| Summary: | Natural selection and domestication have shaped modern sheep populations into a vast range of phenotypically diverse breeds. Among these breeds, dairy sheep have a smaller population than meat sheep and wool sheep, and less research is performed on them, but the lactation mechanism in dairy sheep is critically important for improving animal-production methods. In this study, whole-genome sequences were generated from 10 sheep breeds, including 57 high-milk-yield sheep and 44 low-milk-yield sheep, to investigate the genetic signatures of milk production in dairy sheep, and 59,864,820 valid SNPs (Single Nucleotide Polymorphisms) were kept after quality control to perform population-genetic-structure analyses, gene-detection analyses, and gene-function-validation analyses. For the population-genetic-structure analyses, we carried out PCA (Principal Component Analysis), as well as neighbor-joining tree and structure analyses to classify different sheep populations. The sheep used in our study were well distributed in ten groups, with the high-milk-yield-group populations close to each other and the low-milk-yield-group populations showing similar classifications. To perform an exact signal-selection analysis, we used three different methods to find SNPs to perform gene-annotation analyses within the 995 common regions derived from the fixation index (F<sub>ST</sub>), nucleotide diversity (Ɵπ), and heterozygosity rate (ZHp) results. In total, we found 553 genes that were located in these regions. These genes mainly participate in the protein-binding pathway and the nucleoplasm-interaction pathway, as revealed by the GO- and KEGG-function-enrichment analyses. After the gene selection and function analyses, we found that <i>FCGR3A</i>, <i>CTSK</i>, <i>CTSS</i>, <i>ARNT</i>, <i>GHR</i>, <i>SLC29A4</i>, <i>ROR1</i>, and <i>TNRC18</i> were potentially related to sheep-milk-production traits. We chose the strongly selected genes, <i>FCGR3A</i>, <i>CTSK</i>, <i>CTSS</i>, and <i>ARNT</i> during the signal-selection analysis to perform a RT-qPCR (Reale time Quantitative Polymerase Chain Reaction) experiment to validate their expression-level relationship with milk production, and the results showed that <i>FCGR3A</i> has a significant negative relationship with sheep-milk production, while other three genes did not show any positive or negative relations. In this study, it was discovered and proven that the candidate gene <i>FCGR3A</i> potentially contributes to the milk production of dairy sheep and a basis was laid for the further study of the genetic mechanism underlying the strong milk-production traits of sheep.
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