The spectrum of human rhodopsin disease mutations through the lens of interspecific variation

Briscoe, Adriana D.; Gaur, Charu; Kumar, Sudhir

doi:10.1016/j.gene.2004.02.037

Cited by 40 publications

(71 citation statements)

References 34 publications

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“…A similar trend is observed with Miyata's distance 27 . These Grantham dissimilarity values are close to those reported for interspecific variation in many different proteins [28][29][30] .…”

Section: Frequency Of Polar Amino Acidssupporting

confidence: 86%

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Xia¹,

Kumar²

2006

Series on Advances in Bioinformatics and Computational Biololgy

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The ratio of the number of nonsynonymous substitutions per site (Ka) over the number of synonymous substitutions per site (Ks) has often been used to detect positive selection. Investigators now commonly generate Ka/Ks ratio profiles in a sliding window to look for peaks and valleys in order to identify regions under positive selection. Here we show that the interpretation of peaks in the Ka/Ks profile as evidence for positive selection can be misleading. Genie regions with Ka/Ks > 1 in the MRG gene family, previously claimed to be under positive selection, are associated with a high frequency of polar amino acids with a high mutability. This association between an increased Ka and a high proportion of polar amino acids appears general and not limited to the MRG gene family or the sliding-window approach. For example, the sites detected to be under positive selection in the HIV1 protein-coding genes with a high posterior probability turn out to be mostly occupied by polar amino acids. These findings caution against invoking positive selection from Ka/Ks ratios and highlight the need for considering biochemical properties of the protein domains showing high Ka/Ks ratios. In short, a high Ka/Ks ratio may arise from the intrinsic properties of amino acids instead of from extrinsic positive selection.

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Section: Frequency Of Polar Amino Acidssupporting

confidence: 86%

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Xia¹,

Kumar²

2006

Series on Advances in Bioinformatics and Computational Biololgy

Self Cite

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show abstract

“…This can be seen by considering the extent of amino acid dissimilarity, which can be measured by Grantham 27 . These Grantham dissimilarity values are close to those reported for interspecific variation in many different proteins [28][29][30] . The observations mentioned above suggest that an increase in the number of 2-fold degenerate positions in a sliding window increases the opportunity for nonsynonymous substitutions involving more similar amino acids that would be subjected to less intense purifying selection and would yield elevated fixation rates of nonsynonymous mutations.…”

Section: Sites Of "Positive Selection" Code For a Relatively High Fresupporting

confidence: 86%

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Xia¹,

Kumar²

2006

Series on Advances in Bioinformatics and Computational Biololgy

Self Cite

View full text Add to dashboard Cite

The ratio of the number of nonsynonymous substitutions per site (Ka) over the number of synonymous substitutions per site (Ks) has often been used to detect positive selection. Investigators now commonly generate Ka/Ks ratio profiles in a sliding window to look for peaks and valleys in order to identify regions under positive selection. Here we show that the interpretation of peaks in the Ka/Ks profile as evidence for positive selection can be misleading. Genic regions with Ka/Ks > 1 in the MRG gene family, previously claimed to be under positive selection, are associated with a high frequency of polar amino acids with a high mutability. This association between an increased Ka and a high proportion of polar amino acids appears general and not limited to the MRG gene family or the sliding-window approach. For example, the sites detected to be under positive selection in the HIV1 protein-coding genes with a high posterior probability turn out to be mostly occupied by polar amino acids. These findings caution against invoking positive selection from Ka/Ks ratios and highlight the need for considering biochemical properties of the protein domains showing high Ka/Ks ratios. In short, a high Ka/Ks ratio may arise from the intrinsic properties of amino acids instead of from extrinsic positive selection.

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“…Across the entire amino acid sequence, there is high conservation (82% identity with 92% similarity and 1% gaps). Among rhodopsin amino acids that when mutated cause ADRP (Briscoe, Gaur et al 2004), the conservation is only slightly higher (87% identity and 91% similarity). One amino acid substitution that causes ADRP in humans, V137M (Ayuso, Trujillo et al 1996), is found to occur in the wild-type Xenopus laevis sequence as in teleosts and skates (Briscoe, Gaur et al 2004).…”

Section: Xenopus Laevis Expressing a P23h Rhodopsin Transgene Undergomentioning

confidence: 99%

“…Underlined are the predicted transmembrane spanning regions of rhodopsin. Underneath the aligned sequences are listed mutations occurring in human rhodopsin according to (Briscoe, Gaur et al 2004). Mutations that cause autosomal dominant retinitis pigmentosa are shown in black: missense mutations as letters, nonsense mutations as asterisks and deletions as boxes.…”

Section: Rod Photoreceptor Degeneration Is Most Pronounced In the Venmentioning

confidence: 99%

Xenopus laevis P23H rhodopsin transgene causes rod photoreceptor degeneration that is more severe in the ventral retina and is modulated by light

Zhang

Oglesby

Marsh-Armstrong

2008

Experimental Eye Research

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Rhodopsin transgenes carrying mutations that cause autosomal dominant retinitis pigmentosa in humans have been used to study rod photoreceptor degeneration in various model organisms including Xenopus laevis. To date, the only transgenes shown to cause rod photoreceptor degeneration in Xenopus laevis have been either mammalian rhodopsins or chimeric versions of rhodopsin based mainly on Xenopus laevis rhodopsin sequences but with a mammalian Cterminus. Since the C-terminal sequence of rhodopsin is highly conserved in mammals and divergent in Xenopus laevis, and mammalian and epitope-tagged rhodopsins may have unexpected properties as transgenes, we decided to test whether a Xenopus laevis rhodopsin transgence carrying only the P23H mutation could also cause rod photoreceptor degeneration. Xenopus laevis tadpoles expressing these transgenes indeed had shortened outer segments and, in severely affected animals, the loss of rod photoreceptors but not the loss of cone photoreceptors. RT-PCR analyses showed that less than 10% of mutant transgenic rhodopsin relative to wild-type endogenous rhodopsin mRNA was sufficient to produce severe rod photoreceptor degeneration. As observed in other animal models as well as humans carrying this particular rhodopsin mutation, the rod photoreceptor degeneration was most severe in the ventral retina and was modified by light. Thus, the rod photoreceptor degeneration produced in Xenopus laevis by the P23H mutation in an otherwise untagged Xenopus laevis rhodopsin is generally similar to that seen with mammalian rhodopsins and epitope-tagged versions of Xenopus laevis rhodopsin, though some differences remain to be explained.

show abstract

The spectrum of human rhodopsin disease mutations through the lens of interspecific variation

Cited by 40 publications

References 34 publications

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Codon-Based Detection of Positive Selection Can Be Biased by Heterogeneous Distribution of Polar Amino Acids Along Protein Sequences

Xenopus laevis P23H rhodopsin transgene causes rod photoreceptor degeneration that is more severe in the ventral retina and is modulated by light

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