Identification of bovine CpG SNPs as potential targets for epigenetic regulation via DNA methylation.

Mariângela B C Maldonado,Jesse L Hoff,Marcelo F Carazzolle,Nelson B De Rezende Neto,Stephanie D Mckay,Sheila T Nagamatsu,Robert D Schnabel,Jeremy F Taylor,Susanta K Behura,Lynsey K Whitacre,Flavia L Lopes,Leonardo Mariño-Ramírez

doi:10.1371/journal.pone.0222329

Abstract

Methylation patterns established and maintained at CpG sites may be altered by single nucleotide polymorphisms (SNPs) within these sites and may affect the regulation of nearby genes. Our aims were to: 1) identify and generate a database of SNPs potentially subject to epigenetic control by DNA methylation via their involvement in creating, removing or displacing CpG sites (meSNPs), and; 2) investigate the association of these meSNPs with CpG islands (CGIs), and with methylation profiles of DNA extracted from tissues from cattle with divergent feed efficiencies detected using MIRA-Seq. Using the variant annotation for 56,969,697 SNPs identified in Run5 of the 1000 Bull Genomes Project and the UMD3.1.1 bovine reference genome sequence assembly, we identified and classified 12,836,763 meSNPs according to the nature of variation created at CpGs. The majority of the meSNPs were located in intergenic regions (68%) or introns (26.3%). We found an enrichment (p<0.01) of meSNPs located in CGIs relative to the genome as a whole, and also in differentially methylated sequences in tissues from animals divergent for feed efficiency. Seven meSNPs, located in differentially methylated regions, were fixed for methylation site creating (MSC) or destroying (MSD) alleles in the differentially methylated genomic sequences of animals differing in feed efficiency. These meSNPs may be mechanistically responsible for creating or deleting methylation targets responsible for the differential expression of genes underlying differences in feed efficiency. Our methyl SNP database (dbmeSNP) is useful for identifying potentially functional "epigenetic polymorphisms" underlying variation in bovine phenotypes.

Highlights

Epigenetic events regulate gene expression through potentially transient changes to the chromatin without altering the nucleotide sequence, allowing genetically identical cells to differentiate phenotypically within and between cell lineages [1]
We first confirmed that the reference nucleotide base and the Identification of bovine CpG single nucleotide polymorphisms (SNPs) as potential targets for epigenetic regulation position annotated for each SNP in UMD3.1.1, was completely consistent with the variant SNP annotations identified in Run5 of the 1000BGP
Due to the possible impact of a genome sequence change caused by a meSNP, and the consequence of this change for the potential regulation of gene expression for nearby genes, we classified the meSNPs according to the variation they created at the CpG sites by chromosome (Table 1)

Summary

Introduction

Epigenetic events regulate gene expression through potentially transient changes to the chromatin without altering the nucleotide sequence, allowing genetically identical cells to differentiate phenotypically within and between cell lineages [1]. Such epigenetic mechanisms include DNA methylation, histone remodeling and DNA or mRNA interactions with noncoding RNAs. DNA methylation, primarily characterized by the addition of a methyl group at the 5-position of the cytosine pyrimidine ring in CG dinucleotides, is a fundamental epigenetic modification that occurs in many cellular processes, such as the development and maintenance of chromatin structure, parental imprinting, and X chromosome inactivation in females [2,3,4], and has an important role in the regulation of gene expression [5]. The introduction or removal of a CpG site, potentially subject to DNA methylation, has been suggested as a mechanism by which SNPs can affect gene regulation through altered epigenetic patterns [9]

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