title: Alternative splicing at GYNNGY 5' splice sites: more noise, less regulation.
abstract: Numerous eukaryotic genes are alternatively spliced. Recently, deep transcriptome sequencing has skyrocketed proportion of alternatively spliced genes; over 95% human multi-exon genes are alternatively spliced. One fundamental question is: are all these alternative splicing (AS) events functional? To look into this issue, we studied the most common form of alternative 5' splice sites-GYNNGYs (Y = C/T), where both GYs can function as splice sites. Global analyses suggest that splicing noise (due to stochasticity of splicing process) can cause AS at GYNNGYs, evidenced by higher AS frequency in non-coding than in coding regions, in non-conserved than in conserved genes and in lowly expressed than in highly expressed genes. However, ∼20% AS GYNNGYs in humans and ∼3% in mice exhibit tissue-dependent regulation. Consistent with being functional, regulated GYNNGYs are more conserved than unregulated ones. And regulated GYNNGYs have distinctive sequence features which may confer regulation. Particularly, each regulated GYNNGY comprises two splice sites more resembling each other than unregulated GYNNGYs, and has more conserved downstream flanking intron. Intriguingly, most regulated GYNNGYs may tune gene expression through coupling with nonsense-mediated mRNA decay, rather than encode different proteins. In summary, AS at GYNNGY 5' splice sites is primarily splicing noise, and secondarily a way of regulation.
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Peiwei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Landian
authors.initials: L
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China Graduate School of the Chinese Academy of Sciences, Beijing, People's Republic of China xykong@sibs.ac.cn.
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Kong
authors.affiliation: Institute of Molecular Evolutionary Genetics and Department of Biology, Pennsylvania State University, University Park, PA 16802, USA zhangz.sci@gmail.com.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D009928:Organ Specificity; D022821:RNA Splice Sites
chemical_list: D022821:RNA Splice Sites