Genetic Diversity Among Mycobacterium avium Subspecies Revealed by Analysis of Complete Genome Sequences

Abstract

<i>Mycobacterium avium</i> comprises four subspecies that contain both human and veterinary pathogens. At the inception of this study, twenty-eight <i>M. avium</i> genomes had been annotated as RefSeq genomes, facilitating direct comparisons. These genomes represent strains from around the world and provided a unique opportunity to examine genome dynamics in this species. Each genome was confirmed to be classified correctly based on SNP genotyping, nucleotide identity and presence/absence of repetitive elements or other typing methods. The <i>Mycobacterium avium</i> subspecies <i>paratuberculosis</i> (<i>Map</i>) genome size and organization was remarkably consistent, averaging 4.8 Mb with a variance of only 29.6 kb among the 13 strains. Comparing recombination events along with the larger genome size and variance observed among <i>Mycobacterium avium</i> subspecies <i>avium</i> (<i>Maa</i>) and <i>Mycobacterium avium</i> subspecies <i>hominissuis</i> (<i>Mah</i>) strains (collectively termed non-<i>Map</i>) suggests horizontal gene transfer occurs in non-<i>Map</i>, but not in <i>Map</i> strains. Overall, <i>M. avium</i> subspecies could be divided into two major sub-divisions, with the <i>Map</i> type II (bovine strains) clustering tightly on one end of a phylogenetic spectrum and <i>Mah</i> strains clustering more loosely together on the other end. The most evolutionarily distinct <i>Map</i> strain was an ovine strain, designated Telford, which had >1,000 SNPs and showed large rearrangements compared to the bovine type II strains. The Telford strain clustered with <i>Maa</i> strains as an intermediate between <i>Map</i> type II and <i>Mah</i>. SNP analysis and genome organization analyses repeatedly demonstrated the conserved nature of <i>Map</i> versus the mosaic nature of non-<i>Map M. avium</i> strains. Finally, core and pangenomes were developed for <i>Map</i> and non-<i>Map</i> strains. A total of 80% <i>Map</i> genes belonged to the <i>Map</i> core genome, while only 40% of non-<i>Map</i> genes belonged to the non-<i>Map</i> core genome. These genomes provide a more complete and detailed comparison of these subspecies strains as well as a blueprint for how genetic diversity originated.