Study on the Differential Analysis of Alternative Splicing Based on the Median Value Jensen-Shannon Divergence
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摘要: 可变剪接是一种广泛存在于生物体中造成蛋白质多样性的重要机制，它对细胞的增殖、分化、发育、凋亡等一系列重要的生物过程具有重要精细调控的作用。近年来，人们发现多种复杂疾病的产生往往伴随着剪接异构体的紊乱表达。为了研究剪接异构体在整体分布上的差异，该文提出一种基于中值的JS散度可变剪接(AS)差异分析方法。结果表明，该文的方法能够发现大量在剪接异构体整体分布上具有显著差异的基因。这些基因不仅富集在一些癌症密切相关的通路，而且也富集在一些基于可变剪接调控的信号通路、细胞分裂过程和蛋白质功能等通路。此外，与基因层次的差异分析相比，可变剪接显著差异的基因在生存分析方面也具有更好的性能。总之，该文提出基于中值的JS散度可变剪接差异分析方法，将为进一步揭示可变剪接在癌症中的机制奠定基础。Abstract: Alternative splicing is an important mechanism of protein diversity in a wide range of organisms, which plays an important role in the fine regulation of cell proliferation, differentiation, development, apoptosis and a series of important biological processes. In recent years, it is found that the occurrence of multiple complex diseases is often accompanied by the disordered expression of splicing isoforms. In order to study the difference of splicing isoforms on the whole distribution, a differential analysis method of Alternative Splicing (AS) based on the median value by Jensen-Shannon (JS) divergence is proposed in this paper. The results show the method can finds plenty of genes with significant differences in the overall distribution of splicing isoforms. These genes are not only concentrated in some cancer related pathways, but also in some signaling pathways based on alternative splicing regulation, cell division process and protein function. In addition, compared with the gene-level differential analysis, the genes with significant difference in alternative splicing also have better performance in survival analysis. In conclusion, the proposed method will lay a foundation for further revealing the mechanism of alternative splicing in cancer.
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表 1 癌症数据集统计信息
癌症 癌症样本 正常样本 基因个数 异构体个数 BRCA 1100 112 10178 33481 LIHC 373 50 8871 26234 UCEC 117 24 9765 30953 
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表 2 KEGG通路分析
癌症 通路(Gen Model) 通路(AS Model) Focal adhesion Cell cycle PI3K-Akt signaling pathway p53 signaling pathway Tight junction Pathways in cancer Regulation of lipolysis in adipocytes Oocyte meiosis BRCA Pathways in cancer Viral carcinogenesis Rap1 signaling pathway Adherens junction cAMP signaling pathway Purine metabolism ABC transporters PI3K-Akt signaling pathway Cell adhesion molecules (CAMs) Hippo signaling pathway Leukocyte transendothelial migration Metabolic pathways Metabolic pathways Metabolic pathways Fatty acid degradation Phagosome Protein processing in endoplasmic reticulum Fc gamma R-mediated phagocytosis Proteasome Leishmaniasis LIHC mTOR signaling pathway Homologous recombination AMPK signaling pathway Sphingolipid metabolism Valine, leucine and isoleucine degradation ECM-receptor interaction Spliceosome Cell cycle Ubiquitin mediated proteolysis Fanconi anemia pathway Insulin signaling pathway Ribosome biogenesis in eukaryotes Vascular smooth muscle contraction Osteoclast differentiation cGMP-PKG signaling pathway Cell cycle Focal adhesion Adherens junction MAPK signaling pathway Axon guidance UCEC Proteoglycans in cancer Phagosome Calcium signaling pathway Rheumatoid arthritis Platelet activation AMPK signaling pathway Adherens junction PPAR signaling pathway Oxytocin signaling pathway ECM-receptor interaction Ras signaling pathway Platelet activation
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