Abstract
Our initial genome-wide association study (GWAS) demonstrated that two SNPs (ARS-BFGL-NGS-33248, UA-IFASA-9288) within the protein tyrosine kinase 2 (PTK2) gene were significantly associated with milk production traits in Chinese Holstein dairy cattle. To further validate if the statistical evidence provided in GWAS were true-positive findings, a replication study was performed herein through genotype-phenotype associations. The two tested SNPs were found to show significant associations with milk production traits, which confirmed the associations observed in the original study. Specifically, SNPs lying in the PTK2 gene were also detected by sequencing 14 unrelated sires in Chinese Holsteins and a total of thirty-three novel SNPs were identified. Thirteen out of these identified SNPs were genotyped and tested for association with milk production traits in an independent resource population. After Bonferroni correction for multiple testing, twelve SNPs were statistically significant for more than two milk production traits. Analyses of pairwise D’ measures of linkage disequilibrium (LD) between all SNPs were also explored. Two haplotype blocks were inferred and the association study at haplotype level revealed similar effects on milk production traits. In addition, the RNA expression analyses revealed that a non-synonymous coding SNP (g.4061098T>G) was involved in the regulation of gene expression. Thus the findings presented here provide strong evidence for associations of PTK2 variants with dairy production traits and may be applied in Chinese Holstein breeding program.
Highlights
With the maturing of genome sequencing and high throughput SNP genotyping technologies, genome-wide association studies (GWAS) have become a routine strategy for investigating mutations underlying complex traits
We replicated the associations of the same two SNPs within protein tyrosine kinase 2 (PTK2) that identified in our initial GWAS study [19], and presented a link of several novel PTK2 variants with milk production traits
Using Estimated breeding values (EBVs) as phenotypes may cause double-counting of relatives information, previous studies have shown that EBV-based phenotype does not significantly lower the statistical power [46,47] compared with the other two commonly used phenotypic observations, i.e., yield deviation (YD) [48] and de-regressed EBVs [49]
Summary
With the maturing of genome sequencing and high throughput SNP genotyping technologies, genome-wide association studies (GWAS) have become a routine strategy for investigating mutations underlying complex traits. In our initial GWAS in the Chinese Holstein population [19], in addition to some functional genes such as DGAT1 and GHR reported previously [26,27], several novel potential candidate genes, proxied by hundreds of significant SNPs within these genes or in surrounding regions, were identified. Among these novel genes, the protein tyrosine kinase 2 (PTK2) gene, firstly identified by our GWAS, can be considered as a promising candidate gene for milk production traits. In our previous GWAS results [19], a large proportion of the significant SNPs (61 out of 105) were located on BTA14, 59 of which lied in the reported QTL regions
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