title: Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects BH1, HH2, and HH3 reveal a putative causative mutation in SMC2 for HH3.
abstract: The recent discovery of bovine haplotypes with negative effects on fertility in the Brown Swiss, Holstein, and Jersey breeds has allowed producers to identify carrier animals using commercial single nucleotide polymorphism (SNP) genotyping assays. This study was devised to identify the causative mutations underlying defective bovine embryo development contained within three of these haplotypes (Brown Swiss haplotype 1 and Holstein haplotypes 2 and 3) by combining exome capture with next generation sequencing. Of the 68,476,640 sequence variations (SV) identified, only 1,311 genome-wide SNP were concordant with the haplotype status of 21 sequenced carriers. Validation genotyping of 36 candidate SNP identified only 1 variant that was concordant to Holstein haplotype 3 (HH3), while no variants located within the refined intervals for HH2 or BH1 were concordant. The variant strictly associated with HH3 is a non-synonymous SNP (T/C) within exon 24 of the Structural Maintenance of Chromosomes 2 (SMC2) on Chromosome 8 at position 95,410,507 (UMD3.1). This polymorphism changes amino acid 1135 from phenylalanine to serine and causes a non-neutral, non-tolerated, and evolutionarily unlikely substitution within the NTPase domain of the encoded protein. Because only exome capture sequencing was used, we could not rule out the possibility that the true causative mutation for HH3 might lie in a non-exonic genomic location. Given the essential role of SMC2 in DNA repair, chromosome condensation and segregation during cell division, our findings strongly support the non-synonymous SNP (T/C) in SMC2 as the likely causative mutation. The absence of concordant variations for HH2 or BH1 suggests either the underlying causative mutations lie within a non-exomic region or in exome regions not covered by the capture array.
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: McClure
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Animal Improvement Programs Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Derek
authors.initials: D
authors.lastname: Bickhart
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Animal Improvement Programs Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Null
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Animal Improvement Programs Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Vanraden
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Lingyang
authors.initials: L
authors.lastname: Xu
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Animal Improvement Programs Laboratory, Beltsville, Maryland, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Wiggans
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: Schroeder
authors.affiliation: Cofactor Genomics, St. Louis, Missouri, United States of America.
authors.forename: Jarret
authors.initials: J
authors.lastname: Glasscock
authors.affiliation: Cofactor Genomics, St. Louis, Missouri, United States of America.
authors.forename: Jon
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Animal Improvement Programs Laboratory, Beltsville, Maryland, United States of America.
authors.forename: John B
authors.initials: JB
authors.lastname: Cole
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Curtis P
authors.initials: CP
authors.lastname: Van Tassell
authors.affiliation: United States Department of Agriculture, Agriculture Research Service, Bovine Functional Genomics Laboratory, Beltsville, Maryland, United States of America.
authors.forename: Tad S
authors.initials: TS
authors.lastname: Sonstegard
mesh_terms: D000818:Animals; D002417:Cattle / Q000235:genetics*; D033481:Chromosomes, Mammalian / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D059472:Exome; D005260:Female; D006239:Haplotypes; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: D009687:Nuclear Proteins