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Genome Biol. 2019 Nov 28;20(1):255. doi: 10.1186/s13059-019-1855-4.

Common DNA sequence variation influences 3-dimensional conformation of the human genome.

Author information

1
Ludwig Institute for Cancer Research, La Jolla, CA, USA.
2
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
3
Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
4
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. hum@ccf.org.
5
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
6
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
7
Current address: Arima Genomics, San Diego, CA, 92121, USA.
8
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
9
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
10
Department of Psychiatry, University of California, San Diego, La Jolla, CA, 92093, USA.
11
Department of Genetics, Department of Biostatistics, and Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA.
12
Ludwig Institute for Cancer Research, La Jolla, CA, USA. biren@ucsd.edu.
13
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. biren@ucsd.edu.
14
Institute of Genomic Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. biren@ucsd.edu.

Abstract

BACKGROUND:

The 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation.

RESULTS:

To address these questions, we perform Hi-C on lymphoblastoid cell lines from 20 individuals. We identify thousands of regions across the genome where 3D chromatin conformation varies between individuals and find that this variation is often accompanied by variation in gene expression, histone modifications, and transcription factor binding. Moreover, we find that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality, and density of local cis contacts. We map hundreds of quantitative trait loci associated with 3D chromatin features and find evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk.

CONCLUSION:

Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.

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