Animals have diversified and adapted to fill the numerous habitats and environments on this earth. The long-term goal of our studies is to elucidate mechanisms that drive these adaptive changes at the molecular and functional levels. We plan to accomplish this goal using vision as a model system. To identify critical amino acid (AA) changes that modify the wavelengths of maximal absorption (;maxs) of visual pigments, vision scientists analyze "contemporary" pigments. Experimental evolutionary biologists also manipulate "contemporary" pigments and infer the past. However, by ignoring the evolutionary processes of visual pigments, neither the molecular basis of spectral tuning in visual pigments nor the evolutionary mechanisms of visual pigments can be elucidated. Fortunately, the central unanswered questions in phototransduction and evolutionary biology can be solved simultaneously by genetically engineering and manipulating proper "ancestral pigments." Here, we propose to elucidate the molecular mechanisms that drive adaptive evolution of RH2, SWS1, and SWS2 pigments in vertebrates, which have;maxs of ~450-530, ~355-440, and ~400-460 nm, respectively. We approach the problem not only by determining the molecular basis of spectral tuning in visual pigments but also by establishing the relationships between organisms with different sets of visual pigments and their ecological environments. For each pigment group, we plan to 1) infer the AA sequences of ~15 ancestral pigments and engineer them and determine their;maxs, 2) infer AA changes that shift the;max, 3) identify the critical AA changes by mutating ancestral pigments, and 4) establish the universal chemical principle of the spectral tuning in visual pigments by using the quantum mechanical/molecular mechanical (QM/MM) methods, which have been proven to be highly effective. We shall also test the possibility of adaptive evolution of these visual pigments by examining whether the directions of the;max-shifts of visual pigments in various species match with the changes in the organisms'ecological environments. For this purpose, each of the three pigment groups with variable;maxs in multiple species will be classified into distinct classes according to their environments and tested for the possibility of adaptive evolution. Since virtually all fish SWS1 pigments examined to date are UV-sensitive, we also plan to search for violet-sensitive SWS1 pigments in different fishes, by surveying fishes that live at depths of 0-200 m and prey on small fishes and do not require UV vision for hunting. Considering the strong AA interactions that occur in SWS1 pigments, we also plan to elucidate how various critical AA changes could have accumulated during its evolution and learn the chemical structural preconditions required for UV pigments to become violet-sensitive and vice versa.

Public Health Relevance

Using cell/molecular and quantum chemical methods, we study the structure-function relationships of visual pigments in various vertebrate species and their ancestors. Various levels of misfoldings of visual pigments induced by different amino acid changes in rhodopsins and other visual pigments are known to cause retinitis pigmentosa and other retinal dystrophies. Hence, the results obtained from our mutagenesis experiments and chemical structural computations of visual pigments together provide the fundamental information on the genetic bases of color vision defects and ocular diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Genetic Variation and Evolution Study Section (GVE)
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Neuhold, Lisa
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Emory University
Schools of Arts and Sciences
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Yokoyama, Shozo; Starmer, William T; Liu, Yang et al. (2014) Extraordinarily low evolutionary rates of short wavelength-sensitive opsin pseudogenes. Gene 534:93-9
Ryazantsev, Mikhail N; Altun, Ahmet; Morokuma, Keiji (2012) Color Tuning in rhodopsins: the origin of the spectral shift between the chloride-bound and anion-free forms of halorhodopsin. J Am Chem Soc 134:5520-3
Sekharan, Sivakumar; Morokuma, Keiji (2011) QM/MM study of the structure, energy storage, and origin of the bathochromic shift in vertebrate and invertebrate bathorhodopsins. J Am Chem Soc 133:4734-7
Yokoyama, Shozo; Altun, Ahmet; DeNardo, Dale F (2011) Molecular convergence of infrared vision in snakes. Mol Biol Evol 28:45-8
Altun, Ahmet; Morokuma, Keiji; Yokoyama, Shozo (2011) H-bond network around retinal regulates the evolution of ultraviolet and violet vision. ACS Chem Biol 6:775-80
Sekharan, Sivakumar; Morokuma, Keiji (2011) Why 11-cis-retinal? Why not 7-cis-, 9-cis-, or 13-cis-retinal in the eye? J Am Chem Soc 133:19052-5
Sekharan, Sivakumar; Yokoyama, Shozo; Morokuma, Keiji (2011) Quantum mechanical/molecular mechanical structure, enantioselectivity, and spectroscopy of hydroxyretinals and insights into the evolution of color vision in small white butterflies. J Phys Chem B 115:15380-8
Sekharan, Sivakumar; Altun, Ahmet; Morokuma, Keiji (2010) Photochemistry of visual pigment in a G(q) protein-coupled receptor (GPCR)--insights from structural and spectral tuning studies on squid rhodopsin. Chemistry 16:1744-9
Sekharan, Sivakumar; Morokuma, Keiji (2010) Drawing the Retinal Out of Its Comfort Zone: An ONIOM(QM/MM) Study of Mutant Squid Rhodopsin. J Phys Chem Lett 1:668-672
Yokoyama, Shozo; Tada, Takashi (2010) Evolutionary dynamics of rhodopsin type 2 opsins in vertebrates. Mol Biol Evol 27:133-41

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