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.

Genetics and genomics of reproductive performance in dairy and beef cattle

“…In fact, significant effects on calving rate were observed between matings of carrier sires and daughters of carrier sires, confirming that the haplotypes harbour embryonic lethal mutations (VanRaden et al, 2011;Fritz et al, 2013). Recently, in Holstein, Montbeliarde and Normande cattle Fritz et al (2013) identified 34 candidate haplotypes (P < 10 −4 ) including Brachyspina, CVM, HH1 and HH3 previously reported by VanRaden et al (2011) and three novel mutations that had effects on protein structure. The impact of these mutations is likely to increase as inbreeding accumulates in intensively selected cattle breeds.…”

Inbreeding and purging at the genomic Level: the Chillingham cattle reveal extensive, non‐random SNP heterozygosity

“…In dairy cattle, 25 haplotypes which were not observed in the homozygous state were identified at specific chromosomal positions in particular breeds (van Raden et al 2011;Fritz et al 2013;Sahana et al 2014;Cole et al 2015). It is argued that these positions harbour genes with recessive lethal mutations.…”

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

“…The reasons for these losses remain unclear and likely result from several factors, including embryonic lethal genes (8,9), environmental stressors (7), and endometrial condition (10). Cloning of cattle by somatic cell nuclear transfer (SCNT) induces perturbations in conceptus development and greatly increases the probability of developmental arrest before and after implantation (11,12).…”