Expression quantitative trait loci in sheep liver and muscle contribute to variations in meat traits

Abstract

Background: Variants that regulate transcription, such as expression quantitative trait loci (eQTL), have shown enrichment in genome-wide association studies (GWAS) for mammalian complex traits. However, no study has reported eQTL in sheep, although it is an important agricultural species for which many GWAS of complex meat traits have been conducted. Using RNA sequence data produced from liver and muscle from 149 sheep and imputed whole-genome single nucleotide polymorphisms (SNPs), our aim was to dissect the genetic architecture of the transcriptome by associating sheep genotypes with three major molecular phenotypes including gene expression (geQTL), exon expression (eeQTL) and RNA splicing (sQTL). We also examined these three types of eQTL for their enrichment in GWAS of multi-meat traits and fatty acid profiles.

Results: Whereas a relatively small number of molecular phenotypes were significantly heritable (h² > 0, P < 0.05), their mean heritability ranged from 0.67 to 0.73 for liver and from 0.71 to 0.77 for muscle. Association analysis between molecular phenotypes and SNPs within ± 1 Mb identified many significant cis-eQTL (false discovery rate, FDR < 0.01). The median distance between the eQTL and transcription start sites (TSS) ranged from 68 to 153 kb across the three eQTL types. The number of common variants between geQTL, eeQTL and sQTL within each tissue, and the number of common variants between liver and muscle within each eQTL type were all significantly (P < 0.05) larger than expected by chance. The identified eQTL were significantly (P < 0.05) enriched in GWAS hits associated with 56 carcass traits and fatty acid profiles. For example, several geQTL in muscle mapped to the FAM184B gene, hundreds of sQTL in liver and muscle mapped to the CAST gene, and hundreds of sQTL in liver mapped to the C6 gene. These three genes are associated with body composition or fatty acid profiles.

Conclusions: We detected a large number of significant eQTL and found that the overlap of variants between eQTL types and tissues was prevalent. Many eQTL were also QTL for meat traits. Our study fills a gap in the knowledge on the regulatory variants and their role in complex traits for the sheep model.

Fig. 1

Absolute distance between expression quantitative trait loci (eQTL, which include gene expression QTL, geQTL; exon expression QTL, eeQTL and splicing QTL, sQTL) and gene transcription start sites (TSS) in liver (a) and muscle (b)

Fig. 2

Overlap between the three types of expression quantitative trait loci (eQTL, which include gene expression QTL, geQTL; exon expression QTL, eeQTL and splicing QTL, sQTL) in liver (a) and muscle (b). Table in the top right part shows pair-wise the number of common eQTL and P-values. The numbers in the bottom left part denote the number of significant eQTL for each type. Dots denote the eQTL types. Connection lines connecting the dots show eQTL types included in the comparison. The number above each bar shows the number of eQTL for each type (column 1 to column 3) or shared (column 4 to column 7). UpSet Plot was plotted by UpSetR R package (https://cran.r-project.org/web/packages/UpSetR/)

Fig. 3

Number of expression quantitative trait loci (eQTL, which include gene expression QTL, geQTL; exon expression QTL, eeQTL and splicing QTL, sQTL) that overlap with genome-wide association study (GWAS) hit regions linked with body composition [28]. The scale of red color represents the number of shared pleiotropic single nucleotide polymorphisms (SNPs) between eQTL and GWAS hit regions

Fig. 4

Gene expression quantitative trait loci (geQTL) in muscle associated with the FAM184B gene in red with the significant threshold denoted by the blue dotted line. Black dots are genome-wide association study (GWAS) for multi-traits [28]. Y-axis is the −log10P for both GWAS and geQTL. The vertical purple dotted lines denote the gene boundary

Fig. 5

Splicing quantitative trait loci (sQTL) in liver (a) and muscle (b) mapped to the CAST gene in red, with the significant threshold indicated as the blue dotted line. Black dots are genome-wide association study (GWAS) for multi-trait [28]. Y-axis is the −log10P value. Vertical purple dotted lines denote the CAST gene boundary

Fig. 6

Expression quantitative trait loci (eQTL) in red associated with the C6 gene in liver, the significant threshold is indicated by the blue dotted line.“geQTL, eeQTL, sQTL denote gene expression, exon expression and splicing QTL, respctively. Y-axis denotes the eQTL P-value. The vertical purple dotted lines denote the C6 gene boundary