Evolutionary Genomic and Bacterial Genome-Wide Association Study of Mycobacterium avium subsp. paratuberculosis and Dairy Cattle Johnes Disease Phenotypes

Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease in ruminants, which has important health consequences for dairy cattle. The Regional Dairy Quality Management Alliance (RDQMA) project is a multistate research program involving MAP isolates taken from three intensively studied commercial dairy farms in the northeastern United States, which emphasized longitudinal data collection of both MAP isolates and animal health in three regional dairy herds for a period of about 7 years. This paper reports the results of a panGWAS analysis involving 318 MAP isolates and dairy cow Johne’s disease phenotypes, taken from these three farms. Based on our highly curated accessory gene count, the pan-GWAS analysis identified several MAP genes associated with bovine Johne’s disease phenotypes scored from these three farms, with some of the genes having functions suggestive of possible cause/effect relationships with these phenotypes. This paper reports a pangenomic comparative analysis between MAP and Mycobacterium tuberculosis, assessing functional Gene Ontology category enrichments between these taxa. Finally, we also provide a population genomic perspective on the effectiveness of herd isolation, involving closed dairy farms, in preventing MAP interfarm cross infection on a microgeographic scale. IMPORTANCE Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease in ruminants, which has important health consequences for dairy cattle and enormous economic consequences for the dairy industry. Understanding which genes in this bacterium are correlated with key disease phenotypes can lead to functional experiments targeting these genes and ultimately lead to improved control strategies. This study represents a rare example of a prolonged longitudinal study of dairy cattle where the disease was measured and the bacteria were isolated from the same cows. The genome sequences of over 300 MAP isolates were analyzed for genes that were correlated with a wide range of Johne’s disease phenotypes. A number of genes were identified that were significantly associated with several aspects of the disease and suggestive of further experimental follow-up.