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Genome Biol. 2019 Nov 4;20(1):230. doi: 10.1186/s13059-019-1840-y.

Genetic regulation of gene expression and splicing during a 10-year period of human aging.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, USA. bballiu@stanford.edu.
2
Department of Genetics, Stanford University School of Medicine, Stanford, USA.
3
Department of Pathology, Stanford University School of Medicine, Stanford, USA.
4
Department of Biology, Stanford University School of Medicine, Stanford, USA.
5
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
6
New York Genome Center, New York, USA.
7
Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
8
Laboratory of Genetics, National Institute on Aging, Maryland, USA.
9
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, USA.
10
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, USA. eriking@stanford.edu.
11
Stanford Cardiovascular Institute, Stanford University, Stanford, USA. eriking@stanford.edu.
12
Stanford Diabetes Research Center, Stanford University, Stanford, USA. eriking@stanford.edu.
13
Department of Pathology, Stanford University School of Medicine, Stanford, USA. smontgom@stanford.edu.
14
Department of Genetics, Stanford University School of Medicine, Stanford, USA. smontgom@stanford.edu.

Abstract

BACKGROUND:

Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age.

RESULTS:

We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age.

CONCLUSIONS:

These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

KEYWORDS:

Aging; Alternative splicing; Gene expression; Gene regulation; Longevity

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