Several people have written to me asking for information and
references relevant to the spectrum of spontaneous mutations.
First, a correction on something I said earlier:
> Yeah, and another interesting thing is that deletions in pseudogenes
> are something like an order of magnitude more common than insertions,
Actually, an order of magnitude would be an exaggeration, but there
is a strong bias, 3-fold to 7-fold in the study by Graur, et al.
What people usually mean by "spectrum" is the rate distribution of
different types of mutations (this word was in use something like
40 years ago, in the T4 rII days). The most commonly recognized
types of mutation are nucleotide substitutions, microindels
(sometimes "frameshifts", usually < 20 bp), and everything else
(big deletions, rearrangements, element insertions). In some
studies, mutations may be further categorized according to
chemical criteria (e.g., transitions, transversions, CG-site
vs. non-CG-site) or coding criteria (e.g., nonsense, frameshift).
I'm particularly interested in how mutations affect protein-coding
genes, and so I have also included some references on the effects of
amino acid changes in proteins.
The list of references is below. A good starting point is
the discussion by Brian Golding (under #5 below). I'm sure
that this list *only barely touches on available mutation work*,
which isn't always easy to put in a form that is useful for
If anyone has other references that they would like to share,
please do so, and maybe at some future date I can put up a list of
mutation rate information on my web site. Regards,
Some references (***good starting points)
1. Spontaneous mutation in vivo (animals)
Sager, R., Mutation rates and mutational spectra in tumorigenic cell
lines, Cancer Surv, 7, 325-33 (1988).
Sommer, S. S., Recent human germ-line mutation: inferences from
patients with hemophilia B, Trends Genet, 11, 141-7 (1995).
***Sommer, S. S., and Ketterling, R. P., How precisely can data from
transgenic mouse mutation-detection systems be extrapolated to
humans?: lesions from the human factor IX gene, Mutat Res, 307,
Drost, J. B., and Lee, W. R., Biological basis of germline mutation:
comparisons of spontaneous germline mutation rates among drosophila,
mouse, and human, Environ Mol Mutagen, 25 Suppl 26, 48-64 (1995).
Favor, J., Risk estimation based on germ-cell mutations in animals,
Genome, 31, 844-52 (1989).
2. DNA replication errors in vivo and in vitro (mostly animals)
Roberts, J. D., and Kunkel, T. A., Eukaryotic DNA replication
fidelity, in DNA replication in eukaryotic cells: concepts, enzymes
and systems, De Pamphilis, M., Ed.,, Cold Spring Harbor Press, Cold
Spring Harbor, New York (1995).
***Umar, A., and Kunkel, T. A., DNA-replication fidelity, mismatch
repair and genome instability in cancer cells, Eur. J. Biochem.,
238, 297-307 (1996).
3. Detailed studies of pseudogene divergence (animals)
***Graur, D., Shuali, Y., and Li, W.-H., Deletions in Processed
Pseudogenes Accumulate Faster in Rodents than in Human, J. Mol.
Evol., 28, 279-285 (1989).
Saitou, N., and Ueda, S., Evolutionary rates of insertion and
deletion in noncoding nucleotide sequences of primates, Mol Biol
Evol, 11, 504-12 (1994).
4. Studies of the effects of changing amino acids (eubacteria)
Markiewicz, P., Kleina, L. G., Cruz, C., Ehret, S., and Miller, J.
H., Genetic studies of the lac repressor. XIV. Analysis of 4000
altered Escherichia coli lac repressors reveals essential and
non-essential residues, as well as "spacers" which do not require a
specific sequence, J Mol Biol, 240, 421-33 (1994).
Kleina, L. G., and Miller, J. H., Genetic studies of the lac
repressor. XIII. Extensive amino acid replacements generated by the
use of natural and synthetic nonsense suppressors, J Mol Biol, 212,
***Rennell, D., Bouvier, S. E., Hardy, L. W., and Poteete, A. R.,
Systematic Mutation of Bacteriophage T4 Lysozyme, J. Mol. Biol.,
222, 67-87 (1991).
Suckow, J., Markiewicz, P., Kleina, L. G., Miller, J., Kisters
Woike, B., and Muller Hill, B., Genetic studies of the Lac
repressor. XV: 4000 single amino acid substitutions and analysis of
the resulting phenotypes on the basis of the protein structure, J
Mol Biol, 261, 509-23 (1996).
Pielak, et al., 1995 Biochemistry 34: 3268-3276
5. A few evolutionary studies of interest (mostly
about parallel changes):
Cunningham, C. W., Jeng, K., Husti, J., Badgett, M., Molineux, I.
J., Hillis, D. M., and Bull, J. J., Parallel Molecular Evolution of
Deletions and Nonsense Mutations in Bacteriophage T7, Mol. Biol.
Evol., 14, 113-116 (1997).
Macey, J. R., Larson, A., Ananjeva, N. B., and Papenfuss, T. J.,
Replication Slippage May Cause Parallel Evolution in the Secondary
Structures of Mitochondrial Transfer RNAs, Mol. Biol. Evol., 14,
Foster, P. G., Jermiin, L. S., and Hickey, D. A., Nucleotide
composition bias affects amino acid content in proteins coded by
animal mitochondria, J. Mol. Evol., 44, 282-288 (1997).
***Gu, X., Hewett-Emmett, D., and Li, W.-H., Directional Mutational
Pressure Affects the Amino Acid Composition and Hydrophobicity of
Proteins in Bacteria, Genetica, in press (1997).
***Golding, G. B., Nonrandom Patterns of Mutation are Reflected in
Evolutionary Divergence and May Cause Some of the Unusual Patterns
Observed in Sequences, in Genetic Constraints on Adaptive Evolution,
Loeschcke, V., Ed.,, Springer-Verlag, Berlin, pp. 151-172 (1987).
Marshall, et al. Dollo's law and the death and resurrection of
genes, PNAS 91, 12283 (this may not seem relevant here, but it
is offered an example of how the outcome of an evolutionary model
can rely crucially on a mutation spectrum)