中文摘要：

研究可变剪接和蛋白质结构多样性之间的相关性,对于理解可变剪接的功能具有重要意义。已有研究支持可变剪接增加蛋白质结构多样性的观点,但可变剪接影响蛋白质结构的程度、机制等还尚未阐明。作者基于具有确定三维结构的可变剪接蛋白质变体数据,从蛋白质结构差异和结构稳定性两个方面对致病和非致病的可变剪接蛋白质变体对进行了比较分析;通过建立实际可变剪接变体集和随机可变剪接变体集,并定义蛋白质的多样性增量（increment of diversity,ID）和疏水非均一性（hydrophobic non-uniformity,HI）,研究了可变剪接发生的非随机性。结果表明：现有的多数可变剪接事件与随机剪接相比,倾向于增加蛋白质结构多样性;产生结构差异较大蛋白质的可变剪接事件倾向于导致疾病的发生。作者还提出了正负选择压力的动态平衡假说解释这一现象,认为与生命活动相联系的正选择压力促使增加蛋白质结构多样性的可变剪接事件在群体中固定,但反向的负选择压力约束着可变剪接改变蛋白质结构的尺度,细胞中现有的可变剪接正是这两种正负选择压力之间保持动态平衡的结果。

英文摘要：

Studying the correlation between alternative splicing and protein structural diversity is of great significance for understanding the function of alternative splicing. Several researches show that alternative splicing can increase protein structural diversity, but as for which alternative splicing affects protein structure and the underlying mechanisms have not been elucidated yet. Based on the alternative splicing protein isoforms with three-dimensional structures, the authors analyzed the differences of both protein structure and structural stability between the morbigenous and un-morbigenous protein isoform pairs. Meanwhile, a real alternative splicing dataset and a randomized alternative splicing dataset were constructed, to investigate the non-randomness of alternative splicing by using two parameters, protein increment of diversity and hydrophobic non-uniformity. The results show that the majority of existing alternative splicing events tend to increase the diversity of protein structure, compared with randomized splicing events. And, the alternative splicing events, which are able to produce proteins that differ much in structure from those produced by canonical splicing, tend to cause diseases. The hypothesis of dynamic balance between positive and negative selection pressures was proposed to explain the result： the positive selection pressure associated with life activities facilitates the fixation of alternative splicing events, which could increase the diversity of protein structure, in the population, while the negative selection pressure controls the extent to which alternative splicing changes the protein structure. Alternative splicing in cell is just the result of dynamic balance between positive and negative selection pressure.