Comparative analyses of sperm DNA methylomes among human, mouse and cattle provide insights into epigenomic evolution and complex traits

Authors: FANG, LINGZHAO - University Of Maryland; ZHOU, YANG - Huazhong Agricultural University; LIU, SHULI - China Agricultural University; JIANG, JICAI - University Of Maryland; Bickhart, Derek; Null, Daniel; LI, BINGJIE - Oak Ridge Institute For Science And Education (ORISE); Schroeder, Steven - Steve; Rosen, Benjamin - Ben; Cole, John; Van Tassell, Curtis - Curt; MA, LI - University Of Maryland; Liu, Ge - George

Submitted to: Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/3/2019
Publication Date: 3/24/2019
Citation: Fang, L., Zhou, Y., Liu, S., Jiang, J., Bickhart, D.M., Null, D.J., Li, B., Schroeder, S.G., Rosen, B.D., Cole, J.B., Van Tassell, C.P., Ma, L., Liu, G. 2019. Comparative analyses of sperm DNA methylomes among human, mouse and cattle provide insights into epigenomic evolution and complex traits. Epigenetics. 14(3):260-276. https://doi.org/10.1080/15592294.2019.1582217.
DOI: https://doi.org/10.1080/15592294.2019.1582217

Interpretive Summary: DNA methylation plays important roles in many processes like gene expression, genomic imprinting, repression of transposable elements, and gametogenesis. Using whole-genome bisulfite sequencing (WGBS), we profiled the DNA methylome of cattle sperms through comparison with human sperm methylomes. Our study helps to improve signal prioritization in GWAS and advance our understanding of the mammalian epigenome evolution, hence may benefit human health and cattle genetic improvement. Farmers, scientist, and policy planners who need improve animal health and production based on genome-enable animal selection will benefit from this study.

Technical Abstract: By comparative sperm DNA methylome analyses in mammals, we aimed to study the epigenome evolution and prioritize signals from genome-wide association studies (GWAS) to better explore the genetic and biological basis underlying complex phenotypes. We observed that genomic regions with differential DNA methylation levels were enriched for GWAS signals across many complex traits in human and cattle. Genes with conserved non-methylated promoters (e.g., ANKS1A and WNT7A) were featured by GWAS signals of developmental traits, while genes with shared hypermethylated promoters (e.g., TCAP and CD80) were highlighted by immune-related traits. Genes with human-specific hypomethylated promoters (e.g., FOXP2 and HYDIN) were enriched for brain-related traits, while genes with cattle-specific hypomethylated promoters (e.g., LDHB and DGAT2) mainly participated in lipid storage and metabolism. We further confirmed these findings in mouse and by integrating them with other data, including sperm-retained nucleosome, preimplantation transcriptome, and tissue proteome, as well as several sequence evolutionary features (e.g., mutation rates, recombination rates and selection signatures). Additionally, we showed that DNA methylation alterations induced by aging impacted male fertility in cattle. In conclusion, these results help to improve signal prioritization in GWAS and advance our understanding of the mammalian epigenome evolution, hence may benefit human health and cattle genetic improvement.