Fouéré Corentin, Costes Valentin, Hozé Chris, Raja Ravi Shankar Amrita, Besnard Florian, Costa Monteiro Moreira Gabriel, Sorin Valentin, Le Danvic Chrystelle, Chaulot-Talmon Aurélie, Ali Francesca, Deloche Marie Christine, Bonnet Aurélie, Sellem Eliaou, Jammes Hélène, Fritz Sébastien, Boussaha Mekki, Boichard Didier, Kiefer Hélène, Sanchez Marie-Pierre
Eliance, 149 Rue de Bercy, Paris, 75012, France.
Université Paris-Saclay, INRAE, AgroParisTech, GABI, Jouy-en-Josas, 78352, France.
BMC Genomics. 2025 Aug 22;26(1):771. doi: 10.1186/s12864-025-11934-x.
DNA methylation (DNAm) plays an important functional role and is influenced by genetic variants known as methylation QTLs (meQTLs). The majority of meQTL studies have been conducted in human blood. Despite its unique landscape, the genetic regulation of sperm DNAm remains largely unexplored. In this study, we leveraged DNAm measured in sperm from 405 Holstein bulls using reduced representation bisulfite sequencing (RRBS) and performed sequence-level genome-wide association studies for 166,985 variable CpGs (s.d. >5%). We reported heritability estimates and have mapped both cis-meQTLs and trans-meQTLs.
Heritability estimates ranged from 0 to 1 and averaged 0.26 across all selected CpGs, with 76% of estimates above 0.1. The meQTL mapping revealed that 32.9% of the CpGs had a cis-meQTL, 3.6% had a trans-meQTL and 1.0% had both cis- and trans-meQTLs. The cis-CpGs were located on average 261 kb (absolute mean) from their cis-meQTL top SNPs (defined by the most significant association). MeQTLs were enriched in featured genomic annotations, including regions surrounding transcription start sites and ATAC-seq peaks. We also identified spurious trans-associations by analyzing data across multiple genome assemblies, including the construction of a partial pangenome. Additionally, eight trans-meQTL hotspots, defined as variants associated with at least 30 trans-CpGs, were identified and overlapped with genes involved in epigenetic regulation. Using peripheral blood mononuclear cell DNAm from 54 out of the 405 bulls, we did not observe a similar effect of the trans-meQTL hotspots to that one observed in sperm.
For the first time, meQTLs have been detected and characterized in bovine sperm, contributing to a better understanding of the transmission of paternally inherited DNAm marks. These findings provide useful information for further research aimed at integrating epigenetic information into the prediction of performance traits.
DNA甲基化（DNAm）发挥着重要的功能作用，并受称为甲基化定量性状位点（meQTLs）的遗传变异影响。大多数meQTL研究是在人类血液中进行的。尽管精子DNAm具有独特的格局，但其遗传调控在很大程度上仍未得到探索。在本研究中，我们利用简化代表性亚硫酸氢盐测序（RRBS）对405头荷斯坦公牛精子中的DNAm进行了测量，并对166,985个可变CpG（标准差>5%）进行了序列水平的全基因组关联研究。我们报告了遗传力估计值，并绘制了顺式meQTL和反式meQTL图谱。
遗传力估计值范围为0至1，所有选定CpG的平均值为0.26，76%的估计值高于0.1。meQTL图谱显示，32.9%的CpG有顺式meQTL，3.6%有反式meQTL，1.0%同时有顺式和反式meQTL。顺式CpG与其顺式meQTL顶级单核苷酸多态性（由最显著关联定义）的平均距离为261 kb（绝对均值）。MeQTL在特定的基因组注释中富集，包括转录起始位点周围区域和ATAC-seq峰。我们还通过分析多个基因组组装的数据，包括构建部分泛基因组，鉴定了虚假的反式关联。此外，确定了八个反式meQTL热点，定义为与至少30个反式CpG相关的变异，并与参与表观遗传调控的基因重叠。使用405头公牛中54头的外周血单核细胞DNAm，我们未观察到反式meQTL热点在精子中所观察到的类似效应。
首次在牛精子中检测并表征了meQTL，有助于更好地理解父系遗传DNAm标记的传递。这些发现为旨在将表观遗传信息整合到生产性状预测中的进一步研究提供了有用信息。
