Mutational Biases


Mutational biases refer to systematic asymmetries or nonuniformities in the occurrence of mutations, heritable changes that take place in an individual organism. Mutational biases arise by asymmetries in damage, repair and replication of the genetic material. Many such biases are known: familiar examples include transition:transversion bias, the CpG effect and deletion:insertion bias. Mutation biases are biologically significant to the extent that they modulate the probabilities of heritable diseases and of evolutionary changes.

Keywords: transition–transversion bias; GC bias; strand‐specific bias; insertion–deletion bias

Figure 1.

Nucleotide transversions (solid lines) and transitions (dashed lines) typically occur with different rates (A, adenine; G, guanine; C, cytosine; T, thymine).

Figure 2.

A bubble plot showing the relative rates of different types of DNA substitution mutations typical for mammalian genomes (based on results from Hwang and Green, ). The size of the bubble represents the relative rate of mutation of a nucleotide shown on the vertical axis to the nucleotide shown on the horizontal axis (asterisks, CpG context).

Figure 3.

While deamination of C results in uracil, recognized by repair enzymes as an error, deamination of 5‐methylcytosine results in T, which is not recognized as an error because it is normally present in DNA. In vertebrates, methylation of Cs occurs preferentially at sites followed by a G residue, leading to an unusual mutation pattern at CpG dinucleotides.

Figure 4.

Numbers of short insertion (plus symbols) or deletion (triangles) mutants in the Human Gene Mutation Database (Chuzhanova et al., ), shown on a double‐log scale. Given reasonable assumptions (most such indels are null alleles; the chance of ascertainment is not significantly affected by length), variation in frequencies of different types (insertion or deletion) and lengths of indels directly reflects differences in rates of mutation. Thus, deletion mutations occur at a rate about 4 times that of insertions (from the slopes of the regression lines). The rates fall off sharply with length, according to a power law (grey regression lines).

Figure 5.

Slipped‐strand mispairing (DNA polymerase slippage) causes insertions and deletions during replication of repetitive DNA.



Andersson JO and Andersson SG (1999) Genome degradation is an ongoing process in Rickettsia. Molecular Biology and Evolution 16: 1178–1191.

Arndt PF, Petrov DA and Hwa T (2003) Distinct changes of genomic biases in nucleotide substitution at the time of mammalian radiation. Molecular Biology and Evolution 20(11): 1887–1896.

Bebenek K and Kunkel TA (1995) Analyzing fidelity of DNA polymerases. Methods in Enzymology 262: 217–232.

Chuzhanova NA, Anassis EJ, Ball EV, Krawczak M and Cooper DN (2003) Meta‐analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity. Human Mutation 21(1): 28–44.

Cox EC and Yanofsky C (1967) Altered base ratios in the DNA of an Escherichia coli mutator strain. Proceedings of the National Academy of Sciences of the USA 58: 1895–1902.

Drake JW (1970) The Molecular Basis of Mutation. San Francisco: Holden‐Day.

Ebersberger I, Metzler D, Schwarz C and Pääbo S (2002) Genomewide comparison of DNA sequences between humans and chimpanzees. American Journal of Human Genetics 70(6): 1490–1497.

Frank AC and Lobry JR (1999) Asymmetric substitution patterns: a review of possible underlying mutational or selective mechanisms. Gene 238: 65–77.

Fryxell KJ and Zuckerkandl E (2000) Cytosine deamination plays a primary role in the evolution of mammalian isochores. Molecular Biology and Evolution 17: 1371–1383.

Green P, Ewing B, Killer W et al. (2003) Transcription‐associated mutational asymmetry in mammalian evolution. Nature Genetics 33(4): 514–517.

Hwang DG and Green P (2004) Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution. Proceedings of the National Academy of Sciences of the USA 101: 13994–14001.

Kimura M (1983) The Neutral Theory of Molecular Evolution. Cambridge: Cambridge University Press.

Kondrashov AS (2003) Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Human Mutation 21: 12–27.

