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Home / Equine Research Bank / PLoS Genet / Genome-wide association study implicates testis-sperm specif...
PLoS genetics2012; 8(12); e1003139; doi: 10.1371/journal.pgen.1003139

Genome-wide association study implicates testis-sperm specific FKBP6 as a susceptibility locus for impaired acrosome reaction in stallions.

Abstract: Impaired acrosomal reaction (IAR) of sperm causes male subfertility in humans and animals. Despite compelling evidence about the genetic control over acrosome biogenesis and function, the genomics of IAR is as yet poorly understood, providing no molecular tools for diagnostics. Here we conducted Equine SNP50 Beadchip genotyping and GWAS using 7 IAR-affected and 37 control Thoroughbred stallions. A significant (PA and g.11040379C>A (p.166H>N) in exon 4 that were significantly associated with the IAR phenotype both in the GWAS cohort (n = 44) and in a large multi-breed cohort of 265 horses. All IAR stallions were homozygous for the A-alleles, while this genotype was found only in 2% of controls. The equine FKBP6 was exclusively expressed in testis and sperm and had 5 different transcripts, of which 4 were novel. The expression of this gene in AC/AG heterozygous controls was monoallelic, and we observed a tendency for FKBP6 up-regulation in IAR stallions compared to controls. Because exon 4 SNPs had no effect on the protein structure, it is likely that FKBP6 relates to the IAR phenotype via regulatory or modifying functions. In conclusion, FKBP6 was considered a susceptibility gene of incomplete penetrance for IAR in stallions and a candidate gene for male subfertility in mammals. FKBP6 genotyping is recommended for the detection of IAR-susceptible individuals among potential breeding stallions. Successful use of sperm as a source of DNA and RNA propagates non-invasive sample procurement for fertility genomics in animals and humans.
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Publication Date: 2012-12-20 PubMed ID: 23284302PubMed Central: PMC3527208DOI: 10.1371/journal.pgen.1003139Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study explores the genetic causes of impaired acrosomal reaction (IAR) in stallion sperm, which leads to subfertility. The study identified the FKBP6 gene present in the testis and sperm as a susceptibility locus for IAR.

Research Methodology

  • Researchers conducted a genome-wide association study in order to better understand the genetic aspects of IAR, a cause of subfertility in males.
  • The study involved Equine SNP50 Beadchip genotyping and GWAS (genome-wide association studies) with a group consisting of 7 IAR-affected and 37 control Thoroughbred stallions.
  • A significant association between genotype and phenotype was found on horse chromosome 13, specifically in the FK506 binding protein 6 (FKBP6) gene.
  • The team also undertook direct sequencing of FKBP6 exons in cases and controls, identifying certain significant SNPs (single nucleotide polymorphisms).

Key Findings

  • The FKBP6 gene, part of the immunophilins FKBP family known for involvement in meiosis, calcium homeostasis, vesicles, and membrane fusions, was related to the IAR phenotype.
  • Exon 4 in this gene had SNPs significantly associated with the IAR phenotype. All IAR-affected stallions were homozygous for a specific allele, found only in a small subset (2%) of control stallions.
  • The FKBP6 gene was exclusively found in the testis and sperm and demonstrated 5 different transcripts; four of which were new findings.
  • Interestingly, FKBP6 expression in heterozygous controls was monoallelic, showing a tendency for an increase in expression in IAR stallions in comparison to controls.

Conclusion and Implications

  • The conclusion drawn from these findings is that the FKBP6 gene could be considered as a susceptibility gene to IAR in stallions, and potentially a candidate gene for subfertility in male mammals more generally.
  • Despite exon 4 SNPs seeming to have no effect on protein structure, FKBP6 likely relates to the IAR phenotype via regulatory or modifying functions.
  • Based on these findings, FKBP6 genotyping is recommended for the detection of IAR-susceptibility in potential breeding stallions. This conclusion carries heavy implications for breeders in managing and manipulating stallion fertility.
  • The study’s successful use of sperm as a source of both DNA and RNA suggests potential for non-invasive sample procurement for fertility genomics in both animals and humans alike.

Cite This Article

APA
Raudsepp T, McCue ME, Das PJ, Dobson L, Vishnoi M, Fritz KL, Schaefer R, Rendahl AK, Derr JN, Love CC, Varner DD, Chowdhary BP. (2012). Genome-wide association study implicates testis-sperm specific FKBP6 as a susceptibility locus for impaired acrosome reaction in stallions. PLoS Genet, 8(12), e1003139. https://doi.org/10.1371/journal.pgen.1003139

Publication

PLoS genetics
ISSN: 1553-7404
NlmUniqueID: 101239074
Country: United States
Language: English
Volume: 8
Issue: 12
Pages: e1003139
PII: e1003139

Researcher Affiliations

Raudsepp, Terje
  • Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas, USA. TRaudsepp@cvm.tamu.edu
McCue, Molly E
    Das, Pranab J
      Dobson, Lauren
        Vishnoi, Monika
          Fritz, Krista L
            Schaefer, Robert
              Rendahl, Aaron K
                Derr, James N
                  Love, Charles C
                    Varner, Dickson D
                      Chowdhary, Bhanu P

                        MeSH Terms

                        • Acrosome Reaction / genetics
                        • Alleles
                        • Animals
                        • Genetic Predisposition to Disease
                        • Genome-Wide Association Study
                        • Homozygote
                        • Horse Diseases / genetics
                        • Horse Diseases / physiopathology
                        • Horses / genetics
                        • Humans
                        • Infertility, Male / genetics
                        • Infertility, Male / physiopathology
                        • Infertility, Male / veterinary
                        • Male
                        • Meiosis
                        • Polymorphism, Single Nucleotide
                        • Spermatozoa / metabolism
                        • Spermatozoa / pathology
                        • Tacrolimus Binding Proteins / genetics
                        • Tacrolimus Binding Proteins / metabolism
                        • Testis / metabolism
                        • Testis / pathology

                        Grant Funding

                        • K08 AR055713 / NIAMS NIH HHS
                        • 1K08AR055713-01A2 / NIAMS NIH HHS

                        Conflict of Interest Statement

                        The authors have declared that no competing interests exist.

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