Abstract
Despite the importance of fertility in humans and livestock, there has been little success dissecting the genetic basis of fertility. Our hypothesis was that genes differentially expressed in the endometrium and corpus luteum on Day 13 of the estrous cycle between cows with either good or poor genetic merit for fertility would be enriched for genetic variants associated with fertility. We combined a unique genetic model of fertility (cattle that have been selected for high and low fertility and show substantial difference in fertility) with gene expression data from these cattle and genome-wide association study (GWAS) results in ∼20,000 cattle to identify quantitative trait loci (QTL) regions and sequence variants associated with genetic variation in fertility. Two hundred and forty-five QTL regions and 17 sequence variants associated primarily with prostaglandin F2alpha, steroidogenesis, mRNA processing, energy status, and immune-related processes were identified. Ninety-three of the QTL regions were validated by two independent GWAS, with signals for fertility detected primarily on chromosomes 18, 5, 7, 8, and 29. Plausible causative mutations were identified, including one missense variant significantly associated with fertility and predicted to affect the protein function of EIF4EBP3. The results of this study enhance our understanding of 1) the contribution of the endometrium and corpus luteum transcriptome to phenotypic fertility differences and 2) the genetic architecture of fertility in dairy cattle. Including these variants in predictions of genomic breeding values may improve the rate of genetic gain for this critical trait.
Highlights
The genetic basis of variation in fertility between individuals is of great interest in mammals, humans and livestock
Dairy cattle are a potential model for dissecting the genetic basis of fertility in mammals that have one offspring per parturition and gestation times of approximately 9 mo—fertility phenotypes are routinely recorded in large volumes in several countries, and whole genome sequence data are available for the key ancestors of modern dairy cattle populations [4]
We investigated if the differentially expressed genes (DEG) from the endometrium and corpus luteum (CL) identified above were enriched for significant single nucleotide polymorphisms (SNP) from the genomewide association studies (GWAS)
Summary
The genetic basis of variation in fertility between individuals is of great interest in mammals, humans and livestock. The endometrium and CL are obvious targets for gene expression studies to detect differentially expressed genes (DEG), for example, between high-fertility and low-fertility cattle [19] Another method used to identify genomic variation involved in a trait is a GWAS. Expressed genes in the CL and endometrium affecting fertility were identified using a unique resource herd of cows with similar genetic merit for milk production traits but either good (Fertþ) or poor (FertÀ) genetic merit for fertility [30, 31]. The results of this study enhance our understanding of both the contribution of the endometrium and CL transcriptome to phenotypic reproductive performance and the genetic architecture affecting fertility in a higher mammal that has a small number of offspring per parturition and enables us to identify genetic variants that could be used to accelerate genomic selection for improved fertility in dairy cattle. On Day À2, the CIDR device was removed, and 36 h later, each cow was administered a second i.m. injection of GnRH agonist
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