Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

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Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human.

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Conversion and Compensatory Evolution of the γ-Crystallin Genes and Identification of a Cataractogenic Mutation That Reverses the Sequence of the Human CRYGD Gene to an Ancestral State Olga V. Plotnikova, Fyodor A. Kondrashov, Peter K. Vlasov, Anastasia P. Grigorenko, Evgeny K. Ginter, Evgeny I. Rogaev The American Journal of Human Genetics Volume 81, Issue 1, Pages 32-43 (July 2007) DOI: 10.1086/518616 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1. Abridged PCC-affected pedigree selected from the genetic isolate. The mutation is transmitted as an autosomal dominant trait. The affected individuals are represented by blackened squares (males) and circles (females), and the unaffected individuals are represented by unblackened symbols. Family members participating in this study are indicated by an asterisk (*). One asterisk indicates subjects genotyped by restriction enzyme–digestion analysis, and two asterisks indicate individuals genotyped by direct-sequencing analysis. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2. Identification of the mutation in individuals with PCC. A, The three exons (Ex) that comprise CRYGD. B and C, Sequence chromatogram from a heterozygous patient carrying the P23S mutation (B) and a homozygous wild-type sequence from an unaffected individual (C). D, Exon sequence of CRYGD bearing the cataract-associated PS23S mutation. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence alignment of γ-crystallins. The primate sequences determined in this study are shown in bold. Only functional genes are shown. Red arrows indicate known pathogenic mutations in CRYGD, and black arrows indicate known pathogenic mutations in CRYGC. Amino acids highlighted in red indicate CPDs, and amino acids highlighted in blue indicate compensatory substitutions for site 23, whereas amino acids highlighted in yellow indicate the likely interaction states that cause a deleterious interaction with S23. The amino acid positions in CRYGD are numbered from a second amino acid, since the first M amino acid (designated in bold) is processed and omitted from the mature polypeptide. Accordingly, the E106A corresponds to E107A as numbered by Messina-Baas et al.48 The CRYGC mutations are numbered from the first amino acid residue. The sequences include γA- (CRYGA), γB- (CRYGB), γC- (CRYGC), and γD- (CRYGD) functional crystallins from primates (H. sapiens, Pan troglodytes, Pan paniscus, G. gorilla, Pongo pigmaeus, H. lar, Macaca mulatta, L. lagotricha, and A. geoffroyi) and other mammalian species. Sequences for functional γE- (CRYGE) and γF- (CRYGF) crystallins from nonprimate species are also included. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence alignment of γ-crystallins. The primate sequences determined in this study are shown in bold. Only functional genes are shown. Red arrows indicate known pathogenic mutations in CRYGD, and black arrows indicate known pathogenic mutations in CRYGC. Amino acids highlighted in red indicate CPDs, and amino acids highlighted in blue indicate compensatory substitutions for site 23, whereas amino acids highlighted in yellow indicate the likely interaction states that cause a deleterious interaction with S23. The amino acid positions in CRYGD are numbered from a second amino acid, since the first M amino acid (designated in bold) is processed and omitted from the mature polypeptide. Accordingly, the E106A corresponds to E107A as numbered by Messina-Baas et al.48 The CRYGC mutations are numbered from the first amino acid residue. The sequences include γA- (CRYGA), γB- (CRYGB), γC- (CRYGC), and γD- (CRYGD) functional crystallins from primates (H. sapiens, Pan troglodytes, Pan paniscus, G. gorilla, Pongo pigmaeus, H. lar, Macaca mulatta, L. lagotricha, and A. geoffroyi) and other mammalian species. Sequences for functional γE- (CRYGE) and γF- (CRYGF) crystallins from nonprimate species are also included. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence alignment of γ-crystallins. The primate sequences determined in this study are shown in bold. Only functional genes are shown. Red arrows indicate known pathogenic mutations in CRYGD, and black arrows indicate known pathogenic mutations in CRYGC. Amino acids highlighted in red indicate CPDs, and amino acids highlighted in blue indicate compensatory substitutions for site 23, whereas amino acids highlighted in yellow indicate the likely interaction states that cause a deleterious interaction with S23. The amino acid positions in CRYGD are numbered from a second amino acid, since the first M amino acid (designated in bold) is processed and omitted from the mature polypeptide. Accordingly, the E106A corresponds to E107A as numbered by Messina-Baas et al.48 The CRYGC mutations are numbered from the first amino acid residue. The sequences include γA- (CRYGA), γB- (CRYGB), γC- (CRYGC), and γD- (CRYGD) functional crystallins from primates (H. sapiens, Pan troglodytes, Pan paniscus, G. gorilla, Pongo pigmaeus, H. lar, Macaca mulatta, L. lagotricha, and A. geoffroyi) and other mammalian species. Sequences for functional γE- (CRYGE) and γF- (CRYGF) crystallins from nonprimate species are also included. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence alignment of γ-crystallins. The primate sequences determined in this study are shown in bold. Only functional genes are shown. Red arrows indicate known pathogenic mutations in CRYGD, and black arrows indicate known pathogenic mutations in CRYGC. Amino acids highlighted in red indicate CPDs, and amino acids highlighted in blue indicate compensatory substitutions for site 23, whereas amino acids highlighted in yellow indicate the likely interaction states that cause a deleterious interaction with S23. The amino acid positions in CRYGD are numbered from a second amino acid, since the first M amino acid (designated in bold) is processed and omitted from the mature polypeptide. Accordingly, the E106A corresponds to E107A as numbered by Messina-Baas et al.48 The CRYGC mutations are numbered from the first amino acid residue. The sequences include γA- (CRYGA), γB- (CRYGB), γC- (CRYGC), and γD- (CRYGD) functional crystallins from primates (H. sapiens, Pan troglodytes, Pan paniscus, G. gorilla, Pongo pigmaeus, H. lar, Macaca mulatta, L. lagotricha, and A. geoffroyi) and other mammalian species. Sequences for functional γE- (CRYGE) and γF- (CRYGF) crystallins from nonprimate species are also included. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. Sequence alignment of γ-crystallins. The primate sequences determined in this study are shown in bold. Only functional genes are shown. Red arrows indicate known pathogenic mutations in CRYGD, and black arrows indicate known pathogenic mutations in CRYGC. Amino acids highlighted in red indicate CPDs, and amino acids highlighted in blue indicate compensatory substitutions for site 23, whereas amino acids highlighted in yellow indicate the likely interaction states that cause a deleterious interaction with S23. The amino acid positions in CRYGD are numbered from a second amino acid, since the first M amino acid (designated in bold) is processed and omitted from the mature polypeptide. Accordingly, the E106A corresponds to E107A as numbered by Messina-Baas et al.48 The CRYGC mutations are numbered from the first amino acid residue. The sequences include γA- (CRYGA), γB- (CRYGB), γC- (CRYGC), and γD- (CRYGD) functional crystallins from primates (H. sapiens, Pan troglodytes, Pan paniscus, G. gorilla, Pongo pigmaeus, H. lar, Macaca mulatta, L. lagotricha, and A. geoffroyi) and other mammalian species. Sequences for functional γE- (CRYGE) and γF- (CRYGF) crystallins from nonprimate species are also included. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4. Sequence patterns in the interacting fragments of two γ-crystallin domains. Correlated serine and proline residues in CRYGD are shown in red and green, respectively. H. sap=H. sapiens; P. trog=Pan troglodytes; P. panis=Pan paniscus; P. pyg=Pongo pygmaeus; G. gor=G. gorilla; M. mul=Macaca mulatta; A. geof=A. geoffroyi; L. lagot=L. lagotricha; S. lab=S. labiatus; B. taur=B. taurus; C. fam=C. familiaris; R. nor=R. norvegicus; M. mus=Mus musculus. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5. Contact regions in two symmetrical crystallin domains and four similar Greek key motifs form β-strands in two joined protein domains. The sample is based on the structure of the human γD-crystallin protein. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 6. Gene order of paralogous γ-crystallin genes in mammalian genomes The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 7. Bayesian phylogenies of exon 2 (A) and exon 3 (B) of the γ-crystallins. Gene-conversion events are shown on the phylogeny with a blackened square, and only posterior probabilities <0.90 are indicated. A, B, C, D, E, and F correspond to the CRYGA, CRYGB, CRYGC, CRYGD, CRYGE, and CRYGF genes, respectively. The American Journal of Human Genetics 2007 81, 32-43DOI: (10.1086/518616) Copyright © 2007 The American Society of Human Genetics Terms and Conditions