Royer Barbara, Soares Dinesh C, Barlow Paul N, Bontrop Ronald E, Roll Patrice, Robaglia-Schlupp Andrée, Blancher Antoine, Levasseur Anthony, Cau Pierre, Pontarotti Pierre, Szepetowski Pierre
INSERM UMR 491, Université de la Méditerranée, 13385 Marseille, Cedex 5, France.
BMC Genet. 2007 Oct 18;8:72. doi: 10.1186/1471-2156-8-72.
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.
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.
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.
X连锁的SRPX2基因编码一种功能未知的含寿司重复序列蛋白，在罗兰多/西尔维安语言区的两种疾病中发生突变。由于它与语言产生脑区的功能和发育缺陷有关，因此SRPX2可能参与了此类脑区的适应性组织。为解决这一问题，我们研究了SRPX2基因最近的分子进化情况。
对来自世界各地人群的24条人类X染色体以及6种代表性非人类灵长类物种的完整编码区进行了测序。自人类与黑猩猩分化以来，人类SRPX2中特异性地出现了一个单一的、固定的氨基酸变化（R75K）。R75K替换发生在SRPX2的第一个寿司结构域，距离先前报道的致病突变（Y72S）仅三个氨基酸残基。第一个寿司结构域的三维结构建模显示，Y72和K75都位于通常参与蛋白质-蛋白质相互作用的高变环中。第75位残基的侧链暴露在外，位于高变环一个不寻常的、SRPX特异性的突出延伸部分内。为了检测近期进化过程中的正选择，对灵长类动物的非同义/同义替换率（Ka/Ks）进行了分析。使用分支模型，人类分支的Ka/Ks比率与其他分支显著不同（p = 0.027）。相比之下，分支位点检验未达到显著水平。还通过对SRPX2内含子序列的9908千碱基（kb）进行测序进行了遗传分析。尽管核苷酸多样性较低，但哈德森-克莱特曼-阿瓜德（HKA）检验和塔吉玛D检验均未达到显著水平。
人类特有的R75K变异发生在SRPX2第一个寿司结构域的一个重要功能环中，表明这种进化突变可能具有功能重要性；然而，无法证明R75K受到正选择。尽管如此，我们的数据有助于首次了解人类SPRX2基因的分子进化。现在需要进一步的实验来评估R75K对SRPX2相互作用和功能的可能影响。
