Genome Research
Vol. 7, No. 8, pp. 802-819, August 1997

Multiplex Sequencing of 1.5 Mb of the Mycobacterium leprae Genome

Douglas R. Smith,^1,2 Peter Richterich,² Marc Rubenfield,² Philip W. Rice,² Carol Butler,² Hong-Mei Lee,² Susan Kirst,² Kristin Gundersen,² Kari Abendschan,² Qinxue Xu,² Maria Chung,² Craig Deloughery,² Tyler Aldredge,² James Maher,² Ronald Lundstrom,² Craig Tulig,² Kathleen Falls,² Joan Imrich,² Dana Torrey,² Marcy Engelstein,² Gary Breton,² Deepika Madan,² Raymond Nietupski,² Bruce Seitz,² Steven Connelly,² Steven McDougall,² Hershel Safer,² Rene Gibson,² Lynn Doucette-Stamm,² Karin Eiglmeier,⁵ Staffan Bergh,⁵ Stewart T. Cole,⁵ Keith Robison,⁴ Laura Richterich,⁴ Jason Johnson,⁴ George M. Church,^1,3,4 and Jen-i Mao²

² Genome Therapeutics Corporation, Collaborative Research Division, Waltham, Massachusetts 02154; ³ Howard Hughes Medical Institute and ⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115; ⁵ Unite de Genetique Moleculaire Bacterienne, Institut Pasteur, 75724 Paris CEDEX 15, France

The nucleotide sequence of 1.5 Mb of genomic DNA from Mycobacterium leprae was determined using computer-assisted multiplex sequencing technology. This brings the 2.8-Mb M. leprae genome sequence to ~66% completion. The sequences, derived from 43 recombinant cosmids, contain 1046 putative protein-coding genes, 44 repetitive regions, 3 rRNAs, and 15 tRNAs. The gene density of one per 1.4 kb is slightly lower than that of Mycoplasma (1.2 kb). Of the protein coding genes, 44% have significant matches to genes with well-defined functions. Comparison of 1157 M. leprae and 1564 Mycobacterium tuberculosis proteins shows a complex mosaic of homologous genomic blocks with up to 22 adjacent proteins in conserved map order. Matches to known enzymatic, antigenic, membrane, cell wall, cell division, multidrug resistance, and virulence proteins suggest therapeutic and vaccine targets. Unusual features of the M. leprae genome include large polyketide synthase (pks) operons, inteins, and highly fragmented pseudogenes.

[The sequence data described in this paper have been submitted to GenBank under accession nos. L78811-L78829, U00010-U00023, U15180-U15184, U15186, U15187, L01095, L01536, L04666, and L01263. On-line supplementary information for Table 1 is available at http://www.cshl.org/gr.]

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