title: Genomic variations associated with attenuation in Mycobacterium avium subsp. paratuberculosis vaccine strains.
abstract: BACKGROUND
  Mycobacterium avium subspecies paratuberculosis (MAP) whole cell vaccines have been widely used tools in the control of Johne's disease in animals despite being unable to provide complete protection. Current vaccine strains derive from stocks created many decades ago; however their genotypes, underlying mechanisms and relative degree of their attenuation are largely unknown.
  
  
  RESULTS
  Using mouse virulence studies we confirm that MAP vaccine strains 316 F, II and 2e have diverse but clearly attenuated survival and persistence characteristics compared with wild type strains. Using a pan genomic microarray we characterise the genomic variations in a panel of vaccine strains sourced from stocks spanning over 40 years of maintenance. We describe multiple genomic variations specific for individual vaccine stocks in both deletion (26-32 Kbp) and tandem duplicated (11-40 Kbp) large variable genomic islands and insertion sequence copy numbers. We show individual differences suitable for diagnostic differentiation between vaccine and wild type genotypes and provide evidence for functionality of some of the deleted MAP-specific genes and their possible relation to attenuation.
  
  
  CONCLUSIONS
  This study shows how culture environments have influenced MAP genome diversity resulting in large tandem genomic duplications, deletions and transposable element activity. In combination with classical selective systematic subculture this has led to fixation of specific MAP genomic alterations in some vaccine strain lineages which link the resulting attenuated phenotypes with deficiencies in high reactive oxygen species handling.
authors: St, George's University of London Medical School, SW17 0RE, London, UK. tim.bull@sgul.ac.uk
authors: Tim J
authors: TJ
authors: Bull
authors: Alex
authors: A
authors: Schock
authors: J Michael
authors: JM
authors: Sharp
authors: Mandisa
authors: M
authors: Greene
authors: Iain J
authors: IJ
authors: McKendrick
authors: Jill
authors: J
authors: Sales
authors: Richard
authors: R
authors: Linedale
authors: Karen
authors: K
authors: Stevenson
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000009:adverse effects* / Q000235:genetics*; D004269:DNA, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D014644:Genetic Variation; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D016927:Mycobacterium avium subsp. paratuberculosis / Q000235:genetics* / Q000472:pathogenicity*; D010283:Paratuberculosis / Q000382:microbiology / Q000473:pathology; D016019:Survival Analysis; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000235:genetics
chemical_list: D001428:Bacterial Vaccines; D004269:DNA, Bacterial; D014613:Vaccines, Attenuated