Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues

Abstract

BackgroundMammalian phenotypes are shaped by numerous genome variants, many of which may regulate gene transcription or RNA splicing. To identify variants with regulatory functions in cattle, an important economic and model species, we used sequence variants to map a type of expression quantitative trait loci (expression QTLs) that are associated with variations in the RNA splicing, i.e., sQTLs. To further the understanding of regulatory variants, sQTLs were compare with other two types of expression QTLs, 1) variants associated with variations in gene expression, i.e., geQTLs and 2) variants associated with variations in exon expression, i.e., eeQTLs, in different tissues.ResultsUsing whole genome and RNA sequence data from four tissues of over 200 cattle, sQTLs identified using exon inclusion ratios were verified by matching their effects on adjacent intron excision ratios. sQTLs contained the highest percentage of variants that are within the intronic region of genes and contained the lowest percentage of variants that are within intergenic regions, compared to eeQTLs and geQTLs. Many geQTLs and sQTLs are also detected as eeQTLs. Many expression QTLs, including sQTLs, were significant in all four tissues and had a similar effect in each tissue. To verify such expression QTL sharing between tissues, variants surrounding (±1 Mb) the exon or gene were used to build local genomic relationship matrices (LGRM) and estimated genetic correlations between tissues. For many exons, the splicing and expression level was determined by the same cis additive genetic variance in different tissues. Thus, an effective but simple-to-implement meta-analysis combining information from three tissues is introduced to increase power to detect and validate sQTLs. sQTLs and eeQTLs together were more enriched for variants associated with cattle complex traits, compared to geQTLs. Several putative causal mutations were identified, including an sQTL at Chr6:87392580 within the 5th exon of kappa casein (CSN3) associated with milk production traits.ConclusionsUsing novel analytical approaches, we report the first identification of numerous bovine sQTLs which are extensively shared between multiple tissue types. The significant overlaps between bovine sQTLs and complex traits QTL highlight the contribution of regulatory mutations to phenotypic variations.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4902-8) contains supplementary material, which is available to authorized users.

Quantifying the contribution of sequence variants with regulatory and evolutionary significance to 34 bovine complex traits

“…Conversely, for the expanded region of microsomal glutathione S-transferase 1 (MGST1), a major QTL for milk fat, variants from high-ranking sets were more enriched in two major locations ( Figure 4B). The top variant within the MGST1 gene was again a sQTL, confirming previous results (13). Although not enriched in the MGST1 peak region, conserved sites tagged many variants that were not tagged by other top sets.…”

“…Briefly, regulatory variant sets including geQTLs, sQTLs and allele specific expression QTLs (aseQTLs) were discovered from multiple tissues including white blood and milk cells, liver and muscle. Milk cells which were dominated by immune cells contained a portion of mammary epithelial cells and had high transcriptomic similarities to mammary gland tissues (13,21). The polar lipid metabolites mQTLs were discovered using the multi-trait metaanalysis (22) of 19 metabolite profiles, such as phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine (23), from bovine milk fat.…”

“…Figure 2 illustrates some of the properties of these variant sets. Many sQTLs with strong effects on the intron excision ratio (26) were discovered in a meta-analysis of sQTLs mapped in white blood and milk cells, liver and muscle (13) (Figure 2A). many Significant aseQTLs were discovered using a gene-wise meta-analysis of the effects of the driver variant (dVariant) on the transcript variant (tVariant) at exonic heterozygous sites (27) from blood and milk cells ( Figure 2B).…”

“…This has been demonstrated in many studies of human genomics, including but not limited to the analysis of intermediate trait quantitative trait loci (QTLs), such as metabolic QTLs (mQTLs) (7) and expression QTLs (eQTLs) (8) and analysis of regulatory elements, such as promoters (9) and enhancers (10) which can be identified with chromatin immunoprecipitation sequencing (ChIP-seq). In animals, the Functional Annotation of Animal Genomes (FAANG) project has started (11) and animal functional data species has been accumulating (12)(13)(14). However, it is unclear which types of functional information improve the identification of causal mutations.…”

Elimination of reference mapping bias reveals robust immune related allele-specific expression in crossbred sheep

“…Examples of population level aseQTL, eQTL and sQTL (QTLs associated with RNA splicing) 554 already exist for cattle (Wang et al, 2018;Xiang et al, 2018). Knowledge of favourable ASE 555…”