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Molecular Evolution of the Human SRPX2 Gene That Causes Brain Disorders of the Rolandic and Sylvian Speech Areas

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Molecular Evolution of the Human SRPX2 Gene That Causes Brain Disorders of the Rolandic and Sylvian Speech Areas Edinburgh Research Explorer Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas Citation for published version: Royer, B, Soares, DC, Barlow, PN, Bontrop, RE, Roll, P, Robaglia-Schlupp, A, Blancher, A, Levasseur, A, Cau, P, Pontarotti, P & Szepetowski, P 2007, 'Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas', BMC Genetics, vol. 8, no. 72, pp. 1-9. https://doi.org/10.1186/1471-2156-8-72 Digital Object Identifier (DOI): 10.1186/1471-2156-8-72 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: BMC Genetics General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. 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Sep. 2021 BMC Genetics BioMed Central Research article Open Access Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas Barbara Royer1, Dinesh C Soares2, Paul N Barlow2, Ronald E Bontrop3, Patrice Roll1, Andrée Robaglia-Schlupp1, Antoine Blancher4, Anthony Levasseur5, Pierre Cau1, Pierre Pontarotti5 and Pierre Szepetowski*1 Address: 1INSERM UMR 491, Université de la Méditerranée, 13385 Marseille, Cedex 5, France, 2Edinburgh Biomolecular NMR Unit, The University of Edinburgh, Edinburgh EH9 3JJ, UK, 3Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands, 4LIGM, Université Paul Sabatier, 31403 Toulouse, Cedex 4, France and 5EA 3781, Université d'Aix-Marseille I, 13331 Marseille, Cedex 3, France Email: Barbara Royer - [email protected]; Dinesh C Soares - [email protected]; Paul N Barlow - [email protected]; Ronald E Bontrop - [email protected]; Patrice Roll - [email protected]; Andrée Robaglia-Schlupp - [email protected]; Antoine Blancher - [email protected]; Anthony Levasseur - [email protected] mrs.fr; Pierre Cau - [email protected]; Pierre Pontarotti - [email protected]; Pierre Szepetowski* - [email protected] * Corresponding author Published: 18 October 2007 Received: 29 March 2007 Accepted: 18 October 2007 BMC Genetics 2007, 8:72 doi:10.1186/1471-2156-8-72 This article is available from: http://www.biomedcentral.com/1471-2156/8/72 © 2007 Royer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The X-linked SRPX2 gene encodes a Sushi Repeat-containing Protein of unknown function and is mutated in two disorders of the Rolandic/Sylvian speech areas. Since it is linked to defects in the functioning and the development of brain areas for speech production, SRPX2 may thus have participated in the adaptive organization of such brain regions. To address this issue, we have examined the recent molecular evolution of the SRPX2 gene. Results: The complete coding region was sequenced in 24 human X chromosomes from worldwide populations and in six representative nonhuman primate species. One single, fixed amino acid change (R75K) has been specifically incorporated in human SRPX2 since the human-chimpanzee split. The R75K substitution occurred in the first sushi domain of SRPX2, only three amino acid residues away from a previously reported disease-causing mutation (Y72S). Three-dimensional structural modeling of the first sushi domain revealed that Y72 and K75 are both situated in the hypervariable loop that is usually implicated in protein-protein interactions. The side-chain of residue 75 is exposed, and is located within an unusual and SRPX-specific protruding extension to the hypervariable loop. The analysis of non- synonymous/synonymous substitution rate (Ka/Ks) ratio in primates was performed in order to test for positive selection during recent evolution. Using the branch models, the Ka/Ks ratio for the human branch was significantly different (p = 0.027) from that of the other branches. In contrast, the branch-site tests did not reach significance. Genetic analysis was also performed by sequencing 9,908 kilobases (kb) of intronic SRPX2 sequences. Despite low nucleotide diversity, neither the HKA (Hudson-Kreitman-Aguadé) test nor the Tajima's D test reached significance. Conclusion: The R75K human-specific variation occurred in an important functional loop of the first sushi domain of SRPX2, indicating that this evolutionary mutation may have functional