title: Two-stage genome-wide association study identifies integrin beta 5 as having potential role in bull fertility.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Animal and Dairy Sciences, Mississippi State University, Mississippi State, MS 39762, USA. jn181@ads.msstate.edu
authors.forename: Jean M
authors.initials: JM
authors.lastname: Feugang
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kaya
authors.forename: Grier P
authors.initials: GP
authors.lastname: Page
authors.forename: Lang
authors.initials: L
authors.lastname: Chen
authors.forename: Tapan
authors.initials: T
authors.lastname: Mehta
authors.forename: Kashif
authors.initials: K
authors.lastname: Hirani
authors.forename: Lynne
authors.initials: L
authors.lastname: Nazareth
authors.forename: Einko
authors.initials: E
authors.lastname: Topper
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Erdogan
authors.initials: E
authors.lastname: Memili
mesh_terms: D000818:Animals; D002417:Cattle / Q000235:genetics*; D005298:Fertility / Q000235:genetics*; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D039641:Integrin beta Chains / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013094:Spermatozoa / Q000502:physiology
chemical_list: D005819:Genetic Markers; D039641:Integrin beta Chains; C084344:integrin beta5