Base substitution mutation
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Understanding Base Substitution Mutations
Introduction to Base Substitution Mutations
Base substitution mutations are changes in the DNA sequence where one base pair is replaced by another. These mutations can occur spontaneously or be induced by various DNA-damaging agents4. The consequences of such mutations depend on whether the altered codon codes for a different amino acid or a stop codon, potentially leading to significant changes in protein function4.
Mechanisms and Causes of Base Substitution Mutations
Complementary Base Pairing and Tautomeric Shifts
The Watson-Crick model of complementary base pairing extends beyond the standard A-T and G-C pairs to include less common pairs like A-C and G-T, which can occur due to imino or enol tautomers and syn isomers1. These rare forms can lead to spontaneous substitution mutations, which are usually corrected by DNA polymerase during synthesis1.
Influence of DNA Sequence Context
The local DNA sequence context significantly influences the rates and types of base substitution mutations. For instance, CpG dinucleotides are hotspots for mutations due to methylation-mediated deamination, leading to CG to TG or CA transitions7. Additionally, neighboring nucleotides can affect mutation rates, with certain flanking sequences increasing the likelihood of specific substitutions10.
Environmental and Chemical Inducers
Certain chemicals, such as aflatoxin B1, can induce specific base substitutions. Aflatoxin B1, when metabolically activated, primarily causes G to T transversions, likely through depurination at guanine residues6. Other carcinogens like benzo[a]pyrene diol epoxide also induce similar mutations, highlighting the role of environmental factors in mutation induction6.
Detection and Analysis of Base Substitution Mutations
Experimental Approaches
Base substitution mutations can be detected using various methods. For example, changes that alter restriction enzyme cleavage sites can be identified through DNA blots3. Synthetic oligonucleotides can also be used as hybridization probes to detect known mutations3. Advanced techniques involve electrophoretic separation of DNA heteroduplexes, which can identify single base mismatches3.
Mutation Accumulation Studies
Mutation accumulation (MA) experiments in model organisms like Caenorhabditis elegans provide insights into the rates and fitness effects of spontaneous mutations. These studies have shown that base substitutions and small indels occur at specific rates and exhibit biases, such as a higher frequency of A/T to T/A transversions in certain genomic contexts2 8.
Implications for Human Genetic Diseases
Patterns and Predictions
The mutational spectrum of base substitutions causing human genetic diseases is non-random. For instance, CG dinucleotides are particularly prone to mutations, which aligns with the observed high frequency of CG to TG or CA transitions in disease-causing mutations7. Predictive models, such as MUTPRED, use empirical data to forecast the locations of point mutations within gene coding regions, aiding in the understanding and diagnosis of genetic diseases7.
Tandem Base Substitutions
Tandem base substitutions (TBSs), involving multiple contiguous nucleotide changes, are a distinct category of mutations. These mutations often arise through endogenous mechanisms, such as translesion synthesis (TLS) DNA polymerases, and are implicated in various inherited diseases9. The rates and patterns of TBSs provide further insights into the mutational processes affecting the human genome9.
Conclusion
Base substitution mutations are a fundamental aspect of genetic variation and disease. Understanding their mechanisms, detection methods, and implications for human health is crucial for advancing genetic research and developing diagnostic tools. The interplay between spontaneous mutations, environmental factors, and DNA sequence context underscores the complexity of these genetic changes.
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Most relevant research papers on this topic
Complementary base pairing and the origin of substitution mutations
Complementary base pairing in DNA extends beyond A-T and G-C, explaining the origin and nature of substitution mutations and their enhancement by base analogues.
Highly CitedMutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size.
Spontaneous mutation rates in Caenorhabditis elegans populations vary, suggesting less stringent purifying selection compared to mitochondrial DNA mutations and nuclear copy-number changes.
Detection of single base substitutions in total genomic DNA
This study demonstrates that four different human -thalassaemia alleles with known single base mutations can be detected with as little as 5 g of total genomic DNA, potentially aiding in the localization and diagnosis of genetic diseases.
Highly CitedDemonstration of the production of frameshift and base-substitution mutations by quasipalindromic DNA sequences.
Misaligned quasipalindromic DNA sequences can produce spontaneous frameshift and base-substitution mutations in the T4 rII gene, confirming the prediction of these mutations in vivo.
Highly CitedBase substitution mutations induced by metabolically activated aflatoxin B1.
Metabolically activated aflatoxin B1 specifically induces GxC leads to TxA transversions in the lacI gene of Escherichia coli, potentially affecting gene expression and potentially contributing to carcinogenesis.
Highly CitedThe mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions
CG dinucleotides are hotspots of mutation causing human genetic diseases, with a strong correlation to mispairing frequencies of vertebrate DNA polymerases and in vitro.
Highly CitedMutational Landscape of Spontaneous Base Substitutions and Small Indels in Experimental Caenorhabditis elegans Populations of Differing Size
Spontaneous mutation rates in Caenorhabditis elegans populations vary, with no correlation between population size and mutation rates, suggesting less stringent purifying selection compared to mitochondrial DNA mutations.
Patterns and Mutational Signatures of Tandem Base Substitutions Causing Human Inherited Disease
Tandem base substitutions (TBSs) in human genes cause inherited diseases predominantly through endogenous mechanisms of mutagenesis rather than exposure to exogenous mutagens.
Rigorous JournalNeighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes.
Nearby DNA sequence has a subtle but local influence on single-base-pair substitution rates in human genes, with a moderate correlation between mutability and thermodynamic stability of DNA triplets.
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