Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases

Kun Wang,Kan Cao,Justin Malin,Di Wu,Avinash Das,Haoyue Zhang,Mahashweta Basu,Sridhar Hannenhalli

doi:10.1038/s41598-018-29086-2

Abstract

Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases.

Highlights

Almost all multi-exon genes in human exhibit alternative splicing[1,2], which alongside transcriptional regulation, significantly contribute to the transcriptomic as well as phenotypic diversity at multiple biological scales[3]
Our study addresses these limitations in the previous studies toward a comprehensive investigation of age-associated splicing changes across human tissues, which may provide insights into age-related diseases mediated by splicing changes
Based on ~8500 RNA-seq samples from 544 donors across 48 tissues in the Genotype-Tissue Expression dataset (GTEx version 6)[13], here we report a comprehensive detection of age-associated splicing changes across tissues in human

Summary

Introduction

Almost all multi-exon genes in human exhibit alternative splicing[1,2], which alongside transcriptional regulation, significantly contribute to the transcriptomic as well as phenotypic diversity at multiple biological scales[3]. 7 types of splicing events (exon skipping, alternative 5’, alternative 3’, mutually exclusive exon, alternative first exon, alternative last exon, and intron retention), (3) are based on very few individuals (around 35), in contrast to 177 individuals on average per tissue in our study, and highly importantly, (4) in contrast to our study, do not explicitly control for batch effect and potential hidden confounding factors, which may lead to false positives Our study addresses these limitations in the previous studies toward a comprehensive investigation of age-associated splicing changes across human tissues, which may provide insights into age-related diseases mediated by splicing changes. We identified 49,869 age-associated splicing events of 7 distinct types[14], including 17,447 exon-skipping events, across the 48 tissues

Methods

Results

Conclusion