TY - JOUR
T1 - The symmetrical wave pattern of base-pair substitution rates across the escherichia coli chromosome has multiple causes
AU - Niccum, Brittany A.
AU - Lee, Heewook
AU - Mohammedismail, Wazim
AU - Tang, Haixu
AU - Foster, Patricia L.
N1 - Funding Information:
We thank H. Bedwell-Ivers, C. Coplen, M. Durham, J. Eagan, N. Gruenhagen, J. A. Healy, N. Ivers, C. Klineman, E. Popodi, I. Rameses, S. Riffert, H. Rivera, D. Simon, K. Smith, J. Townes, L. Tran, and L. Whitson for technical help. Bacterial strains were kindly provided by R. Schaaper, R. Reyes-Lamothe, D. Kearns, M. Konkol, and The National BioResource Project at the (Japanese) National Institute of Genetics. We also thank S. E. Bell and X. Wang for technical help and discussions and the reviewers of this paper for useful suggestions. This research was supported by U.S. Army Research Office Multidisciplinary University Research Initiative (MURI) award W911NF-09-1-0444 to P.L.F. and H.T., by National Institutes of Health grant T32 GM007757 to B.A.N., and by funding provided by the U.S. Army Undergraduate Research Apprenticeship Program to J. A. Healy and S. Riffert. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Funding Information:
This research was supported by U.S. Army Research Office Multidisciplinary University Research Initiative (MURI) award W911NF–09–1–0444 to P.L.F. and H.T., by National Institutes of Health grant T32 GM007757 to B.A.N., and by funding provided by the U.S. Army Undergraduate Research Apprenticeship Program to J. A. Healy and S. Riffert. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2019 Niccum et al.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Mutation accumulation experiments followed by whole-genome sequencing have revealed that, for several bacterial species, the rate of base-pair substitutions (BPSs) is not constant across the chromosome but varies in a wave-like pattern that is symmetrical about the origin of replication. The experiments reported here demonstrated that, in Escherichia coli, several interacting factors determine the wave. The origin is a major driver of BPS rates. When it is relocated, the BPS rates in a 1,000-kb region surrounding the new origin reproduce the pattern that surrounds the normal origin. However, the pattern across distant regions of the chromosome is unaltered and thus must be determined by other factors. Increasing the deoxy-nucleoside triphosphate (dNTP) concentration shifts the wave pattern away from the origin, supporting the hypothesis that fluctuations in dNTP pools coincident with replication firing contribute to the variations in the mutation rate. The nucleoid binding proteins (HU and Fis) and the terminus organizing protein (MatP) are also major factors. These proteins alter the three-dimensional structure of the DNA, and results suggest that mutation rates increase when highly structured DNA is replicated. Biases in error correction by proofreading and mismatch repair, both of which may be responsive to dNTP concentrations and DNA structure, also are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates. IMPORTANCE It has been found in several species of bacteria that the rate at which single base pairs are mutated is not constant across the genome but varies in a wave-like pattern that is symmetrical about the origin of replication. Using Escherichia coli as our model system, we show that this pattern is the result of several interconnected factors. First, the timing and progression of replication are important in determining the wave pattern. Second, the three-dimensional structure of the DNA is also a factor, and the results suggest that mutation rates increase when highly structured DNA is replicated. Finally, biases in error correction, which may be responsive both to the progression of DNA synthesis and to DNA structure, are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates.
AB - Mutation accumulation experiments followed by whole-genome sequencing have revealed that, for several bacterial species, the rate of base-pair substitutions (BPSs) is not constant across the chromosome but varies in a wave-like pattern that is symmetrical about the origin of replication. The experiments reported here demonstrated that, in Escherichia coli, several interacting factors determine the wave. The origin is a major driver of BPS rates. When it is relocated, the BPS rates in a 1,000-kb region surrounding the new origin reproduce the pattern that surrounds the normal origin. However, the pattern across distant regions of the chromosome is unaltered and thus must be determined by other factors. Increasing the deoxy-nucleoside triphosphate (dNTP) concentration shifts the wave pattern away from the origin, supporting the hypothesis that fluctuations in dNTP pools coincident with replication firing contribute to the variations in the mutation rate. The nucleoid binding proteins (HU and Fis) and the terminus organizing protein (MatP) are also major factors. These proteins alter the three-dimensional structure of the DNA, and results suggest that mutation rates increase when highly structured DNA is replicated. Biases in error correction by proofreading and mismatch repair, both of which may be responsive to dNTP concentrations and DNA structure, also are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates. IMPORTANCE It has been found in several species of bacteria that the rate at which single base pairs are mutated is not constant across the genome but varies in a wave-like pattern that is symmetrical about the origin of replication. Using Escherichia coli as our model system, we show that this pattern is the result of several interconnected factors. First, the timing and progression of replication are important in determining the wave pattern. Second, the three-dimensional structure of the DNA is also a factor, and the results suggest that mutation rates increase when highly structured DNA is replicated. Finally, biases in error correction, which may be responsive both to the progression of DNA synthesis and to DNA structure, are major determinants of the wave pattern. These factors should apply to most bacterial and, possibly, eukaryotic genomes and suggest that different areas of the genome evolve at different rates.
KW - Escherichia coli
KW - Mismatch repair
KW - Mutation accumulation
KW - Mutation rate
KW - Nucleoid-associated proteins
KW - Nucleoside triphosphate pools
KW - Proofreading
KW - Replication timing
KW - Whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85069268895&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069268895&partnerID=8YFLogxK
U2 - 10.1128/mBio.01226-19
DO - 10.1128/mBio.01226-19
M3 - Article
C2 - 31266871
AN - SCOPUS:85069268895
SN - 2161-2129
VL - 10
JO - mBio
JF - mBio
IS - 4
M1 - e01226-19
ER -