Stabilization of the genome of the mismatch repair deficient Mycobacterium tuberculosis by context-dependent codon choice.
BACKGROUND
The rate at which a stretch of DNA mutates is determined by the cellular systems for DNA replication and repair, and by the nucleotide sequence of the stretch itself. One sequence feature with a particularly strong influence on the mutation rate are nucleotide repeats. Some microbial pathogens use nucleotide repeats in their genome to stochastically vary phenotypic traits and thereby evade host defense. However, such unstable sequences also come at a cost, as mutations are often deleterious. Here, we analyzed how these opposing forces shaped genome stability in the human pathogen Mycobacterium tuberculosis. M. tuberculosis lacks a mismatch repair system, and this renders nucleotide repeats particularly unstable.


RESULTS
We found that proteins of M. tuberculosis are encoded by using codons in a context-dependent manner that prevents the emergence of nucleotide repeats. This context-dependent codon choice leads to a strong decrease in the estimated frame-shift mutation rate and thus to an increase in genome stability.


CONCLUSIONS
These results indicate that a context-specific codon choice can partially compensate for the lack of a mismatch repair system, and helps to maintain genome integrity in this pathogen.
Wanner
Roger M
RM
Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, CH-8006 Zürich, Switzerland. rwanner@immv.uzh.ch
Güthlein
Carolin
C
Springer
Burkhard
B
Böttger
Erik C
EC
Ackermann
Martin
M
D003062:Codon / Q000235:genetics*; D053843:DNA Mismatch Repair; D021901:DNA, Intergenic / Q000235:genetics; D018900:Dinucleotide Repeats; D040961:Genetic Drift; D016680:Genome, Bacterial / Q000235:genetics*; D042822:Genomic Instability; D009169:Mycobacterium tuberculosis / Q000235:genetics*; D012641:Selection, Genetic; D018911:Trinucleotide Repeats
D003062:Codon; D021901:DNA, Intergenic