Common DNA sequence variation influences 3-dimensional conformation of the human genome,Genome Biology

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Common DNA sequence variation influences 3-dimensional conformation of the human genome
Genome Biology ( IF 10.1 ) Pub Date : 2019-11-28 , DOI: 10.1186/s13059-019-1855-4
David U Gorkin _{1,

2} , Yunjiang Qiu _{1,

3} , Ming Hu ₄ , Kipper Fletez-Brant _{5,

6} , Tristin Liu ₁ , Anthony D Schmitt _{1,

7} , Amina Noor ₂ , Joshua Chiou _{8,

9} , Kyle J Gaulton ₈ , Jonathan Sebat _{2,

10} , Yun Li ₁₁ , Kasper D Hansen _{5,

6} , Bing Ren _{1,

2,

12}

Affiliation

Ludwig Institute for Cancer Research, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Current address: Arima Genomics, San Diego, CA, 92121, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of California, San Diego, La Jolla, CA, 92093, USA.
Department of Genetics, Department of Biostatistics, and Department of Computer Science, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA.
Institute of Genomic Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

BackgroundThe 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.ResultsTo 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.ConclusionOur 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.

中文翻译：

常见的 DNA 序列变异影响人类基因组的 3 维构象

背景核内染色质的 3 维 (3D) 构象是转录调控、DNA 复制和 DNA 损伤修复等多种核过程不可或缺的一部分。 3D 染色质构象的畸变与发育异常和癌症有关。尽管 3D 染色质构象对细胞功能和人类健康很重要，但人们对 3D 染色质构象在人群中如何变化，或者个体之间的 DNA 序列变异是否影响 3D 染色质构象知之甚少。结果为了解决这些问题，我们进行了 Hi-C 20 个人的淋巴母细胞系。我们确定了基因组中数千个区域，其中 3D 染色质构象在个体之间存在差异，并发现这种差异通常伴随着基因表达、组蛋白修饰和转录因子结合的变化。此外，我们发现DNA序列变异影响3D染色质构象的几个特征，包括环强度、接触绝缘性、接触方向性和局部顺式接触的密度。我们绘制了数百个与 3D 染色质特征相关的数量性状基因座，并发现证据表明其中一些相同的变异与其他分子表型以及复杂的疾病风险在适度水平上相关。结论我们的结果表明常见的 DNA 序列变异可以影响 3D 染色质构象，指出 3D 染色质构象在人类表型变异中的作用比之前认识到的更为普遍。

更新日期：2019-11-28

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