Sequence variants in gene regulatory regions alter gene expression and contribute to phenotypes of individual cells and the whole organism, including disease susceptibility and progression. Single-nucleotide variants in enhancers or promoters may affect gene transcription by altering transcription factor binding sites. Differential transcription factor binding in heterozygous genomic loci provides a natural source of information on such regulatory variants. We present a novel approach to call the allele-specific transcription factor binding events at single-nucleotide variants in ChIP-Seq data, taking into account the joint contribution of aneuploidy and local copy number variation, that is estimated directly from variant calls. We have conducted a meta-analysis of more than 7 thousand ChIP-Seq experiments and assembled the database of allele-specific binding events listing more than half a million entries at nearly 270 thousand single-nucleotide polymorphisms for several hundred human transcription factors and cell types. These polymorphisms are enriched for associations with phenotypes of medical relevance and often overlap eQTLs, making candidates for causality by linking variants with molecular mechanisms. Specifically, there is a special class of switching sites, where different transcription factors preferably bind alternative alleles, thus revealing allele-specific rewiring of molecular circuitry.

中文翻译：

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人类基因组中等位基因特异性转录因子结合的态势

基因调控区的序列变异会改变基因表达，并导致单个细胞和整个生物的表型，包括疾病的易感性和进展。增强子或启动子中的单核苷酸变体可通过改变转录因子结合位点来影响基因转录。杂合基因组基因座中的差异转录因子结合提供了有关此类调控变体的信息的天然来源。我们提出一种新颖的方法来调用ChIP-Seq数据中单核苷酸变异体上的等位基因特异性转录因子结合事件，同时考虑到非整倍性和局部拷贝数变异的联合贡献，这是直接从变异体调用中估算的。我们进行了超过7,000项ChIP-Seq实验的荟萃分析，并建立了等位基因特异性结合事件的数据库，该数据库列出了针对数百种人类转录因子和细胞类型的近270,000个单核苷酸多态性的超过一百万个条目。这些多态性丰富了与医学相关性表型的关联，并且经常重叠eQTL，通过将变异与分子机制联系起来，成为因果关系的候选者。具体而言，有一类特殊的转换位点，其中不同的转录因子优选结合替代等位基因，从而揭示了分子电路的等位基因特异性重新接线。