Rate, molecular spectrum, and consequences of human mutation

Contributed by Michael Lynch, December 3, 2009 (sent for review September 13, 2009)
January 4, 2010
107 (3) 961-968
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Beth Azar

Abstract

Although mutation provides the fuel for phenotypic evolution, it also imposes a substantial burden on fitness through the production of predominantly deleterious alleles, a matter of concern from a human-health perspective. Here, recently established databases on de novo mutations for monogenic disorders are used to estimate the rate and molecular spectrum of spontaneously arising mutations and to derive a number of inferences with respect to eukaryotic genome evolution. Although the human per-generation mutation rate is exceptionally high, on a per-cell division basis, the human germline mutation rate is lower than that recorded for any other species. Comparison with data from other species demonstrates a universal mutational bias toward A/T composition, and leads to the hypothesis that genome-wide nucleotide composition generally evolves to the point at which the power of selection in favor of G/C is approximately balanced by the power of random genetic drift, such that variation in equilibrium genome-wide nucleotide composition is largely defined by variation in mutation biases. Quantification of the hazards associated with introns reveals that mutations at key splice-site residues are a major source of human mortality. Finally, a consideration of the long-term consequences of current human behavior for deleterious-mutation accumulation leads to the conclusion that a substantial reduction in human fitness can be expected over the next few centuries in industrialized societies unless novel means of genetic intervention are developed.

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Acknowledgments

The author thanks M. Ackerman, C. Baer, J. Drake, A. Kondrashov, and S. Yi for helpful comments, and M. Ackerman for assistance in some key computations. This work was funded by National Institutes of Health Grant GM36827, National Science Foundation Grant EF-0827411, and the MetaCyte program derived from Lilly Foundation funding to Indiana University.

