title: Molecular Effects of Polymorphism in the 3'UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins.
abstract: Conception rates among dairy cows in Japan have declined in recent decades. To enhance our understanding of the genes involved in conception rates, we conducted a genome-wide association study (GWAS) using 822 Holsteins and identified a single-nucleotide polymorphism (SNP) associated with conception rate: A+169G in the 3' untranslated region (UTR) of unc-5 homolog C (UNC5C). Cows with higher conception rates carried the A polymorphism in the UNC5C 3'UTR. Luciferase assays and quantitative analysis of allele ratios revealed that UNC5C transcripts with the A polymorphism were expressed at higher levels than those carrying the G polymorphism. UNC5C transmits either pro- or anti-apoptotic signals depending on the availability of its ligand, Netrin-1. UNC5C expression is negatively regulated by reproductive homeobox X-linked 5 (Rhox5), and the Rhox5 locus is methylated by G9a methyltransferase. G9a-knockout mice have previously been demonstrated to be subfertile, and we found that UNC5C, G9a, and Netrin-1 expression levels increased from the 4-cell stage to the blastocyst stage in fertilized murine embryos, whereas Rhox5 expression decreased. Repression of UNC5C, G9a, or Netrin-1 or forced expression of Rhox5 in the anterior nucleus stage inhibited development to the blastocyst stage, suggesting that cows carrying the G polymorphism in UNC5C might have lower conception rates because of the poor development of preimplantation embryos. This study provides novel insights into the role of UNC5C during embryonic development.
authors.affiliation: National Livestock Breeding Center, Nishigo, Fukushima, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Holstein Cattle Association of Japan, Hokkaido Branch, Sapporo, Hokkaido, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Gotoh
authors.affiliation: Holstein Cattle Association of Japan, Hokkaido Branch, Sapporo, Hokkaido, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kawahara
authors.affiliation: Shirakawa Institute of Animal Genetics, Nishigo, Fukushima, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001755:Blastocyst; D002417:Cattle / Q000145:classification / Q000235:genetics* / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D005306:Fertilization / Q000235:genetics*; D055106:Genome-Wide Association Study; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology; D007564:Japan; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology; D000075386:Netrin Receptors; D000075388:Netrin-1; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; C498048:Rhox5 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase