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

Area of Science:

• Genomics
• Epigenetics
• Animal Genetics

Background:

• Genome sequence variants linked to complex traits are often in functional genomic regions, influencing gene expression.
• Linkage disequilibrium complicates pinpointing quantitative trait loci (QTL).
• Allele-specific binding (ASB) QTL (asbQTL) can explain variations in histone modifications.

Purpose of the Study:

• To identify asbQTL impacting histone modifications (H3K4me3, H3K27ac) in cow mammary glands.
• To develop predictive models for variant effects on chromatin immunoprecipitation sequencing (ChIP-seq) peak heights.

Main Methods:

• Utilized gapped k-mer support vector machine, best linear unbiased prediction, and multiple linear regression models.
• Predicted variant impacts on ChIP-seq peak heights to identify candidate asbQTL.
• Assessed prediction accuracy (0.59–0.74) and functional enrichment of candidate asbQTL using independent data.

Main Results:

• Identified candidate asbQTL enriched for ASB compared to non-causal sites (P < 0.01) for H3K4me3.
• Candidate asbQTL did not show enrichment for expression QTL (eQTL), allele-specific expression QTL (aseQTL), or conserved sites.
• Prediction models identified putatively causal sites for asbQTL based on surrounding DNA sequences.

Conclusions:

• Developed a method to identify putatively causal asbQTL using DNA sequence information.
• Results indicate that many histone modification-influencing sites may not directly alter gene expression.
• Statistical power limitations may challenge the distinction between causal ASB sites and linked non-causal sites affecting gene expression.