Lei Huimeng, Yan Zhangming, Sun Xiaohong, Zhang Yue, Wang Jianhong, Ma Caihong, Xu Qunyuan, Wang Rui, Jarvis Erich D, Sun Zhirong
Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, Beijing 100069, China.
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Brain Lang. 2017 Nov;174:1-8. doi: 10.1016/j.bandl.2017.06.007. Epub 2017 Jul 8.
Human and several nonhuman species share the rare ability of modifying acoustic and/or syntactic features of sounds produced, i.e. vocal learning, which is the important neurobiological and behavioral substrate of human speech/language. This convergent trait was suggested to be associated with significant genomic convergence and best manifested at the ROBO-SLIT axon guidance pathway. Here we verified the significance of such genomic convergence and assessed its functional relevance to human speech/language using human genetic variation data. In normal human populations, we found the affected amino acid sites were well fixed and accompanied with significantly more associated protein-coding SNPs in the same genes than the rest genes. Diseased individuals with speech/language disorders have significant more low frequency protein coding SNPs but they preferentially occurred outside the affected genes. Such patients' SNPs were enriched in several functional categories including two axon guidance pathways (mediated by netrin and semaphorin) that interact with ROBO-SLITs. Four of the six patients have homozygous missense SNPs on PRAME gene family, one youngest gene family in human lineage, which possibly acts upon retinoic acid receptor signaling, similarly as FOXP2, to modulate axon guidance. Taken together, we suggest the axon guidance pathways (e.g. ROBO-SLIT, PRAME gene family) served as common targets for human speech/language evolution and related disorders.
人类和几种非人类物种都具备一种罕见的能力，即能够改变所发出声音的声学和/或句法特征，也就是声乐学习能力，这是人类言语/语言重要的神经生物学和行为基础。这种趋同特征被认为与显著的基因组趋同相关，并且在ROBO-SLIT轴突导向通路中表现得最为明显。在此，我们利用人类遗传变异数据验证了这种基因组趋同的重要性，并评估了其与人类言语/语言的功能相关性。在正常人群中，我们发现受影响的氨基酸位点固定良好，并且与其他基因相比，同一基因中与之相关的蛋白质编码单核苷酸多态性（SNP）显著更多。患有言语/语言障碍的个体具有显著更多的低频蛋白质编码SNP，但它们优先出现在受影响基因之外。此类患者的SNP在包括两条与ROBO-SLIT相互作用的轴突导向通路（由netrin和semaphorin介导）在内的几个功能类别中富集。六名患者中有四名在PRAME基因家族上具有纯合错义SNP，PRAME基因家族是人类谱系中最年轻的基因家族之一，它可能像FOXP2一样作用于视黄酸受体信号传导，以调节轴突导向。综上所述，我们认为轴突导向通路（如ROBO-SLIT、PRAME基因家族）是人类言语/语言进化及相关疾病的共同靶点。
