Dataset Information

EQTL Discovery and their Association with Severe Equine Asthma in European Warmblood Horses

ABSTRACT: Severe equine asthma, also known as recurrent airway obstruction (RAO), is a debilitating, performance limiting, obstructive respiratory condition in horses that is phenotypically similar to human asthma. We searched genome wide for associations between genotypes and additive changes in gene expression, i.e. expression quantitative trait loci (eQTLs). We analyzed peripheral blood mononuclear cells (PBMCs) from two half-sib families and one unrelated cohort that were stimulated in four conditions: no stimulation (MCK), lipopolysaccharides (LPS), recombinant cyathostomin antigen (RCA), and hay-dust extract (HDE). We identified high confidence eQTLs that do not violate linear modeling assumptions and are not due to single outlier individuals that heavily influence significance. On average, we identified 4347 high confidence eQTLs in four treatments of PBMCs, discover two trans regulatory hotspots regulating genes involved in related biological pathways, and identify SNPs strongly linked with previously RAO associated disease SNPs that regulate gene expression of dexamethasone-induced protein (DEXI).

INSTRUMENT(S): -

ORGANISM(S): Equus Caballus

SUBMITTER: University of Bern

PROVIDER: PRJEB23301 | EVA | 2017-12-06

REPOSITORIES: EVA

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			Action	DRS
	379_RAO_HD_Warmbloods.ne1000.accessioned.vcf.gz	Vcf
	379_RAO_HD_Warmbloods.ne1000.vcf.gz	Vcf
	379_RAO_HD_Warmbloods.ne1000.vcf.gz.tbi	Vcf

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Project description:tRNAs are encoded by a large gene family, usually with several isogenic tRNAs interacting with the same codon. Mutations in the anticodon region of other tRNAs can overcome specific tRNA deficiencies. Phylogenetic analysis suggests that such mutations have occurred in evolution, but the driving force is unclear. We show that in yeast suppressor mutations in other tRNAs are able to overcome deficiency of the essential TRT2-encoded tRNAThrCGU at high temperature (40°C). Surprisingly, these tRNA suppressor mutations were obtained after whole-genome transformation with DNA from thermotolerant Kluyveromyces marxianus or Ogataea polymorpha strains, but from which the mutations did apparently not originate. We suggest that transient presence of donor DNA in the host facilitates proliferation at high temperature and thus increases the chances for occurrence of spontaneous mutations suppressing defective growth at high temperature. Whole-genome sequence analysis of three transformants revealed only four to five non-synonymous mutations of which one causing TRT2 anticodon stem stabilization and two anticodon mutations in non-threonyl-tRNAs, tRNALysCUU and tRNAeMetCAU, were causative. Both anticodon mutations suppressed lethality of TRT2 deletion and apparently caused the respective tRNAs to become novel substrates for threonyl-tRNA synthetase. LC-MS/MS data could not detect any significant mistranslation and RT-qPCR results contradicted induction of the unfolded protein response. We suggest that stress conditions have been a driving force in evolution for the selection of anticodon-switching mutations in tRNAs as revealed by phylogenetic analysis. Importance of the work In this work we have identified for the first time the causative elements in a eukaryotic organism introduced by applying whole-genome transformation and responsible for the selectable trait of interest, i.e. high temperature tolerance. Surprisingly, the whole-genome transformants contained just a few SNPs, which were unrelated to the sequence of the donor DNA. In each of three independent transformants, we have identified a SNP in a tRNA, either stabilizing the essential tRNAThrCGU at high temperature or switching the anticodon of tRNALysCUU or tRNAeMetCAU into CGU, which is apparently enough for in vivo recognition by threonyl-tRNA synthetase. LC-MS/MS analysis indeed indicated absence of significant mistranslation. Phylogenetic analysis showed that similar mutations have occurred throughout evolution and we suggest that stress conditions may have been a driving force for their selection. The low number of SNPs introduced by whole-genome transformation may favor its application for improvement of industrial yeast strains.

Dataset Information

EQTL Discovery and their Association with Severe Equine Asthma in European Warmblood Horses

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