Genome sequence variants affecting complex traits (quantitative trait loci, QTL) are enriched in functional regions of the genome, such as those marked by certain histone modifications. These variants are believed to influence gene expression. However, due to the linkage disequilibrium among nearby variants, pinpointing the precise location of QTL is challenging. We aimed to identify allele-specific binding (ASB) QTL (asbQTL) that cause variation in the level of histone modification, as measured by the height of peaks assayed by ChIP-seq (chromatin immunoprecipitation sequencing). We identified DNA sequences that predict the difference between alleles in ChIP-seq peak height in H3K4me3 and H3K27ac histone modifications in the mammary glands of cows. We used a gapped k-mer support vector machine, a novel best linear unbiased prediction model, and a multiple linear regression model that combines the other two approaches to predict variant impacts on peak height. For each method, a subset of 1000 sites with the highest magnitude of predicted ASB was considered as candidate asbQTL. The accuracy of this prediction was measured by the proportion where the predicted direction matched the observed direction. Prediction accuracy ranged between 0.59 and 0.74, suggesting that these 1000 sites are enriched for asbQTL. Using independent data, we investigated functional enrichment in the candidate asbQTL set and three control groups, including non-causal ASB sites, non-ASB variants under a peak, and SNPs (single nucleotide polymorphisms) not under a peak. For H3K4me3, a higher proportion of the candidate asbQTL were confirmed as ASB when compared to the non-causal ASB sites (P < 0.01). However, these candidate asbQTL did not enrich for the other annotations, including expression QTL (eQTL), allele-specific expression QTL (aseQTL) and sites conserved across mammals (P > 0.05). We identified putatively causal sites for asbQTL using the DNA sequence surrounding these sites. Our results suggest that many sites influencing histone modifications may not directly affect gene expression. However, it is important to acknowledge that distinguishing between putative causal ASB sites and other non-causal ASB sites in high linkage disequilibrium with the causal sites regarding their impact on gene expression may be challenging due to limitations in statistical power.

中文翻译：

---

导致组蛋白修饰 ChIP-seq 峰高的等位基因特异性结合变异在表达 QTL 注释中未富集


影响复杂性状（数量性状基因座，QTL）的基因组序列变异在基因组的功能区域中丰富，例如那些由某些组蛋白修饰标记的区域。这些变异被认为影响基因表达。然而，由于附近变异之间的连锁不平衡，精确定位QTL的精确位置具有挑战性。我们的目的是确定导致组蛋白修饰水平变化的等位基因特异性结合 (ASB) QTL (asbQTL)，通过 ChIP-seq（染色质免疫沉淀测序）测定的峰高度来测量。我们鉴定了可预测奶牛乳腺 H3K4me3 和 H3K27ac 组蛋白修饰 ChIP-seq 峰高等位基因之间差异的 DNA 序列。我们使用了间隙 k 聚体支持向量机、新颖的最佳线性无偏预测模型以及结合其他两种方法来预测变量对峰高影响的多元线性回归模型。对于每种方法，预测 ASB 幅度最高的 1000 个位点的子集被视为候选 asbQTL。该预测的准确性是通过预测方向与观测方向匹配的比例来衡量的。预测准确度在 0.59 到 0.74 之间，表明这 1000 个位点富含 asbQTL。使用独立数据，我们研究了候选 asbQTL 集和三个对照组的功能富集，包括非因果 ASB 位点、峰值下的非 ASB 变异和不在峰值下的 SNP（单核苷酸多态性）。对于 H3K4me3，与非因果 ASB 位点相比，更高比例的候选 asbQTL 被确认为 ASB（P < 0.01）。 然而，这些候选asbQTL并没有丰富其他注释，包括表达QTL（eQTL）、等位基因特异性表达QTL（aseQTL）和跨哺乳动物保守的位点（P>0.05）。我们利用这些位点周围的 DNA 序列确定了 asbQTL 的假定因果位点。我们的结果表明，许多影响组蛋白修饰的位点可能不会直接影响基因表达。然而，重要的是要承认，由于统计功效的限制，区分假定的因果 ASB 位点和其他与因果位点高度连锁不平衡的非因果 ASB 位点对基因表达的影响可能具有挑战性。