Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals
- Alexis Battle1,
- Sara Mostafavi1,
- Xiaowei Zhu1,
- James B. Potash2,
- Myrna M. Weissman3,
- Courtney McCormick4,
- Christian D. Haudenschild5,
- Kenneth B. Beckman6,
- Jianxin Shi7,
- Rui Mei8,
- Alexander E. Urban1,
- Stephen B Montgomery1,
- Douglas F. Levinson1 and
- Daphne Koller1,9
- 1 Stanford University;
- 2 University of Iowa Hospitals & Clinics;
- 3 Columbia University and New York State Psyciatric Institute;
- 4 Illumina, Inc.;
- 5 Personalis, Inc.;
- 6 University of Minnesota;
- 7 National Cancer Institute;
- 8 Centrillion Biosciences, Inc.
- ↵* Corresponding author; email: koller{at}cs.stanford.edu
Abstract
Understanding the consequences of regulatory variation in the human genome remains a major challenge, with important implications for understanding gene regulation and interpreting the many disease-risk variants that fall outside of protein-coding regions. Here, we provide a direct window into the regulatory consequences of genetic variation by sequencing RNA from 922 genotyped individuals. We present a comprehensive description of the distribution of regulatory variation - by the specific expression phenotypes altered, the properties of affected genes, and the genomic characteristics of regulatory variants. We detect variants influencing expression of over ten thousand genes, and through the enhanced resolution offered by RNA-sequencing, for the first time we identify thousands of variants associated with specific phenotypes including splicing and allelic expression. Evaluating the effects of both long-range intra-chromosomal and trans (cross-chromosomal) regulation, we observe modularity in the regulatory network, with three-dimensional chromosomal configuration playing a particular role in regulatory modules within each chromosome. We also observe a significant depletion of regulatory variants affecting central and critical genes, along with a trend of reduced effect sizes as variant frequency increases, providing evidence that purifying selection and buffering have limited the deleterious impact of regulatory variation on the cell. Further, generalizing beyond observed variants, we have analyzed the genomic properties of variants associated with expression and splicing, and developed a Bayesian model to predict regulatory consequences of genetic variants, applicable to the interpretation of individual genomes and disease studies. Together, these results represent a critical step toward characterizing the complete landscape of human regulatory variation.
- Received January 24, 2013.
- Accepted October 1, 2013.
- Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
