Positive selection at codon 38 of the human KCNE1 (= minK) gene and sporadic absence of 38Ser-coding mRNAs in Gly38Ser heterozygotes.
Positive selection at codon 38 of the human KCNE1 (= minK) gene and sporadic absence of 38Ser-coding mRNAs in Gly38Ser heterozygotes.
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DOI：
10.1186/1471-2148-9-188
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发表时间：
2009-08-06
影响因子：
3.4
通讯作者：
Haaf T
中科院分区：
文献类型：
--
作者：
Herlyn H;Zechner U;Oswald F;Pfeufer A;Zischler H;Haaf T
KCNE1代表缓慢激活的延迟整流钾通道(IKS)的调节性β亚基。KCNE1的变异多次被认为与长QT综合征(LQTS)有关，LQTS是一种易患耳聋、室性快速性心律失常、晕厥和心脏性猝死的疾病。我们在这里分析了常见的Gly38Ser变体(Rs1805127)的进化，使用了总共19个哺乳动物物种的基因组DNA、互补DNA和HEK293表达的变体。物种间的比较表明，人类特有的Gly38Ser多态是在达尔文式的强正向选择下进化的，可能是为了适应IKS通道微调中的特定挑战。所涉及的氨基酸交换(Asp&Gt；Gly，Gly&Gt；Ser)是中等自由基的，不会引起翻译后修饰的明显变化。根据群体遗传学分析(HapMap第二阶段)，杂合子优势解释了人类Gly38Ser多态的维持。另一方面，38Ser等位基因的表达在某些条件下似乎是不利的，这表明在杂合子中欧人中38Ser编码mRNAs的零星缺失和约鲁班样本中纯合子38Ser的缺失。我们推测，基因组印迹或基因组编码的个体差异可能是导致最近Gly38Ser多态与QT表型之间的关联研究结果相互矛盾的原因之一。因此，这些发现突出了信使核糖核酸数据在未来的基因分型和临床疾病的相关性研究中的相关性。就我们所知，它们还首次为一种独特的模式提供了证据；即积极的达尔文选择和多态与零星抑制的一个等位基因的表达相吻合。
KCNE1 represents the regulatory beta-subunit of the slowly activating delayed rectifier potassium channel (IKs). Variants of KCNE1 have repeatedly been linked to the long-QT syndrome (LQTS), a disorder which predisposes to deafness, ventricular tachyarrhythmia, syncope, and sudden cardiac death. We here analyze the evolution of the common Gly38Ser variant (rs1805127), using genomic DNAs, complementary DNAs, and HEK293-expressed variants of altogether 19 mammalian species. The between species comparison reveals that the human-specific Gly38Ser polymorphism evolved under strong positive Darwinian selection, probably in adaptation to specific challenges in the fine-tuning of IKs channels. The involved amino acid exchanges (Asp > Gly, Gly > Ser) are moderately radical and do not induce apparent changes in posttranslational modification. According to population genetic analyses (HapMap phase II) a heterozygote advantage accounts for the maintenance of the Gly38Ser polymorphism in humans. On the other hand, the expression of the 38Ser allele seems to be disadvantageous under certain conditions, as suggested by the sporadic deficiency of 38Ser-coding mRNAs in heterozygote Central Europeans and the depletion of homozygotes 38Ser in the Yoruban sample. We speculate that individual differences in genomic imprinting or genomic recoding might have contributed to conflicting results of recent association studies between Gly38Ser polymorphism and QT phenotype. The findings thus highlight the relevance of mRNA data in future association studies of genotypes and clinical disorders. To the best of our knowledge, they moreover provide first time evidence for a unique pattern; i.e. coincidence of positive Darwinian selection and polymorphism with a sporadically suppressed expression of one allele.
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