Adaptive evolution of genes underlying schizophrenia
Adaptive evolution of genes underlying schizophrenia
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DOI：
10.1098/rspb.2007.0876
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发表时间：
2007-11-22
影响因子：
4.7
通讯作者：
Dorus, Steve
中科院分区：
文献类型：
--
作者：
Crespi, Bernard;Summers, Kyle;Dorus, Steve
精神分裂症构成了一个进化遗传悖论，因为它表现出强烈的负适应性效应和高遗传性，但它在所有人类文化中的流行率约为1%。最近的理论提出了一个解决方案：精神分裂症的遗传易感性已经演变为人类认知特征选择的次要后果。这一假说预测，在人类和其他灵长类动物的进化历史中，增加这种疾病风险的基因一直受到积极选择的影响。我们使用最近在人类群体中进行的选择性扫描测试和灵长类进化过程中选择的最大似然测试来评估这一预测。使用一种或两种方法对76个基因中的28个进行正选择的重要证据是显而易见的，这些基因被证明介导精神分裂症的易感性，包括DISCI，DTNBP1和NRG 1，它们与这种疾病表现出特别强的和良好的复制功能和遗传联系。强有力的证据，非中性，加速进化发现DISCI，特别是外显子2，唯一的编码区内的精神分裂症相关的单倍型。此外，与精神分裂症相关的基因表现出统计学显着丰富的信号，积极的选择在HapMap和PAML分析沿着人类谱系的进化，当与控制组的基因参与神经元活动。这些基因的适应性进化的选择力仍然在很大程度上是未知的，但这些发现提供了一致的假设，精神分裂症代表，在某种程度上，适应不良的副产品在人类进化过程中的适应性变化的证据。
Schizophrenia poses an evolutionary-genetic paradox because it exhibits strongly negative fitness effects and high heritability, yet it persists at a prevalence of approximately 1% across all human cultures. Recent theory has proposed a resolution: that genetic liability to schizophrenia has evolved as a secondary consequence of selection for human cognitive traits. This hypothesis predicts that genes increasing the risk of this disorder have been subject to positive selection in the evolutionary history of humans and other primates. We evaluated this prediction using tests for recent selective sweeps in human populations and maximum-likelihood tests for selection during primate evolution. Significant evidence for positive selection was evident using one or both methods for 28 of 76 genes demonstrated to mediate liability to schizophrenia, including DISCI, DTNBP1 and NRG1, which exhibit especially strong and well-replicated functional and genetic links to this disorder. Strong evidence of non-neutral, accelerated evolution was found for DISCI, particularly for exon 2, the only coding region within the schizophrenia-associated haplotype. Additionally, genes associated with schizophrenia exhibited a statistically significant enrichment in their signals of positive selection in HapMap and PAML analyses of evolution along the human lineage, when compared with a control set of genes involved in neuronal activities. The selective forces underlying adaptive evolution of these genes remain largely unknown, but these findings provide convergent evidence consistent with the hypothesis that schizophrenia represents, in part, a maladaptive by-product of adaptive changes during human evolution.