Genome-wide association study and pathway analysis identify NTRK2 as a novel candidate gene for litter size in sheep

Abstract

Litter size is one of the most important economic traits in sheep. Identification of gene variants that are associated with the prolificacy rate is an important step in breeding program success and profitability of the farm. So, to identify genetic mechanisms underlying the variation in litter size in Iranian Baluchi sheep, a two-step genome-wide association study (GWAS) was performed. GWAS was conducted using genotype data from 91 Baluchi sheep. Estimated breeding values (EBVs) for litter size calculated for 3848 ewes and then used as the response variable. Besides, a pathway analysis using GO and KEGG databases were applied as a complementary approach. A total of three single nucleotide polymorphisms (SNPs) associated with litter size were identified, one each on OAR2, OAR10, and OAR25. The SNP on OAR2 is located within a novel putative candidate gene, Neurotrophic receptor tyrosine kinase 2. This gene product works as a receptor which is essential for follicular assembly, early follicular growth, and oocyte survival. The SNP on OAR25 is located within RAB4A which is involved in blood vessel formation and proliferation through angiogenesis. The SNP on OAR10 was not associated with any gene in the 1Mb span. Moreover, gene-set analysis using the KEGG database identified several pathways, such as Ovarian steroidogenesis, Steroid hormone biosynthesis, Calcium signaling pathway, and Chemokine signaling. Also, pathway analysis using the GO database revealed several functional terms, such as cellular carbohydrate metabolic, biological adhesion, cell adhesion, cell junction, and cell-cell adherens junction, among others. This is the first study that reports the NTRK2 gene affecting litter size in sheep and our study of this gene functions showed that this gene could be a good candidate for further analysis.

Meta-analysis of genome-wide association studies for litter size in sheep

“…Given the different layers that make up the follicles and the need for communication and transfer material through these layers to the oocyte, the signi cance of these pathways seems logical. Identi ed pathways are frequently reported in previous studies (15,16,41,42).…”

“…PI3K-Akt signaling pathway has been identi ed in multiple publications associated with reproduction (15,42). Various normal cellular processes, such as cell proliferation, survival, motility, growth, cytoskeletal rearrangement, and metabolism, through multiple downstream targets, are regulated by the PI3K/PTEN/Akt pathway (43).…”

“…Abnormalities in the PI3K-Akt signaling pathway may associate with some status of female infertility attributed to primordial follicle depletion, including premature ovarian failure and primary amenorrhea (44). Studies identi ed the Calcium signaling pathway as a signi cant KEGG term associated with proli cacy (15,42). Also, (1) reported calcium ion binding GO term as pathway affecting proli cacy in Chinese sheep.…”

Genes and Pathways Affecting Sheep Productivity Traits: Genetic Parameters, Genome-Wide Association Mapping, and Pathway Enrichment Analysis

“…The small number of available genotypes in this study can contribute to the low power of the association analysis, but the use of EBVs can increase the power to some extent as we have a better estimate of the actual genetic variance. EBVs can largely compensate for the limited number of genotypes to get reasonable estimates ( Abdoli et al, 2018 , 2019 ; Esmaeili-Fard et al, 2021 ). In this approach, first, we ran a pedigree-BLUP analysis using the classical repeatability animal model in the BLUPF90 software ( Masuda, 2019 ), and breeding values of all animals (genotyped and not genotyped animals) were estimated for all traits.…”

Genome-Wide Identification of mRNAs, lncRNAs, and Proteins, and Their Relationship With Sheep Fecundity

“…Understanding the molecular mechanism is essential for multiple births sheep breeding. Previous studies have shown that the prolificacy trait is quantitative and controlled by multiple genes ( Tang et al, 2019 ; Yang et al, 2019 ; Esmaeili-Fard et al, 2021 ). Identification of genes associated with reproduction is essential for sheep breeding.…”