Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits

Min Wang,Jennie E Pryce,Timothy P Hancock,Amanda J Chamberlain,Christy J Vander Jagt,Benjamin J Hayes,Benjamin G Cocks,Mike E Goddard

doi:10.1186/s12864-018-4800-0

Abstract

BackgroundTopological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants.ResultsWe used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping genes, transfer RNA genes, CTCF binding motifs, short interspersed elements, H3K4me3 and H3K27ac. We showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows’ white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The linearly-furthermost, and most-significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value < 0.001).ConclusionsOur results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.

Highlights

Topological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions
No input TADs were in chromosome Y or mitochondrial chromosome, but some TAD fragments were mapped to the bovine mitochondrial chromosome
We found across all P-value thresholds tested ranging from 10−5 to 10−8, the significant allele-specific expression quantitative trait locus (aseQTL) and expression quantitative trait locus (eQTL) in white blood and milk cell were highly enriched at putative bovine CCCTC binding factor (CTCF) binding motifs (P-value ≤ 10−5; Table 3) in comparison to the null distribution sampled from the entire bovine genome

Summary

Introduction

Topological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. Identifying causal mutations is essential for improving the accuracy and reliability of genomic selection [1]. The heterozygous locus is called eSNP or eVariant, and the gene that displays expression variation is called eGene [3,4,5,6,7] Both aseQTL and eQTL mappings require high computational capacities to test association between any eSNP and any eGene genome-wide. To reduce the computing time and space, we propose to take into account the transcriptional regulatory structure that confines the scope of chromosomal interactions, so we may only need to test cis-association between eSNPs and eGenes under the same transcriptional control

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