Insight into the evolution and origin of leprosy bacilli from the genome sequence of Mycobacterium lepromatosis

Pushpendra Singh, Andrej Benjak, Verena J. Schuenemann, Alexander Herbig, Charlotte Avanzi, Philippe Busso, Kay Nieselt, Johannes Krause, Lucio Vera-Cabrera, and Stewart T. Cole
PNAS published ahead of print March 23, 2015 https://doi.org/10.1073/pnas.1421504112

  1. Edited by Roland Brosch, Institut Pasteur, Paris, France, and accepted by the Editorial Board February 20, 2015 (received for review November 17, 2014)

Significance

Leprosy was thought to be exclusively caused by infection of humans by Mycobacterium leprae. In 2008, Han et al. proposed that Mycobacterium lepromatosis, a separate unculturable species, might be responsible for a rare yet severe form of the disease called diffuse lepromatous leprosy. Here, by using comparative genomics, we show that the two species are very closely related and derived from a common ancestor that underwent genome downsizing and gene decay. Since their separation 13.9 Mya, the two species have continued to lose genes, but from different regions of the genome, and M. leprae appears to be more recent. In a phylogeographic survey, by using differential PCR, we found that M. lepromatosis was scarce and restricted to patients from Mexico.

Abstract

Mycobacterium lepromatosis is an uncultured human pathogen associated with diffuse lepromatous leprosy and a reactional state known as Lucio's phenomenon. By using deep sequencing with and without DNA enrichment, we obtained the near-complete genome sequence of M. lepromatosis present in a skin biopsy from a Mexican patient, and compared it with that of Mycobacterium leprae, which has undergone extensive reductive evolution. The genomes display extensive synteny and are similar in size (∼3.27 Mb). Protein-coding genes share 93% nucleotide sequence identity, whereas pseudogenes are only 82% identical. The events that led to pseudogenization of 50% of the genome likely occurred before divergence from their most recent common ancestor (MRCA), and both M. lepromatosis and M. leprae have since accumulated new pseudogenes or acquired specific deletions. Functional comparisons suggest that M. lepromatosis has lost several enzymes required for amino acid synthesis whereas M. leprae has a defective heme pathway. M. lepromatosis has retained all functions required to infect the Schwann cells of the peripheral nervous system and therefore may also be neuropathogenic. A phylogeographic survey of 227 leprosy biopsies by differential PCR revealed that 221 contained M. leprae whereas only six, all from Mexico, harbored M. lepromatosis. Phylogenetic comparisons indicate that M. lepromatosis is closer than M. leprae to the MRCA, and a Bayesian dating analysis suggests that they diverged from their MRCA approximately 13.9 Mya. Thus, despite their ancient separation, the two leprosy bacilli are remarkably conserved and still cause similar pathologic conditions.

Footnotes

  • ↵1P.S. and A.B. contributed equally to this work.

  • ↵2Present address: National Hansen’s Disease Program, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803.

  • ↵3To whom correspondence should be addressed. Email: stewart.cole{at}epfl.ch.

  • Author contributions: P.S., A.B., V.J.S., A.H., J.K., and S.T.C. designed research; P.S., A.B., V.J.S., C.A., P.B., K.N., and L.V.-C. performed research; J.K. contributed new reagents/analytic tools; A.B., A.H., and J.K. analyzed data; and P.S., A.B., C.A., and S.T.C. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. R.B. is a guest editor invited by the Editorial Board.

  • All raw read files have been deposited in the trace archive of the National Center for Biotechnology Information Sequence Read Archive (accession no. SRP047206). The de novo assembly of M. lepromatosis genome has been deposited at DNA Data Bank of Japan/European Molecular Biology Laboratory/GenBank (accession no. JRPY01000000).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1421504112/-/DCSupplemental.

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The genome of Mycobacterium lepromatosis
Pushpendra Singh, Andrej Benjak, Verena J. Schuenemann, Alexander Herbig, Charlotte Avanzi, Philippe Busso, Kay Nieselt, Johannes Krause, Lucio Vera-Cabrera, Stewart T. Cole
Proceedings of the National Academy of Sciences Mar 2015, 201421504; DOI: 10.1073/pnas.1421504112
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Proceedings of the National Academy of Sciences: 116 (7)
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