Discovery of expression quantitative trait loci associated with Johne’s disease using both RNA-seq and DNA variants
Bissonnette, N., J.-S. Brouard, O. Ariel, N. Gévry, E. Ibeagha-Awemu, and F. Miglior. 2018. Discovery of expression quantitative trait loci associated with Johne’s disease using both RNA-seq and DNA variants. 11th World Congress on Genetics Applied to Livestock Production. February 10th-16th 2018, Auckland, New-Zealand.
Johne’s disease (JD) is a debilitating chronic disease in ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP) which manipulates gut macrophages as survival strategies and for its dissemination. The endemic situation of JD can be in part explained by the lack of genetic resistance to MAP infection in cattle populations. A successful genetic improvement strategy results from a comprehensive understanding of the genetic variability associated with disease susceptibility/resistance, while providing information about the affected biological pathways. In this functional genomics study, accurate phenotypic data (e.g. diagnosis records) for JD were used to identify 22 MAP-infected (JD(+)) and 28 healthy/resistant (JD(–)) cows. The transcriptome of their blood circulating primary macrophages were analysed using the next-generation RNA sequencing (RNA-Seq) technology. DNA genotypes were also identified using a complementary strategy: the BovineSNP50 DNAchip imputed to the high density (HD) DNAchip. More than 60% of the 1,356,248 variants (call rate ≥ 0.2, minor allele frequency ≥ 0.05) were identified by RNA-seq, among which 12% (161,951) were novel variants. Genome-wide association study identified two major expression quantitative trait loci (eQTL) on BTA4 and 11 at –log10 (P) ≥ 7. Interestingly, 2,435 RNA-seq variants are predicted to produce high functional effect on known genes, while only 33 DNA genotypes (HD) were found in this category. Network and pathway analysis using BovineMine from JD(+/–) macrophages revealed interesting cue regarding pathways that deserved further investigation (e.g. STAT transcription factor). RNA-Seq is an effective strategy to identify eQTL and thus increases the power to detect functional genetic variants. In the present study, we succeeded to identify eQTL and the regulatory pathways that discriminate MAP infected from healthy/resistant cows. Genetic variations in susceptible cows allow MAP to proliferate and escape the normal mycobacterial killing process of the macrophages. This strategy is thus highly relevant in genetic selection, as it may reduce disease susceptibility. An integration of the findings of this research (genomic information), into the conventional young sire selection and progeny testing program could yield a better, more accurate and rapid genetic improvement of resistance to bovine paratuberculosis in Canadian dairy herds.
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