importance; however, positive selection for R75K could not be demonstrated. Nevertheless, our data contribute to the first understanding of molecular evolution of the human SPRX2 gene. Further experiments are now required in order to evaluate the possible consequences of R75K on SRPX2 interactions and functioning. Page 1 of 9 (page number not for citation purposes) BMC Genetics 2007, 8:72 http://www.biomedcentral.com/1471-2156/8/72 Background 200 000 years ago, or that there has been no episode of Evolution studies have been undertaken to identify those positive selection on SRPX2. genetic changes that underlie human-specific features such as susceptibility to acquired immunodeficiency syn- Results and discussion drome, bipedalism, a large brain, and higher-order cogni- One single amino acid substitution (R75K) has been fixed tive functions. Several phenotypic differences in human SRPX2 since the human-chimpanzee split distinguishing human from other great apes species obvi- In silico screening of publicly available databases followed ously rely on cerebral activity. Large-scale studies in by phylogenetic analysis showed that SRPX2 belongs to a human and chimpanzee using either genome compari- family of five genes: SRPX2 itself (sushi-repeat-containing sons [1,2] or brain transcriptome analyses [3-5] have led protein, X-linked 2), SRPX (sushi-repeat-containing pro- to the identification of a subset of genes that may have tein, X-linked), SELP (selectin P precursor), SELE (selectin contributed to the evolution of human brain anatomy E precursor), and SVEP1 (selectin-like protein) gene (Fig. and activity from a common primate ancestor. An impor- 1; Additional file 1). This family emerged during verte- tant complementary approach has relied on the study of brate evolution. In order to trace the recent evolutionary candidate genes selected on the basis of their importance history of SRPX2, all coding exons were sequenced from a in specific human phenotypes. Consequently, several subset of primate species that represent key evolutionary genes involved in the structure and/or functioning of the steps: human [Genbank: NM_014467], chimpanzee human brain have been associated with recent positive [Genbank: EF369515], gorilla [Genbank: EF369516], selection: ASPM [6,7], MCPH1 [8-10], GLUD2 [11], orangutan [Genbank: EF369517], gibbon [Genbank: MAOA [12,13], SHH [14], and the "speech gene" FOXP2 EF369518], macaque [Genbank: EF369519], and baboon [15-17]. More recently, accelerated evolution of noncod- [Genbank: EF369520]. Sequence comparison (Fig. 2) ing sequences has also been shown [18,19]. The Rolandic and Sylvian fissures divide the cortex hemi- spheres of primates into their main anatomical structures. In human, these areas participate in speech production under the control of the Broca's area. We recently identi- fied the SRPX2 gene as being responsible for two related disorders of the Rolandic and Sylvian speech areas [20,21]. Since it is linked to defects in the functioning and the development of such brain regions, such as epileptic seizures, oral and speech dyspraxia, or bilateral perisyl- vian polymicrogyria, SRPX2 may be one of the specific genes whose evolution at the DNA-level may have partic- ipated in the recent emergence of higher-order cognitive functions, including the adaptive organization of brain areas for speech production. In this study, we have examined the molecular evolution of the SRPX2 gene. One single, fixed amino acid change occurred in the first sushi domain (also known as CCP – complement control protein – module, or short consen- sus repeat) of SRPX2 after the human-chimpanzee split. Three-dimensional modeling showed that both this evo- lutionary mutation and a previously identified disease- associated mutation [20] lie within a hypervariable loop shared by all sushi modules and that has been implicated in some cases in protein-protein interactions [22]. Using PhylogeneticFigure 1 tree of the SRPX2 family members the branch models, the synonymous/non-synonymous Phylogenetic tree of the SRPX2 family members. ag: Anophe- analysis was consistent with accelerated evolution in the les gambiae; bt: Bos taurus; cn: Canis familiaris; dr: Danio human lineage but this could not be confirmed when the rerio; gg: Gallus gallus; hs: Homo sapiens;
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