a range of stimuli in their environments. Thus, binding site affinity and transcription factor levels are finely tuned to regulate stochastic expression, setting the ratio of alternative fates and ultimately determining color preference. Klu is expressed at intermediate levels to determine the normal ratio of Ss ON to Ss OFF cells. The genetic variant increases the binding affinity for Klumpfuss (Klu), a zinc finger transcriptional repressor that regulates ss expression.
This change in photoreceptor fates shifts the innate color preference of flies from green to blue.
In a genome-wide association study, we identified a naturally occurring insertion in a regulatory DNA element in ss that lowers the ratio of Ss ON to Ss OFF cells. In the fly eye, the random mosaic of color-detecting R7 photoreceptor subtypes is determined by stochastic on/off expression of the transcription factor Spineless (Ss). Annie went on to win seven Tony awards and became the third longest running musical of the 1970s with 2,377 performances.Each individual perceives the world in a unique way, but little is known about the genetic basis of variation in sensory perception. Warbucks soon decides he wants to adopt Annie, but when he learns about her dream of finding her parents and the secret of the half-locket she has treasured for so long, he sets his own feelings aside and orders an exhaustive search for Annie's parents. Billionaire Oliver Warbucks invites Annie to spend Christmas with him in his mansion, and together, they each discover new happiness. Life in the orphanage had been rough under the strict hand of Miss Hannigan, but Annie's life was about to change. As an infant, Annie had been abandoned on the front steps of The New York City Municipal Orphanage with a note from her parents promising to return for her someday. The show, which places Annie, Daddy Warbucks and Annie's mutt, Sandy in New York City in the midst of the Depression, opened on Broadway on April 21, 1977. The idea of turning Harold Gray's "Little Orphan Annie" into a musical comedy was the inspiration of lyricist-director Martin Charnin, who convinced composer Charles Strouse and librettist Thomas Meehan to join in creating it.