Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Ford, Christopher B. ; Lin, Philana Ling ; Chase, Michael ; Shah, Rupal R. ; Iartchouk, Oleg ; Galagan, James ; Mohaideen, Nilofar ; Ioerger, Thomas R. ; Sacchettini, James C. ; Lipsitch, Marc ; Flynn, JoAnne L. ; Fortune, Sarah M.
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• Description:
  Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance.
• Subjects:
  • Animals
  • Antitubercular Agents
  • Base Sequence
  • DNA, Bacterial
  • Disease Models, Animal
  • Drug Resistance, Bacterial
  • Genome, Bacterial
  • Humans
  • Isoniazid
  • Latent Tuberculosis
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• Source:
  Nat Genet. 43(5):482-486
• Pubmed ID:
  21516081
• Pubmed Central ID:
  PMC3101871
• Document Type:
  Journal Article
• Funding:
  R01 HL075845/HL/NHLBI NIH HHSUnited States/ ; DP2 0D001378/DP/NCCDPHP CDC HHSUnited States/ ; R33 HL092883-02/HL/NHLBI NIH HHSUnited States/ ; K08 AI063101/AI/NIAID NIH HHSUnited States/ ; U19 AI076217/AI/NIAID NIH HHSUnited States/ ; R33 HL092883/HL/NHLBI NIH HHSUnited States/ ; T32 AI007638/AI/NIAID NIH HHSUnited States/ ; U54 GM088558/GM/NIGMS NIH HHSUnited States/ ; HHSN266200400001C/AO/NIAID NIH HHSUnited States/ ; U54GM088558/GM/NIGMS NIH HHSUnited States/ ; R01 HL075845-05/HL/NHLBI NIH HHSUnited States/ ; R01 HL106804-01/HL/NHLBI NIH HHSUnited States/ ; K08 AI063101-05/AI/NIAID NIH HHSUnited States/ ; R01 HL106804/HL/NHLBI NIH HHSUnited States/
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• Volume:
  43
• Issue:
  5
• Download URL:
  https://stacks.cdc.gov/view/cdc/22788/cdc_22788_DS1.pdf
• File Type:
  [PDF - 505.70 KB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d48162ac1a1e5144e2f6e237b62cafd6521bc850fdceb0b0d91694574e1f4ae8