Department of Biochemistry, Applied Genomics Laboratory and HKH Bioinformatics Center, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
PLoS One. 2007 May 23;2(5):e462. doi: 10.1371/journal.pone.0000462.
The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor beta(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2), especially its long isoform. Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.
γ-氨基丁酸 A 型（GABA(A))受体在抑制性神经传递中起主要作用。GABRB2 基因中的内含子 SNP 和单倍型与精神分裂症有关，并与两种选择性剪接的β(2)亚型的表达相关。在本研究中，我们以黑猩猩作为祖先参考，发现 GABRB2 中的四个 SNP(rs6556547、rs187269、rs1816071 和 rs1816072)的衍生(D)等位基因在黑猩猩中高频出现，提示这些衍生等位基因发生了正选择。基于合并的模拟显示，在各种人口统计学模型中，群体频率谱和具有所有四个 D 等位基因的 H56 单倍型的频率明显偏离中性进化的预期。与包含其祖先等位基因的单倍型相比，包含 rs1816072 衍生等位基因的单倍型显示出明显较少的多样性，进一步支持了正选择。五种人类群体中 DD 基因型频率的变化提供了进化历史的快照，表明 D 等位基因的正选择是最近发生的，可能仍在继续。精神分裂症和对照组样本的 DD 基因型谱的差异表明正选择与精神分裂症有关，与对照组相比，精神分裂症样本的选择减弱。这些 DD 基因型先前被发现增加了β(2)的表达，特别是其长亚型。电生理分析表明，这种由正选择偏好的长β(2)亚型比短亚型对 GABA(A)受体功能的抑制更敏感，因为能量耗竭。这些发现代表了在与精神分裂症相关的基因中首次证明了正选择。
