Fang Lingzhao, Zhou Yang, Liu Shuli, Jiang Jicai, Bickhart Derek M, Null Daniel J, Li Bingjie, Schroeder Steven G, Rosen Benjamin D, Cole John B, Van Tassell Curtis P, Ma Li, Liu George E
Animal Genomics and Improvement Laboratory, BARC, Agricultural Research Service, USDA, Beltsville, MD 20705, USA.
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
Epigenomes. 2019 May 16;3(2):10. doi: 10.3390/epigenomes3020010.
Decreased male fertility is a big concern in both human society and the livestock industry. Sperm DNA methylation is commonly believed to be associated with male fertility. However, due to the lack of accurate male fertility records (i.e., limited mating times), few studies have investigated the comprehensive impacts of sperm DNA methylation on male fertility in mammals. In this study, we generated 10 sperm DNA methylomes and performed a preliminary correlation analysis between signals from sperm DNA methylation and signals from large-scale ( = 27,214) genome-wide association studies (GWAS) of 35 complex traits (including 12 male fertility-related traits). We detected genomic regions, which experienced DNA methylation alterations in sperm and were associated with aging and extreme fertility phenotypes (e.g., sire-conception rate or SCR). In dynamic hypomethylated regions (HMRs) and partially methylated domains (PMDs), we found genes (e.g., gene clusters and microRNAs) that were involved in the embryonic development. We demonstrated that genomic regions, which gained rather than lost methylations during aging, and in animals with low SCR were significantly and selectively enriched for GWAS signals of male fertility traits. Our study discovered 16 genes as the potential candidate markers for male fertility, including and . Collectively, this initial effort supported a hypothesis that sperm DNA methylation may contribute to male fertility in cattle and revealed the usefulness of functional annotations in enhancing biological interpretation and genomic prediction for complex traits and diseases.
男性生育能力下降在人类社会和畜牧业中都是一个重大问题。精子DNA甲基化通常被认为与男性生育能力有关。然而，由于缺乏准确的男性生育记录（即交配次数有限），很少有研究调查精子DNA甲基化对哺乳动物雄性生育能力的全面影响。在本研究中，我们生成了10个精子DNA甲基化组，并对精子DNA甲基化信号与35个复杂性状（包括12个与男性生育相关的性状）的大规模（=27214）全基因组关联研究（GWAS）信号进行了初步相关性分析。我们检测到了基因组区域，这些区域在精子中经历了DNA甲基化改变，并与衰老和极端生育表型（如父系受孕率或SCR）相关。在动态低甲基化区域（HMRs）和部分甲基化结构域（PMDs）中，我们发现了参与胚胎发育的基因（如基因簇和微小RNA）。我们证明，在衰老过程中以及SCR较低的动物中获得而非失去甲基化的基因组区域，在雄性生育性状的GWAS信号中显著且选择性地富集。我们的研究发现了16个基因作为男性生育能力的潜在候选标记，包括 和 。总的来说，这一初步研究支持了一个假设，即精子DNA甲基化可能有助于牛的雄性生育能力，并揭示了功能注释在增强对复杂性状和疾病的生物学解释及基因组预测方面的有用性。
