TY - JOUR
T1 - Genetic variants in the upstream region of activin receptor IIA are associated with female fertility in Japanese Black cattle
AU - Sasaki, Shinji
AU - Ibi, Takayuki
AU - Matsuhashi, Tamako
AU - Takeda, Kenji
AU - Ikeda, Shogo
AU - Sugimoto, Mayumi
AU - Sugimoto, Yoshikazu
N1 - Funding Information:
We would like to thank Toshio Watanabe helping with the data analysis, as well as Takatoshi Kojima and other lab members for providing generous support and valuable suggestions. We are grateful to Pamela Mellon for the LβT2 cells and Jun-ichi Miyazaki for the pCAGGS plasmid. We are grateful to Emiko Watanabe for technical assistance. This work was supported by funding from the KIEIKAI Research Foundation (H24-KIEIKAI and H25-KIEIKAI) to SS, the JSPS KAKENHI (Grant Number 26450384) to SS, and the Japan Racing and Livestock Promotion to YS.
Publisher Copyright:
© 2015 Sasaki et al.
PY - 2015/10/20
Y1 - 2015/10/20
N2 - Background: Female fertility, a fundamental trait required for animal reproduction, has gradually declined in the last 2 decades in Japanese Black cattle. To identify associated genetic variants in Japanese Black cattle, we evaluated female fertility as a metric to describe the average inverse of the number of artificial inseminations required for conception from the first through the fourth parity (ANAI4) and conducted a genome-wide association study (GWAS) using 430 animals with extreme ANAI4 values from 10,399 animals. Results: We found that 2 variants, namely a single-nucleotide polymorphisms (SNP; g.48476925C > T) and a 3-bp indel (g.48476943_48476946insGGC), in the upstream region of the activin receptor IIA gene (ACVR2A) were associated with ANAI4. ACVR2A transcripts from Japanese Black cattle of the Q haplotype, defined by the SNP and the 3-bp indel, with increased ANAI4 were 1.29-1.32-fold more abundant than q-derived transcripts. In agreement, reporter assay results revealed that the activity of the ACVR2A promoter was higher in reporter constructs with the Q haplotype than in those with the q haplotype by approximately 1.2 fold. Expression of exogenous ACVR2A induced dose-dependent increases of reporter activity from the follicle-stimulating hormone, beta polypeptide (FSHB) promoter in response to activin A in a pituitary gonadotrophic cell line. The findings suggested that sequence variations in the upstream region of ACVR2A with the Q haplotype increased ACVR2A transcription, which in turn induced FSHB expression. This association was replicated using a sample population size of 1,433 animals; the frequency of the Q haplotype was 0.39, and Q-to-q haplotype substitution resulted in an increase of 0.02 in terms of ANAI4. Conclusions: This GWAS identified variants in the upstream region of ACVR2A, which were associated with female fertility in Japanese Black cattle. The variants affected the level of ACVR2A mRNA expression, which could lead to an allelic imbalance. This association was replicated with a sample population of 1,433 animals. Thus, the results suggest that the Q haplotype could serve as a useful marker to select Japanese Black cattle with superior female fertility.
AB - Background: Female fertility, a fundamental trait required for animal reproduction, has gradually declined in the last 2 decades in Japanese Black cattle. To identify associated genetic variants in Japanese Black cattle, we evaluated female fertility as a metric to describe the average inverse of the number of artificial inseminations required for conception from the first through the fourth parity (ANAI4) and conducted a genome-wide association study (GWAS) using 430 animals with extreme ANAI4 values from 10,399 animals. Results: We found that 2 variants, namely a single-nucleotide polymorphisms (SNP; g.48476925C > T) and a 3-bp indel (g.48476943_48476946insGGC), in the upstream region of the activin receptor IIA gene (ACVR2A) were associated with ANAI4. ACVR2A transcripts from Japanese Black cattle of the Q haplotype, defined by the SNP and the 3-bp indel, with increased ANAI4 were 1.29-1.32-fold more abundant than q-derived transcripts. In agreement, reporter assay results revealed that the activity of the ACVR2A promoter was higher in reporter constructs with the Q haplotype than in those with the q haplotype by approximately 1.2 fold. Expression of exogenous ACVR2A induced dose-dependent increases of reporter activity from the follicle-stimulating hormone, beta polypeptide (FSHB) promoter in response to activin A in a pituitary gonadotrophic cell line. The findings suggested that sequence variations in the upstream region of ACVR2A with the Q haplotype increased ACVR2A transcription, which in turn induced FSHB expression. This association was replicated using a sample population size of 1,433 animals; the frequency of the Q haplotype was 0.39, and Q-to-q haplotype substitution resulted in an increase of 0.02 in terms of ANAI4. Conclusions: This GWAS identified variants in the upstream region of ACVR2A, which were associated with female fertility in Japanese Black cattle. The variants affected the level of ACVR2A mRNA expression, which could lead to an allelic imbalance. This association was replicated with a sample population of 1,433 animals. Thus, the results suggest that the Q haplotype could serve as a useful marker to select Japanese Black cattle with superior female fertility.
KW - Activin receptor IIA (ACVR2A)
KW - Beef cattle
KW - Female fertility
KW - Genome-wide association study
KW - Japanese Black cattle
KW - Reproductive efficiency
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U2 - 10.1186/s12863-015-0282-0
DO - 10.1186/s12863-015-0282-0
M3 - Article
C2 - 26486459
AN - SCOPUS:84945195665
VL - 16
JO - BMC Genetics
JF - BMC Genetics
SN - 1471-2156
IS - 1
M1 - 123
ER -