Evidence of reduced recombination rate in human regulatory domains.
Evidence of reduced recombination rate in human regulatory domains.
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DOI：
10.1186/s13059-017-1308-x
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发表时间：
2017-10-20
期刊：
影响因子：
12.3
通讯作者：
Kellis M
中科院分区：
文献类型：
--
作者：
Liu Y;Sarkar A;Kheradpour P;Ernst J;Kellis M
突变率在人类基因组中的分布是不均匀的。重组率在精细和大尺度上的变化不能完全由DNA序列单独解释。表观遗传因素，特别是DNA甲基化，最近被提出影响重组率的变化。我们研究了重组率和基因调控域之间的关系，由一个基因及其连接的控制元件定义。我们使用表达数量性状基因座（eQTL），甲基化数量性状基因座（meQTL），来自公开数据集（Hi-C和ChIA-PET）的染色质构象以及我们推断的跨细胞类型的相关活性链接来定义这些链接。与匹配的对照区相比，每种连接类型显示出重组率显著降低的“重组率谷”。这种重组率谷是最明显的早期胚胎发育基因，管家基因和组成型调控元件，这是已知的，以显示跨物种的进化约束增加的基因调控结构域。扩增速率谷显示DNA甲基化增加，双链断裂起始减少，修复效率增加，特别是在导致生殖系的谱系中。此外，通过仅使用生殖细胞中功能链接的重叠和DNA甲基化，我们能够以高精度预测重组率。我们的研究结果表明，存在一个重组率谷的调控结构域，并提供了一个潜在的分子机制来解释遗传和表观遗传变异之间的相互作用。本文的在线版本（doi：10.1186/s13059-017-1308-x）包含补充材料，可供授权用户使用。
Recombination rate is non-uniformly distributed across the human genome. The variation of recombination rate at both fine and large scales cannot be fully explained by DNA sequences alone. Epigenetic factors, particularly DNA methylation, have recently been proposed to influence the variation in recombination rate. We study the relationship between recombination rate and gene regulatory domains, defined by a gene and its linked control elements. We define these links using expression quantitative trait loci (eQTLs), methylation quantitative trait loci (meQTLs), chromatin conformation from publicly available datasets (Hi-C and ChIA-PET), and correlated activity links that we infer across cell types. Each link type shows a “recombination rate valley” of significantly reduced recombination rate compared to matched control regions. This recombination rate valley is most pronounced for gene regulatory domains of early embryonic development genes, housekeeping genes, and constitutive regulatory elements, which are known to show increased evolutionary constraint across species. Recombination rate valleys show increased DNA methylation, reduced doublestranded break initiation, and increased repair efficiency, specifically in the lineage leading to the germ line. Moreover, by using only the overlap of functional links and DNA methylation in germ cells, we are able to predict the recombination rate with high accuracy. Our results suggest the existence of a recombination rate valley at regulatory domains and provide a potential molecular mechanism to interpret the interplay between genetic and epigenetic variations. The online version of this article (doi:10.1186/s13059-017-1308-x) contains supplementary material, which is available to authorized users.
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