Krawczak M, Ball EV and Cooper DN (1998) Neighboring‐nucleotide effects on the rates of germ‐line single‐base‐pair substitution in human genes. American Journal of Human Genetics 63: 474–488.

Lobry JR (1996) Asymmetric substitution patterns in the two DNA strands of bacteria. Molecular Biology and Evolution 13: 660–665.

Marais G (2003) Biased gene conversion: implications for genome and sex evolution. Trends in Genetics 19: 330–338.

Meunier J and Duret L (2004) Recombination drives the evolution of the GC‐content in the human genome. Molecular Biology and Evolution 21(6): 984–990.

Nachman MW and Crowell SL (2000) Estimate of the mutation rate per nucleotide in humans. Genetics 156: 297–304.

Petrov DA (2002) DNA loss and evolution of genome size in Drosophila. Genetica 115: 81–91.

Rosche WA and Foster PL (2000) Determining mutation rates in bacterial populations. Methods 20: 4–17.

Schaaper RM and Dunn RL (1987) Spectra of spontaneous mutations in E. coli strains defective in mismatch correction: the nature of in vivo DNA replication errors. Proceedings of the National Academy of Sciences of the USA 84: 6220–6224.

Sinden RR, Potaman VN, Oussatcheva EA et al. (2002) Triplet repeat DNA structures and human genetic disease: dynamic mutations from dynamic DNA. Journal of Bioscience 27: 53–65.

Stenson PD, Ball EV, Mort M et al. (2003) Human Gene Mutation Database (HGMD): 2003 update. Human Mutation 21(6): 577–581.

Stoltzfus A (2006) Mutationism and the dual causation of evolutionary change. Evolution & Development 8: 304–317.

Sueoka N (1988) Directional mutation pressure and neutral molecular evolution. Proceedings of the National Academy of Sciences of the USA 85: 2653–2657.

Sueoka N and Kawanishi Y (2000) DNA G+C content of the third codon position and codon usage biases of human genes. Gene 261: 53–62.

Wakeley J (1996) The excess of transitions among nucleotide substitutions: new methods of estimating transition bias underscore its significance. Trends in Ecology and Evolution 11: 158–162.

Yampolsky LY, Kondrashov FA and Kondrashov AS (2005) Distribution of the strength of selection against amino acid replacements in human proteins. Human Molecular Genetics 14(21): 3191–3201.

Zhang Z and Gerstein M (2003) Patterns of nucleotide substitution, insertion and deletion in the human genome inferred from pseudogenes. Nucleic Acids Research 31(18): 5338–5348.

Further Reading

Duret L, Eyre‐Walker A and Galtier N (2006) A new perspective on isochore evolution. Gene 385: 71–74.

Maki H (2002) Origins of spontaneous mutations: specificity and directionality of base‐substitution, frameshift, and sequence‐substitution mutageneses. Annual Review of Genetics 36: 279–303.

Montoya‐Burgos JI, Boursot P and Galtier N (2003) Recombination explains isochores in mammalian genomes. Trends in Genetics 19(3): 128–130.

Petrov DA and Hartl DL (1999) Patterns of nucleotide substitution in Drosophila and mammalian genomes. Proceedings of the National Academy of Sciences of the USA 96: 1475–1479.

Qu HQ, Lawrence SG, Guo F, Majewski J and Polychronakos C (2006) Strand bias in complementary single‐nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms. BMC Genomics 7: 213.

Rubinsztein DC, Amos B and Cooper G (1999) Microsatellite and trinucleotide‐repeat evolution: evidence for mutational bias and different rates of evolution in different lineages. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 354: 1095–1099.

Schmegner C, Hoegel J, Vogel W and Assum G (2007) The rate, not the spectrum, of base pair substitutions changes at a GC‐content transition in the human NF1 gene region: implications for the evolution of the mammalian genome structure. Genetics 175(1): 421–428.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Yampolsky, Lev Y, and Stoltzfus, Arlin(Jul 2008) Mutational Biases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001729.pub2]