Maternal variant in the upstream of FOXP3 gene on the X chromosome is associated with recurrent infertility in Japanese Black cattle

BMC Genet. 2017 Dec 6;18(1):103. doi: 10.1186/s12863-017-0573-8.


Background: Repeat breeding, which is defined as cattle failure to conceive after three or more inseminations in the absence of clinical abnormalities, is a substantial problem in cattle breeding. To identify maternal genetic variants of repeat breeding in Japanese Black cattle, we selected 29 repeat-breeding heifers that failed to conceive following embryo transfer (ET) and conducted a genome-wide association study (GWAS) using the traits.

Results: We found that a single-nucleotide polymorphism (SNP; g.92,377,635A > G) in the upstream region of the FOXP3 gene on the X chromosome was highly associated with repeat breeding and failure to conceive following ET (P = 1.51 × 10-14). FOXP3 is a master gene for differentiation of regulatory T (Treg) cells that function in pregnancy maintenance. Reporter assay results revealed that the activity of the FOXP3 promoter was lower in reporter constructs with the risk-allele than in those with the non-risk-allele by approximately 0.68 fold. These findings suggest that the variant in the upstream region of FOXP3 with the risk-allele decreased FOXP3 transcription, which in turn, could reduce the number of maternal Treg cells and lead to infertility. The frequency of the risk-allele in repeat-breeding heifers is more than that in cows, suggesting that the risk-allele could be associated with infertility in repeat-breeding heifers.

Conclusions: This GWAS identified a maternal variant in the upstream region of FOXP3 that was associated with infertility in repeat-breeding Japanese Black cattle that failed to conceive using ET. The variant affected the level of FOXP3 mRNA expression. Thus, the results suggest that the risk-allele could serve as a useful marker to reduce and eliminate animals with inferior fertility in Japanese Black cattle.

Keywords: Beef cattle; Embryo transfer (ET); FOXP3; Genome-wide association study (GWAS); Infertility; Repeat breeding.

MeSH terms

  • Animals
  • Cattle
  • Cattle Diseases / genetics*
  • Embryo Transfer
  • Female
  • Forkhead Transcription Factors / genetics*
  • Gene Expression
  • Genome-Wide Association Study
  • Infertility, Female / genetics
  • Infertility, Female / veterinary*
  • X Chromosome*


  • Forkhead Transcription Factors