Unrevealing functional candidate genes for bovine fertility through RNA sequencing meta-analysis and regulatory elements networks of co-expressed genes and lncRNAs.

The high genetic heterogeneity and environmental effects of subfertility in livestock species make the elucidation of the genetic mechanisms associated with reproductive efficiency a difficult task. Network and co-expression network meta-analyses were applied alongside genetic variant calling and long non-coding RNA (lncRNA) characterization to identify functionally relevant target genes and regulatory subnetworks associated with fertility in dairy cattle. In total, 505 lncRNAs (441 previously annotated in the bovine reference genome ARS-UCD 1.2 and 64 novel lncRNAs) were identified. Seven differentially expressed genes between high-fertile (HF) and sub-fertile (SF) Holstein cows were identified in the network meta-analysis (CA5A, ENSBTAG00000051149, ENSBTAG00000003272, DEFB7, DIO2, TRPV3, and COL4A4). Additionally, seven functional candidate differentially co-expressed (DcoExp) modules with a differential regulatory pattern (|z-score|>2) were identified between HF and SF cows. The functional candidate genes and DcoExp modules identified were associated with fertility relevant processes such as the regulation of embryonic implantation and proliferation, interaction and molecule transfer between the fetus and the cow, and the immune system. These results help to better understand the genetic mechanisms associated with reproductive efficiency in dairy cattle through the identification of potential biomarkers and genetic variants associated with differentially expressed regulatory gene and lncRNAs regulatory element networks.