Journal Article

Allele-specific binding variants causing ChIP-seq peak height of histone modification are not enriched in expression QTL annotations

Prowse-Wilkins, Claire P., Pryce, Jennie E., Ghoreishifar, Mohammad, Goddard, Michael E., Xiang, Ruidong, Littlejohn, Mathew D., Chamberlain, Amanda J., Lopdell, Thomas J.

2024

Overview

Background 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. Results 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). Conclusions 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Agriculture / Alleles / Animal Genetics and Genomics / Animals / Annotations / Binding / Binding sites / Biomedical and Life Sciences / Cattle - genetics / Chromatin / chromatin immunoprecipitation / Chromatin Immunoprecipitation Sequencing - methods / Conserved sequence / Deoxyribonucleic acid / DNA / DNA sequencing / Enrichment / Evolutionary Biology / Female / Gene expression / Gene mapping / Gene sequencing / Genes / genome / Genomes / Genomics / Genotype & phenotype / Histone Code / Histones / Histones - genetics / Histones - metabolism / Immunoprecipitation / Life Sciences / Linkage Disequilibrium / Mammary gland / Mammary glands / Molecular Sequence Annotation / Nucleotide sequence / nucleotide sequences / Nucleotide sequencing / Nucleotides / Polymorphism, Single Nucleotide / prediction / Prediction models / Predictions / Quantitative genetics / Quantitative Trait Loci / quantitative traits / regression analysis / Regression models / Research Article / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Statistical analysis / Support vector machines