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Molecular Effects of Polymorphism in the 3'UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins.

Sugimoto M, Gotoh Y, Kawahara T, Sugimoto Y - PLoS ONE (2015)

Bottom Line: 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).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.This study provides novel insights into the role of UNC5C during embryonic development.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Nishigo, Fukushima, Japan.

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.

No MeSH data available.


Conception rate is associated with a locus on chromosome 6.A. The distribution of conception rate among cows (females). B. The distribution of conception rate among sires. C. Manhattan plots for the genome-wide screen for loci associated with conception rate. The dotted line represents the threshold for a genome-wide significance of P < 1.2×10-6 based on the Bonferroni correction for multiple comparisons.
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pone.0131283.g001: Conception rate is associated with a locus on chromosome 6.A. The distribution of conception rate among cows (females). B. The distribution of conception rate among sires. C. Manhattan plots for the genome-wide screen for loci associated with conception rate. The dotted line represents the threshold for a genome-wide significance of P < 1.2×10-6 based on the Bonferroni correction for multiple comparisons.

Mentions: We collected DNA from 2,529 Holstein sires and evaluated the estimated breeding values (EBVs) for the conception rates [1, 21]. The EBV is a genetic component obtained by subtracting an environmental component from a phenotype. The EBVs for the conception rates of the sires were evaluated based on their daughters’ conception rates. The EBVs for conception rates of daughters were evaluated by threshold linear models using insemination event data after first calving. The model can be written as:l=Xβ+Whh+Wss+Zaa+Zpp+ewhere l is a vector of unobserved liabilities; β is the vector of systematic effects (herd-year of insemination, month of insemination, days from calving to insemination, regression coefficients on inbreeding, calving ease score of first calving, herd size, and milk yield of the first lactation); h is vector of herd, age, season of insemination; s is vector of service sires; a is vector of additive breeding values; p is vector of permanent environmental effects; e is the vector of residual terms; and X, Wh, Ws, Za, and Zp are known incidence matrices with the appropriate dimensions. The mean EBV for the conception rates of the cows was 46.3%. Cows lower than 41.8% belong to the 15th percentile of this population while cows higher than 51% belong to the 85th percentile (Fig 1A). We selected 646 samples with low conception rates (lower than 41.8%) and 176 with high rates (higher than 51%) among the 2,529 sampled sires. We also confirmed that the selected 646 samples had appropriate deregressed EBV (dEBV) because the reliability of specific animal EBVs differs markedly. The dEBV was calculated as follows:dEBV = (EBV−base)/reliability + base


Molecular Effects of Polymorphism in the 3'UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins.

Sugimoto M, Gotoh Y, Kawahara T, Sugimoto Y - PLoS ONE (2015)

Conception rate is associated with a locus on chromosome 6.A. The distribution of conception rate among cows (females). B. The distribution of conception rate among sires. C. Manhattan plots for the genome-wide screen for loci associated with conception rate. The dotted line represents the threshold for a genome-wide significance of P < 1.2×10-6 based on the Bonferroni correction for multiple comparisons.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493121&req=5

pone.0131283.g001: Conception rate is associated with a locus on chromosome 6.A. The distribution of conception rate among cows (females). B. The distribution of conception rate among sires. C. Manhattan plots for the genome-wide screen for loci associated with conception rate. The dotted line represents the threshold for a genome-wide significance of P < 1.2×10-6 based on the Bonferroni correction for multiple comparisons.
Mentions: We collected DNA from 2,529 Holstein sires and evaluated the estimated breeding values (EBVs) for the conception rates [1, 21]. The EBV is a genetic component obtained by subtracting an environmental component from a phenotype. The EBVs for the conception rates of the sires were evaluated based on their daughters’ conception rates. The EBVs for conception rates of daughters were evaluated by threshold linear models using insemination event data after first calving. The model can be written as:l=Xβ+Whh+Wss+Zaa+Zpp+ewhere l is a vector of unobserved liabilities; β is the vector of systematic effects (herd-year of insemination, month of insemination, days from calving to insemination, regression coefficients on inbreeding, calving ease score of first calving, herd size, and milk yield of the first lactation); h is vector of herd, age, season of insemination; s is vector of service sires; a is vector of additive breeding values; p is vector of permanent environmental effects; e is the vector of residual terms; and X, Wh, Ws, Za, and Zp are known incidence matrices with the appropriate dimensions. The mean EBV for the conception rates of the cows was 46.3%. Cows lower than 41.8% belong to the 15th percentile of this population while cows higher than 51% belong to the 85th percentile (Fig 1A). We selected 646 samples with low conception rates (lower than 41.8%) and 176 with high rates (higher than 51%) among the 2,529 sampled sires. We also confirmed that the selected 646 samples had appropriate deregressed EBV (dEBV) because the reliability of specific animal EBVs differs markedly. The dEBV was calculated as follows:dEBV = (EBV−base)/reliability + base

Bottom Line: 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).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.This study provides novel insights into the role of UNC5C during embryonic development.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Nishigo, Fukushima, Japan.

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.

No MeSH data available.