title: Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2.
abstract: The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10(-4)) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.
authors.affiliation: UNCEIA, Genetics Team, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fritz
authors.forename: Aurelien
authors.initials: A
authors.lastname: Capitan
authors.forename: Anis
authors.initials: A
authors.lastname: Djari
authors.forename: Sabrina C
authors.initials: SC
authors.lastname: Rodriguez
authors.forename: Anne
authors.initials: A
authors.lastname: Barbat
authors.forename: Aurélia
authors.initials: A
authors.lastname: Baur
authors.forename: Cécile
authors.initials: C
authors.lastname: Grohs
authors.forename: Bernard
authors.initials: B
authors.lastname: Weiss
authors.forename: Mekki
authors.initials: M
authors.lastname: Boussaha
authors.forename: Diane
authors.initials: D
authors.lastname: Esquerré
authors.forename: Christophe
authors.initials: C
authors.lastname: Klopp
authors.forename: Dominique
authors.initials: D
authors.lastname: Rocha
authors.forename: Didier
authors.initials: D
authors.lastname: Boichard
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics*; D001947:Breeding; D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D002417:Cattle / Q000235:genetics*; D003612:Dairying; D020964:Embryo Loss / Q000235:genetics*; D005260:Female; D005298:Fertility / Q000235:genetics; D056726:Genetic Association Studies; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D008297:Male; D009154:Mutation / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D017920:Antiporters; D011956:Receptors, Cell Surface; C063572:sex hormone-binding globulin receptor; D019731:Carbon-Nitrogen Ligases