How much do we know about spontaneous human mutation rates?

Crow, James F.

doi:10.1002/em.2850210205

Cited by 136 publications

(70 citation statements)

References 21 publications

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“…This simple relationship has been used several times to estimate the spontaneous rate of mutation (Crow 1993;Drake et al 1998;Nachman & Crowell 2000;Kumar & Subramanian 2002;Silva & Kondrashov 2002;Mitchell & Graur 2005), with varying degrees of success. In particular, it has been suggested that contrasting the rate of evolution of neutral sequences with that of sequences under selection can be used to estimate the rate of deleterious mutation (Kondrashov & Crow 1993 Cutter & Payseur 2003), yet the accuracy of the underlying rate of spontaneous mutations in these estimates has been questioned, most notably on account of the usage of synonymous sites as neutral markers (Kondrashov 2001).…”

Section: Methods For Determining Mutation Ratesmentioning

confidence: 99%

Measurements of spontaneous rates of mutations in the recent past and the near future

Kondrashov

2010

Phil. Trans. R. Soc. B

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The rate of spontaneous mutation in natural populations is a fundamental parameter for many evolutionary phenomena. Because the rate of mutation is generally low, most of what is currently known about mutation has been obtained through indirect, complex and imprecise methodological approaches. However, in the past few years genome-wide sequencing of closely related individuals has made it possible to estimate the rates of mutation directly at the level of the DNA, avoiding most of the problems associated with using indirect methods. Here, we review the methods used in the past with an emphasis on next generation sequencing, which may soon make the accurate measurement of spontaneous mutation rates a matter of routine.

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Section: Methods For Determining Mutation Ratesmentioning

confidence: 99%

Measurements of spontaneous rates of mutations in the recent past and the near future

Kondrashov

2010

Phil. Trans. R. Soc. B

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“…It is generally believed that mutation rates are much higher in males than in females because of the many more cell divisions in spermatogenesis than in oogenesis (Crow, 1993). Indeed, Weber and Wong (1993) observed a bias towards paternal mutation events in their study on human STRPs, and a strong tendency for mutations to occur in male germlines was found in a number of VNTRs (eg, Vergnaud et al, 1991).…”

Section: Mutation Ratementioning

confidence: 99%

Multiple paternity and female-biased mutation at a microsatellite locus in the olive ridley sea turtle (Lepidochelys olivacea)

et al. 2002

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Multiple paternity in the olive ridley sea turtle (Lepidochelys olivacea) population nesting in Suriname was demonstrated using two microsatellite loci, viz., Ei8 and Cm84. The large number of offspring sampled per clutch (70 on average, ranging from 15 to 103) and the number of alleles found at the two loci (18 and eight alleles, respectively) enabled unambiguous assessment of the occurrence of multiple paternity. In two out of 10 clutches analysed, the offspring had been sired by at least two males, which was confirmed at both loci. In both clutches, unequal paternity occurred: 73% and 92% of the offspring had been sired by the primary male. The probability of detecting multiple paternity was 0.903, and therefore there is a small chance that multiple

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“…base substitutions | human genetic disorders | introns | mutation rate | mutational spectrum D espite its central significance to matters of health and phenotypic evolution, many uncertainties still remain about the rate and spectrum of mutations spontaneously arising in the human genome (1)(2)(3). How frequently do germline and somatic mutations arise, and to what extent does this vary between the sexes?…”

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confidence: 99%

Rate, molecular spectrum, and consequences of human mutation

Lynch

2010

Proc. Natl. Acad. Sci. U.S.A.

711

603

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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 splicesite 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.base substitutions | human genetic disorders | introns | mutation rate | mutational spectrum D espite its central significance to matters of health and phenotypic evolution, many uncertainties still remain about the rate and spectrum of mutations spontaneously arising in the human genome (1-3). How frequently do germline and somatic mutations arise, and to what extent does this vary between the sexes? What is the relative incidence of various forms of mutations, e.g., missense and nonsense base substitutions, insertions, duplications, and deletions, especially among alterations having major phenotypic effects? How does the mutational spectrum in humans compare with that in other species? And most importantly, what are the consequences of mutation for the long-term genetic well-being of our species?In the near future, it should be possible to provide refined answers to these and many more questions by sequencing the complete genomes of well defined pedigrees and somatic tissues (4, 5). However, it is already possible to achieve a relatively complete picture of the point-mutation process from databases on mutations at loci known to underlie monogenic disorders with major phenotypic effects. In the case of autosomal-dominant and X-linked disorders, affected individuals can generally be identified as de novo mutants by comparison with the parental phenotypes, thereby providing a nearly unbiased view of the rate and spectrum of locus-specific mutations, similar to what has been achieved ...

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How much do we know about spontaneous human mutation rates?

Cited by 136 publications

References 21 publications

Measurements of spontaneous rates of mutations in the recent past and the near future

Measurements of spontaneous rates of mutations in the recent past and the near future

Multiple paternity and female-biased mutation at a microsatellite locus in the olive ridley sea turtle (Lepidochelys olivacea)

Rate, molecular spectrum, and consequences of human mutation

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