Widespread splicing changes in human brain development and aging

• Published in: Molecular systems biology 2013, Vol.9 (1), p.633-n/a
• Main Authors: Mazin, Pavel, Xiong, Jieyi, Liu, Xiling, Yan, Zheng, Zhang, Xiaoyu, Li, Mingshuang, He, Liu, Somel, Mehmet, Yuan, Yuan, Phoebe Chen, Yi‐Ping, Li, Na, Hu, Yuhui, Fu, Ning, Ning, Zhibin, Zeng, Rong, Yang, Hongyi, Chen, Wei, Gelfand, Mikhail, Khaitovich, Philipp
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Aging - genetics; Alternative Splicing; Alzheimer's disease; Animals; Brain; Brain research; Cell adhesion & migration; Cerebellum; Cerebellum - growth & development; Cerebellum - physiology; Child; Child, Preschool; Datasets; development; EMBO09; EMBO10; EMBO27; Exons; Gene expression; Gene Expression Profiling; Geriatrics; Grants; human; Humans; Infant; Infant, Newborn; Infants; Life span; Macaca mulatta; Macaca mulatta - genetics; Mass spectrometry; Mass spectroscopy; Middle Aged; Older people; Prefrontal cortex; Prefrontal Cortex - growth & development; Prefrontal Cortex - physiology; Proteins; Proteins - genetics; Proteins - metabolism; Ribonucleic acid; RNA; RNA Splicing; RNA‐seq; Science; Sequence Analysis, RNA - methods; Splicing; Splicing factors; Young Adult
• ISSN: 1744-4292; 1744-4292
• DOI: 10.1038/msb.2012.67

While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high‐throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA‐seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense‐mediated decay in infants and elderly. Human brain transcriptome analysis revealed widespread age‐related splicing changes in the prefrontal cortex and cerebellum. While most of the splicing changes take place in development, approximately one‐third of them extends into aging. Synopsis Human brain transcriptome analysis revealed widespread age‐related splicing changes in the prefrontal cortex and cerebellum. While most of the splicing changes take place in development, approximately one‐third of them extends into aging. More than one‐third of genes expressed in the human brain change splicing with age. Approximately 30% of observed splicing changes occur in aging. Age‐related splicing patterns are largely conserved between the human and macaque brains. High frequency of intron retention events suggests the role of nonsense‐mediated decay in age‐related gene expression regulation.