Abstract
Tuberculosis (TB) affects a wide range of host species worldwide. Understanding host-pathogen co-evolution remains a global challenge owing to complex interactions among host genetic factors, pathogen traits and environmental conditions. We used an endemic wild boar population that had undergone a huge increase in Mycobacterium bovis infection prevalence, from 45% in 2002/06 to 83% in 2009/12, to understand the effects of host genetics on host TB outcomes and disease dynamics. Host genomic variation was characterized using a high-density single nucleotide polymorphism (SNP) array, while host TB phenotype was assessed using both gross pathology and mycobacterial culture. Two complementary genome-wide association (GWAS) analyses were conducted: (i) infected-uninfected; and (ii) 2002/06–2009/12. The SNPs with the highest allelic frequency differences between time-periods and TB outcomes were identified and validated in a large dataset. In addition, we quantified the expression levels of some of their closest genes. These analyses highlighted various SNPs (i.e. rs81465339, rs81394585, rs81423166) and some of the closest genes (i.e. LOC102164072, BDNF/NT-3, NTRK2, CDH8, IGSF21) as candidates for host genetic susceptibility. In addition to TB-driven selection, our findings outline the putative role of demographic events in shaping genomic variation in natural populations and how population crashes and drift may impact host genetic susceptibility to TB over time.
Highlights
Tuberculosis (TB), which is caused by members of the Mycobacterium tuberculosis complex (MTC), affects a broad range of host species worldwide[1,2,3]
Recent advances in understanding the genetic basis of host susceptibility to TB have revealed several gene variants associated with increased genetic susceptibility in humans[28] (i.e., ASAP1) and in cattle[17,18,19] (i.e., PTPRT, MYO3B and SLC6A6)
Our findings highlighted the putative role of extreme demographic events in shaping host genetic variation in natural
Summary
Tuberculosis (TB), which is caused by members of the Mycobacterium tuberculosis complex (MTC), affects a broad range of host species worldwide[1,2,3]. Despite the fact that one-third of the human population may harbor this mycobacteria in an asymptomatic state[8], only 10% of infected individuals develop clinical TB9 This inter-individual variation in susceptibility to TB is still poorly understood, host genetic factors[6,10,11], pathogen traits[4,5,12] and environmental conditions[13,14,15] have been reported to be the main drivers of distinct TB outcomes. The environmental stressors induced by hot dry seasons coupled with strong MTC infection pressure, resulting from both high population abundance/aggregation and the indirect contact with MTC through a contaminated environment (i.e., waterholes)[38], makes these wild boar populations an exceptional model with which to understand host-pathogen interactions Under these conditions, the genetic capability of individuals to resist or succumb to MTC infection would be evidenced[21]. Unraveling the wild boar genetic mechanisms involved in susceptibility to TB may lead to a better understanding of TB pathogenesis and facilitate the development of new strategies for the prevention and treatment of TB in humans and animals
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