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Efforts to control the spread of Buruli ulcer – an emerging ulcerative skin infection caused by  Mycobacterium ulcerans  - have been hampered by our poor understanding of reservoirs and transmission. To help address this issue, we compared whole genomes from 18 clinical  M .  ulcerans  isolates from a 30km 2  region within the Asante Akim North District, Ashanti region, Ghana, with 15 other  M .  ulcerans  isolates from elsewhere in Ghana and the surrounding countries of Ivory Coast, Togo, Benin and Nigeria. Contrary to our expectations of finding minor DNA sequence variations among isolates representing a single  M .  ulcerans  circulating genotype, we found instead two distinct genotypes. One genotype was closely related to isolates from neighbouring regions of Amansie West and Densu, consistent with the predicted local endemic clone, but the second genotype (separated by 138 single nucleotide polymorphisms [SNPs] from other Ghanaian strains) most closely matched  M .  ulcerans  from Nigeria, suggesting another introduction of  M .  ulcerans  to Ghana, perhaps from that country. Both the exotic genotype and the local Ghanaian genotype displayed highly restricted intra-strain genetic variation, with less than 50 SNP differences across a 5.2Mbp core genome within each genotype. Interestingly, there was no discernible spatial clustering of genotypes at the local village scale. Interviews revealed no obvious epidemiological links among BU patients who had been infected with identical  M .  ulcerans  genotypes but lived in geographically separate villages. We conclude that  M .  ulcerans  is spread widely across the region, with multiple genotypes present in any one area. These data give us new perspectives on the behaviour of possible reservoirs and subsequent transmission mechanisms of  M .  ulcerans . These observations also show for the first time that  M .  ulcerans  can be mobilized, introduced to a new area and then spread within a population. Potential reservoirs of  M .  ulcerans  thus might include humans, or perhaps  M .  ulcerans -infected animals such as livestock that move regularly between countries.

Whole Genome Comparisons Suggest Random Distribution of Mycobacterium ulcerans Genotypes in a Buruli Ulcer Endemic Region of Ghana