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The genomic structure and genetic variation of this species have been widely studied in different parts of the world. However, in some countries, this information is still yet unknown, as is the genomic behaviour of the main antigens used in VL diagnosis (rK39 and rK28), which have demonstrated variable sensitivity and specificity in a manner dependent on the geographic region analysed. The objective of this study was to explore the genomic architecture and diversity of four Colombian <jats:italic>L. infantum<\/jats:italic> isolates obtained in this study and to compare these results with the genetic analysis of 183 <jats:italic>L<\/jats:italic>. <jats:italic>infantum<\/jats:italic> isolates from across the world (obtained from public databases), as well as to analyse the whole rK39 and rK28 antigen sequences in our dataset. The results showed that, at the global level, <jats:italic>L. infantum<\/jats:italic> has high genetic homogeneity and extensive aneuploidy. Furthermore, we demonstrated that there are distinct populations of <jats:italic>L. infantum<\/jats:italic> circulating in various countries throughout the globe and that populations of distant countries have close genomic relationships. Additionally, this study demonstrated the high genetic variability of the rK28 antigen worldwide. In conclusion, our study allowed us to (i) expand our knowledge of the genomic structure of global <jats:italic>L. infantum<\/jats:italic>; (ii) describe the intra-specific genomic variability of this species; and (iii) understand the genomic characteristics of the main antigens used in the diagnosis of VL. 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