Conserved exchange of paralog proteins during neuronal differentiation

Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence the differentiation of immature neuron. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.

基因重复（Gene duplication）可通过降低整体进化压力，促使新功能的产生。过往研究已阐明特定旁系同源基因（paralog）在细胞分化过程中的作用，例如在染色质重塑复合物中。目前尚不明确此类机制是否可拓展至其他生物学功能，以及旁系同源基因的调控模式是否在不同物种间保守。本研究分析了鱼类、啮齿类及人类的旁系同源基因在人体组织、发育进程以及神经元分化阶段的表达情况。尽管约80%的旁系同源基因存在共调控现象，但仍有部分旁系同源基因呈现出差异化表达谱，进而导致蛋白质复合物的多样性增加。本研究鉴定出78对在神经元分化过程中出现且跨物种保守的旁系同源基因替换事件。其中，我们重点关注了COPII复合物（COPII complex）的Sec23a与Sec23b亚基这一对旁系同源基因间的替换事件。通过RNA干扰（RNAi）介导的基因敲低改变这两个基因的表达比例，足以影响未成熟神经元的分化过程。我们提出，通过旁系同源基因替换实现囊泡运输系统的重塑，是一种进化保守的、可推动神经元分化的机制。