Two-stage genome-wide association study identifies integrin beta 5 as having potential role in bull fertility

Department of Animal and Dairy Sciences, Mississippi State University, Mississippi State, MS 39762, USA.
BMC Genomics (Impact Factor: 3.99). 05/2009; 10(1):176. DOI: 10.1186/1471-2164-10-176
Source: PubMed


Fertility is one of the most critical factors controlling biological and financial performance of animal production systems and genetic improvement of lines. The objective of this study was to identify molecular defects in the sperm that are responsible for uncompensable fertility in Holstein bulls. We performed a comprehensive genome wide analysis of single nucleotide polymorphisms (SNP) for bull fertility followed by a second-stage replication in additional bulls for a restricted set of markers.
In the Phase I association study, we genotyped the genomic sperm DNA of 10 low-fertility and 10 high-fertility bulls using Bovine SNP Gene Chips containing approximately 10,000 random SNP markers. In these animals, 8,207 markers were found to be polymorphic, 97 of which were significantly associated with fertility (p < 0.01). In the Phase II study, we tested the four most significant SNP from the Phase I study in 101 low-fertility and 100 high-fertility bulls, with two SNPs (rs29024867 and rs41257187) significantly replicated. Rs29024867 corresponds to a nucleotide change of C --> G 2,190 bp 3' of the collagen type I alpha 2 gene on chromosome 4, while the rs41257187 (C --> T) is in the coding region of integrin beta 5 gene on chromosome 1. The SNP rs41257187 induces a synonymous (Proline --> Proline), suggesting disequilibrium with the true causative locus (i), but we found that the incubation of bull spermatozoa with integrin beta 5 antibodies significantly decreased the ability to fertilize oocytes. Our findings suggest that the bovine sperm integrin beta 5 protein plays a role during fertilization and could serve as a positional or functional marker of bull fertility.
We have identified molecular markers associated with bull fertility and established that at least one of the genes harboring such variation has a role in fertility. The findings are important in understanding mechanisms of uncompensatory infertility in bulls, and in other male mammals. The findings set the stage for more hypothesis-driven research aimed at discovering the role of variation in the genome that affect fertility and that can be used to identify molecular mechanisms of development.

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    • "Recently, some studies have addressed bull fertility using a genome-wide association approach. For instance , Feugang et al. (2009), using a 2-stage GWAS, showed that the ITGB5 (integrin β 5) gene is involved in the fertilization process in Holstein bulls; ITGB5 is thought to play a role in cell–cell interaction as well as potentially serve as a signaling receptor at the time of fertilization (Feugang et al., 2009). In addition, Blaschek et al. (2011) identified several genomic regions associated with noncompensatory bull fertility. "
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    ABSTRACT: In recent years, it has become evident that genetic selection to improve milk production has resulted in a decline in dairy cattle fertility. Growing evidence suggests that the greatest loss occurs early in pregnancy around the time of embryo implantation. As a means to make genetic improvements and to assist in reproductive performance, use of artificial reproductive technologies such as artificial insemination and in vitro production of embryos have been widely used. Both of these technologies rely on the competence and quality of gametes for successful development of embryos. Often, selection of animals is based on the genetic merit of the animal, although specific fertility markers are relatively underdeveloped compared with markers for production traits. Similarly, current in vitro fertilization systems could benefit from a uniform method for selection of the best quality embryos to transfer into recipients for successful implantation and delivery of healthy offspring. As genetics underlie biological processes such as fertility, the need exists to further identify and characterize genes that affect fertility and development within both the parental gametes and the embryo. Furthermore, the magnitude of the contribution of each parental genome to the success of embryo development and pregnancy is not clear. As such, the objective of this review is to provide an overview of studies relating to genetic markers at the DNA level, parental and embryonic gene expression, and the effects of epigenetics on embryonic development. Future studies should exploit advances in molecular technologies to identify and classify genes underlying fertility and development to establish biomarkers and predictors for improved genetic selection.
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    • "Recently, many GWASs have been focused on the economic traits in dairy cattle, including production traits [8,10-15], fertility traits [8,16-18], disease resistance [9,19,20], and somatic cell score [13], and many statistically significant SNPs and biologically meaningful genes have been reported. However, comparatively few studies about body conformation traits have been published [8,21]. "
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    ABSTRACT: Genome-wide association study (GWAS) is a powerful tool for revealing the genetic basis of quantitative traits. However, studies using GWAS for conformation traits of cattle is comparatively less. This study aims to use GWAS to find the candidates genes for body conformation traits. The Illumina BovineSNP50 BeadChip was used to identify single nucleotide polymorphisms (SNPs) that are associated with body conformation traits. A least absolute shrinkage and selection operator (LASSO) was applied to detect multiple SNPs simultaneously for 29 body conformation traits with 1,314 Chinese Holstein cattle and 52,166 SNPs. Totally, 59 genome-wide significant SNPs associated with 26 conformation traits were detected by genome-wide association analysis; five SNPs were within previously reported QTL regions (Animal Quantitative Trait Loci (QTL) database) and 11 were very close to the reported SNPs. Twenty-two SNPs were located within annotated gene regions, while the remainder were 0.6-826 kb away from known genes. Some of the genes had clear biological functions related to conformation traits. By combining information about the previously reported QTL regions and the biological functions of the genes, we identified DARC, GAS1, MTPN, HTR2A, ZNF521, PDIA6, and TMEM130 as the most promising candidate genes for capacity and body depth, chest width, foot angle, angularity, rear leg side view, teat length, and animal size traits, respectively. We also found four SNPs that affected four pairs of traits, and the genetic correlation between each pair of traits ranged from 0.35 to 0.86, suggesting that these SNPs may have a pleiotropic effect on each pair of traits. A total of 59 significant SNPs associated with 26 conformation traits were identified in the Chinese Holstein population. Six promising candidate genes were suggested, and four SNPs showed genetic correlation for four pairs of traits.
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    • "The genes, identified from the GWAS results, that might be important for milk quality traits included ABCG2PPARGC1AACSS2DGAT1ACLYSREBF1STAT5AGHFASNSCD1 and AGPAT6. Another four GWAS reported 198 significant SNPs related to the fertility trait such as fertilization rate, clastocyst rate and calving [12-15]. These SNPs were mainly on chromosomes 3, 4, 5, 6, 10, 12, 13, 18, 19, 20, 24 and 25, and the important genes detected from the GWAS results were collagen type I alpha 2 and integrin beta 5. "
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