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References

1
JF Crow, How much do we know about spontaneous human mutation rates? Environ Mol Mutagen 21, 122–129 (1993).
2
JF Crow, The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94, 8380–8386 (1997).
3
JF Crow, The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1, 40–47 (2000).
4
Y Xue, et al., Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Curr Biol 19, 1453–1457 (2009).
5
ER Mardis, RK Wilson, Cancer genome sequencing: a review. Hum Mol Genet 18, R163–R168 (2009).
6
JW Drake, A constant rate of spontaneous mutation in DNA-based microbes. Proc Natl Acad Sci USA 88, 7160–7164 (1991).
7
JBS Haldane, The rate of spontaneous mutation of a human gene. J Genet 31, 317–326 (1935).
8
AS Kondrashov, Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum Mutat 21, 12–27 (2003).
9
M Lynch The Origins of Genome Architecture (Sinauer Assoc, Sunderland, MA, 2007).
10
DR Denver, et al., A genome-wide view of Caenorhabditis elegans base-substitution mutation processes. Proc Natl Acad Sci USA 106, 16310–16314 (2009).
11
S Ossowski, et al., The rate and molecular spectrum of spontaneous mutations in Arabidopsis thaliana. Science, in press. (2009).
12
PD Keightley, et al., Analysis of the genome sequences of three Drosophila melanogaster spontaneous mutation accumulation lines. Genome Res 19, 1195–1201 (2009).
13
M Lynch, et al., A genome-wide view of the spectrum of spontaneous mutations in yeast. Proc Natl Acad Sci USA 105, 9272–9277 (2008).
14
M Bulmer, The selection-mutation-drift theory of synonymous codon usage. Genetics 129, 897–907 (1991).
15
FA Kondrashov, AY Ogurtsov, AS Kondrashov, Selection in favor of nucleotides G and C diversifies evolution rates and levels of polymorphism at mammalian synonymous sites. J Theor Biol 240, 616–626 (2006).
16
M Lynch, The origins of eukaryotic gene structure. Mol Biol Evol 23, 450–468 (2006).
17
W-H Li, Models of nearly neutral mutations with particular implications for nonrandom usage of synonymous codons. J Mol Evol 24, 337–345 (1987).
18
DN Cooper, M Krawczak, The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 85, 55–74 (1990).
19
L Duret, PF Arndt, The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet 4, e1000071 (2008).
20
G Albrecht-Buehler, The spectra of point mutations in vertebrate genomes. Bioessays 31, 98–106 (2009).
21
SH Kim, N Elango, C Warden, E Vigoda, SV Yi, Heterogeneous genomic molecular clocks in primates. PLoS Genet 2, e163 (2006).
22
F Eckhardt, et al., DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38, 1378–1385 (2006).
23
JL Weber, et al., Human diallelic insertion/deletion polymorphisms. Am J Hum Genet 71, 854–862 (2002).
24
TR Bhangale, MJ Rieder, RJ Livingston, DA Nickerson, Comprehensive identification and characterization of diallelic insertion-deletion polymorphisms in 330 human candidate genes. Hum Mol Genet 14, 59–69 (2005).
25
C Haag-Liautard, et al., Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007).
26
DR Denver, K Morris, M Lynch, WK Thomas, High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature 430, 679–682 (2004).
27
M Lynch, The cellular, developmental and population-genetic determinants of mutation-rate evolution. Genetics 180, 933–943 (2008).
28
JB Drost, WR Lee, Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among Drosophila, mouse, and human. Environ Mol Mut 26, 48–64 (1995).
29
AS Wilkins Genetic Analysis of Animal Development (Wiley-Liss, 2nd Ed, New York, 1992).
30
PD Hoffman, JM Leonard, GE Lindberg, SR Bollmann, JB Hays, Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defective Arabidopsis. Genes Dev 18, 2676–2685 (2004).
31
, Annex Table 2: Deaths by cause, sex and mortality stratum in WHO regions, estimates for 2002. The World Health Report 2004 – changing history (WHO, Geneva, 2004).
32
HW Hethcote, AG Knudson, Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci USA 75, 2453–2457 (1978).
33
PH Fitzgerald, J Stewart, RD Suckling, Retinoblastoma mutation rate in New Zealand and support for the two-hit model. Hum Genet 64, 128–130 (1983).
34
JA Morris, Spontaneous mutation rate in retinoblastoma. J Clin Pathol 43, 496–498 (1990).
35
RA Lloyd, DG Papworth, Retinoblastoma: a model for deriving the mutation rate without using any estimate of the size of the population at risk. Mutat Res 326, 117–124 (1995).
36
T Iwama, Somatic mutation rate of the APC gene. Jpn J Clin Oncol 31, 185–187 (2001).
37
EG Luebeck, SH Moolgavkar, Multistage carcinogenesis and the incidence of colorectal cancer. Proc Natl Acad Sci USA 99, 15095–15100 (2002).
38
C Hornsby, KM Page, I Tomlinson, The in vivo rate of somatic adenomatous polyposis coli mutation. Am J Pathol 172, 1062–1068 (2008).
39
EG Lichtenauer-Kaligis, et al., Comparison of spontaneous hprt mutation spectra at the nucleotide sequence level in the endogenous hprt gene and five other genomic positions. Mutat Res 351, 147–155 (1996).
40
DJ Araten, et al., A quantitative measurement of the human somatic mutation rate. Cancer Res 65, 8111–8117 (2005).
41
NP Bhattacharyya, et al., Molecular analysis of mutations in mutator colorectal carcinoma cell lines. Hum Mol Genet 4, 2057–2064 (1995).
42
WE Glaab, KR Tindall, Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. Carcinogenesis 18, 1–8 (1997).
43
A Umar, et al., Functional overlap in mismatch repair by human MSH3 and MSH6. Genetics 148, 1637–1646 (1998).
44
MJ Dycaico, et al., The use of shuttle vectors for mutation analysis in transgenic mice and rats. Mutat Res 307, 461–478 (1994).
45
CA Walter, GW Intano, JR McCarrey, CA McMahan, RB Walter, Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci USA 95, 10015–10019 (1998).
46
KA Hill, et al., Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice. Environ Mol Mutagen 45, 442–454 (2005).
47
S Jones, et al., Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
48
K Jabbari, G Bernardi, Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. Gene 333, 143–149 (2004).
49
HJ Muller, Our load of mutations. Am J Hum Genet 2, 111–176 (1950).
50
AS Kondrashov, Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over? J Theor Biol 175, 583–594 (1995).
51
M Lynch, et al., Spontaneous deleterious mutation. Evolution 53, 645–663 (1999).
52
R Woods, The measurement of historical trends in fetal mortality in England and Wales. Popul Stud 59, 147–162 (2005).
53
MJ Horner, et al. SEER Cancer Statistics Review, 1975-2006 (Natl Cancer Inst, Bethesda, MD, 2009).
54
M Lynch, JB Walsh Genetics and Analysis of Quantitative Traits (Sinauer Assoc, Sunderland, MA, 1998).
55
LY Yampolsky, FA Kondrashov, AS Kondrashov, Distribution of the strength of selection against amino acid replacements in human proteins. Hum Mol Genet 14, 3191–3201 (2005).
56
A Eyre-Walker, M Woolfit, T Phelps, The distribution of fitness effects of new deleterious amino acid mutations in humans. Genetics 173, 891–900 (2006).
57
L Eöry, DL Halligan, PD Keightley, Distributions of selectively constrained sites and deleterious mutation rates in the hominid and murid genomes. Mol Biol Evol, in press. (2009).
58
DQ Nguyen, et al., Reduced purifying selection prevails over positive selection in human copy number variant evolution. Genome Res 18, 1711–1723 (2008).
59
KD Makova, W-H Li, Strong male-driven evolution of DNA sequences in humans and apes. Nature 416, 624–626 (2002).

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Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 107 | No. 3
January 19, 2010
PubMed: 20080596

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Submission history

Published online: January 4, 2010
Published in issue: January 19, 2010

Keywords

  1. base substitutions
  2. human genetic disorders
  3. introns
  4. mutation rate
  5. mutational spectrum

Acknowledgments

The author thanks M. Ackerman, C. Baer, J. Drake, A. Kondrashov, and S. Yi for helpful comments, and M. Ackerman for assistance in some key computations. This work was funded by National Institutes of Health Grant GM36827, National Science Foundation Grant EF-0827411, and the MetaCyte program derived from Lilly Foundation funding to Indiana University.

Authors

Affiliations

Michael Lynch1 [email protected]
Department of Biology, Indiana University, Bloomington, IN 47405

Notes

Author contributions: M.L. designed research; performed research; analyzed data; and wrote the paper.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.

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    Rate, molecular spectrum, and consequences of human mutation
    Proceedings of the National Academy of Sciences
    • Vol. 107
    • No. 3
    • pp. 949-1254

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