Novel Heredity Basis of the Four-Horn Phenotype in Sheep Using Genome-Wide Sequence Data

SIMPLE SUMMARY: We performed a genome-wide association study of 100 sheep genomes to investigate the hereditary basis of the four-horn phenotype (FHP) in sheep. The results revealed that a total of 3 InDels (e.g., CHR2: g.133,742,709delA and g.133,743,215insC) and 14 SNPs (e.g., CHR2: g.133,727,513C > T and CHR16: g.40,351,378G > A) in CHR2 and CHR16 were significantly associated with the four-horn trait. Furthermore, HOXD1 and ADAMTS12 annotated from both CHR sequences were the key candidate gene loci contributing to FHP in sheep. This study provided a novel understanding of the Mendelian genetic basis for four horns in sheep. ABSTRACT: Horns are an important breeding trait for sheep. However, no widely recognized viewpoint on the regulatory genes and mechanisms of horns is available, and the genetic basis of the four-horn phenotype (FHP) is unclear. This work conducted a genome-wide association study with 100 sheep genomes from multiple breeds to investigate the genetic basis of the FHP. The results revealed three significant associations (corrected as p < 1.64 × 10(−8)) of the InDels (CHR2: g.133,742,709delA, g.133,743,215insC, and g.133,743,940delT) for FHP in the intergenic sequence (IGS) between the MTX2 and the LOC105609047 of CHR2. Moreover, 14 significant associations (corrected as p < 1.42 × 10(−9)) of SNPs with the FHP phenotype were identified in CHR2 and CHR16, including five (e.g., CHR16: g.40,351,378G > A and g.40,352,577G > A) located in the intron of the ADAMTS12 gene, eight (e.g., CHR2: g.133,727,513C > T and g.133,732,145T > G) in the IGS between MTX2 and LOC105609047, and only one (CHR2: g.133,930,761A > G) in the IGS between HOXD1 and MTX2. Obvious divergence was also observed in genotype patterns between the FHP and others (two horns and hornless) in the HOXD1 and ADAMTS12 gene regions. An extremely significant linkage also occurred between Loci I and Loci II within 100 individuals (LD = −156.02186, p < 0.00001). In summary, our study indicated that the genomic sequences from CHR2 and CHR16 contributed to the FHP in sheep, specifically the key candidate genes HOXD1 and ADAMTS12. These results improved our understanding of the Mendelian genetic basis of the FHP in sheep.