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

Scientific Reports
Kun WangSridhar Hannenhalli

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 p...Continue Reading

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Citations

Dec 14, 2019·Human Genetics·Malini BhadraWilliam B Mair
Mar 20, 2020·Journal of Clinical Pathology·Kohei FujikuraKazuma Uesaka
Nov 7, 2019·Genome Biology·Brunilda BalliuStephen B Montgomery
Jul 8, 2020·Biomedicines·Carla Almendáriz-PalaciosChristopher H Eskiw
Feb 11, 2021·Wiley Interdisciplinary Reviews. RNA·Brittany Lynn Angarola, Olga Anczuków
Jan 16, 2021·Life Science Alliance·Nowsheen MullaniChristian Muchardt
Feb 19, 2021·Cellular and Molecular Gastroenterology and Hepatology·Virginia Díez-ObreroVíctor Moreno
Mar 27, 2021·PLoS Genetics·Kun WangSridhar Hannenhalli
Apr 4, 2021·Science Advances·Mahashweta BasuSridhar Hannenhalli
Jun 30, 2021·European Journal of Heart Failure·Gianfranco SinagraMarta Gigli

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Methods Mentioned

BETA
RNA-seq
MDS

Software Mentioned

David
TreeMap
REVIGO
SUPPA
NIH
PEER
GENCODE

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