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Widespread splicing changes in human brain development and aging

Mazin, Pavel
Xiong, Jieyi
Liu, Xiling
Yan, Zheng
Zhang, Xiaoyu
Li, Mingshuang
He, Liu
Somel, Mehmet
Yuan, Yuan
Chen, Yi-Ping Phoebe
Li, Na
Hu, Yuhui
Fu, Ning
Ning, Zhibin
Zeng, Rong
Yang, Hongyi
Chen, Wei
Gelfand, Mikhail
Khaitovich, Philipp
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. Molecular Systems Biology 9: 633; published online 22 January 2013; doi:10.1038/msb.2012.67