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PubMed1996

The Genetic Variance Maintained by Pleiotropic Mutation

The equilibrium genetic variance of a quantitative trait under mutation-selection balance is analysed using a population genetic model. I assume that mutations have both phenotypic effects on a quantitative trait and deleterious effects on fitness itself. Hence, genetic variance is generated by pleiotropic effects of such deleterious mutations. If the deleterious effect is large, the predicted genetic variance is notably smaller than the equilibrium genetic variance predicted by the mutation-selection balance model with the rare-alleles approximation. The model further suggests that the ratio of the equilibrium genetic variance to the variance of allelic effects of new mutations is proportional to the ratio of total mutation load to the net selection coefficient on new mutations. It is also suggested that the net selection coefficient is equal to the per-generation proportional increment of genetic variance by new mutations.

Journal Article↗

PubMed2001

Somatic mutations in organisms with complex life histories.

A theoretical model is developed of the fate of mutations for organisms with such life-history characteristics as indeterminate growth and clonal reproduction. It focuses on how the fate of a particular mutant depends on whether it arises during mitotic cell division (somatic mutation) or during meiotic cell division (meiotic mutation). At gamete production, individuals carrying somatic mutations will produce some proportion of gametes reflecting the original, zygotic genotype and some proportion reflecting genotypes carrying the somatic mutation. Focusing on allele frequencies at gamete production allows the effects of growth and clonal reproduction to be summarized. The relative strengths of somatic and meiotic mutation can be determined, as well as the conditions under which the change in allele frequency due to one is greater than that due to the other. Examples from a published demographic study of clonal corals are used to compare somatic and meiotic mutation. When there is no selection acting on either type of mutation, only a few cell divisions per time unit on average are needed for the change in allele frequency due to somatic mutation to be greater, given empirically based mutation rates. When somatic selection is added, the most dramatic effect is seen with fairly strong negative selection acting against the somatic mutation within individuals. In this case, selection within organisms can effectively counteract the effects of somatic mutation, and the change in allele frequency due to somatic mutations will not be greater than that due to meiotic mutations for reasonable numbers of within-generation cell divisions. The majority of the mutation load, which would have been due to somatic mutation, is purged by selection within the individual organism.

Animals↗

PubMed2001

Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment.

The p53 tumor suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence, and apoptosis. Mutations in the p53 gene can abrogate these functions and may lead to genetic instability and progress to cancer. The molecular archeology of the p53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of cancer. The spectrum of somatic mutations in the p53 gene implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic p53 mutation also can manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. aflatoxin B1 (AFB1) exposure and codon 249ser mutations in hepatocellular carcinoma, ultraviolet (UV) exposure and CC to TT tandem mutations in skin cancer, and cigarette smoke and the prevalence of G to T transversions in lung cancer. Although several different exogenous carcinogens have been shown to selectively target p53, evidence supporting the endogenous insult of p53 from oxyradical and nitrogen-oxyradicals is accumulating. p53 mutations can be a biomarker of carcinogen effect. Determining the characteristic p53 mutation load in nontumorous tissue, with a highly sensitive mutation assay, can indicate a specific carcinogen exposure and also may help in identifying individuals at an increased risk of cancer.

Carcinogens↗

PubMed2004

Homogeneous polymerase chain reaction nucleobase quenching assay to detect the 1-kbp deletion in CLN3 that causes Batten disease.

Batten disease is an autosomal recessive disorder also known as juvenile neuronal ceroid lipofuscinosis. The most common mutation for this disease is an approximately 1-kbp deletion in the CLN3 gene, which accounts for about 80 to 85% of the mutation load. We developed a rapid assay for this mutation using the PCR to produce amplicons that are detected by nucleobase quenching of the fluorescent signal from a probe labeled with a fluorescent dye. The probe overlaps the deletion breakpoint and is completely base paired to the mutant amplicon. However, three bases at the 5' end of the probe do not base pair with the wild-type amplicon. The alleles are distinguished by the different melting temperatures of the probe amplicon hybrids. Comparison of this new method with an allele-specific PCR and gel electrophoresis-based method showed 100% concordance in determination of the genotype for 30 specimens (11 homozygous mutant, 8 heterozygotes, and 11 homozygous normal). PCR followed by allele-specific melting curve analysis using nucleobase quenching has utility as a rapid method for detection of the most common mutation that causes Batten disease.

Female↗

PubMed2001

Mutation-selection models solved exactly with methods of statistical mechanics.

We reconsider deterministic models of mutation and selection acting on populations of sequences, or, equivalently, multilocus systems with complete linkage. Exact analytical results concerning such systems are few, and we present recent and new ones obtained with the help of methods from quantum statistical mechanics. We consider a continuous-time model for an infinite population of haploids (or diploids without dominance), with N sites each, two states per site, symmetric mutation and arbitrary fitness function. We show that this model is exactly equivalent to a so-called Ising quantum chain. In this picture, fitness corresponds to the interaction energy of spins, and mutation to a temperature-like parameter. The highly elaborate methods of statistical mechanics allow one to find exact solutions for non-trivial examples. These include quadratic fitness functions, as well as 'Onsager's landscape'. The latter is a fitness function which captures some essential features of molecular evolution, such as neutrality, compensatory mutations and flat ridges. We investigate the mean number of mutations, the mutation load, and the variance in fitness under mutation-selection balance. This also yields some insight into the 'error threshold' phenomenon, which occurs in some, but not all, examples.

Evolution, Molecular↗

PubMed1999

Dynamics of inbreeding depression due to deleterious mutations in small populations: mutation parameters and inbreeding rate.

A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.

Animals↗

PubMed1995

Contamination of the genome by very slightly deleterious mutations: why have we not died 100 times over?

It is well known that when s, the selection coefficient against a deleterious mutation, is below approximately 1/4Ne, where Ne is the effective population size, the expected frequency of this mutation is approximately 0.5, if forward and backward mutation rates are similar. Thus, if the genome size, G, in nucleotides substantially exceeds the Ne of the whole species, there is a dangerous range of selection coefficients, 1/G < s < 1/4Ne. Mutations with s within this range are neutral enough to accumulate almost freely, but are still deleterious enough to make an impact at the level of the whole genome. In many vertebrates Ne approximately 10(4), while G approximately 10(9), so that the dangerous range includes more than four orders of magnitude. If substitutions at 10% of all nucleotide sites have selection coefficients within this range with the mean 10(-6), an average individual carries approximately 100 lethal equivalents. Some data suggest that a substantial fraction of nucleotides typical to a species may, indeed, be suboptimal. When selection acts on different mutations independently, this implies too high a mutation load. This paradox cannot be resolved by invoking beneficial mutations or environmental fluctuations. Several possible resolutions are considered, including soft selection and synergistic epistasis among very slightly deleterious mutations.

Animals↗

PubMed2004

Pyrophosphorolysis by Type II DNA polymerases: implications for pyrophosphorolysis-activated polymerization.

We find that Type II DNA polymerases can catalyze pyrophosphorolysis, the reverse reaction of DNA polymerization. This property is applied utilizing pyrophosphorolysis-activated polymerization (PAP), a method of nucleic acid amplification using serial coupling of pyrophosphorolysis and polymerization. PAP can be used for ultrarare allele detection (detection of minimal residual disease and cancer risk assessment through measurement of mutation load) and for microarray-based scanning for unknown mutations. Herein, we show that Type II DNA polymerases efficiently catalyze template-dependent pyrophosphorolysis to activate oligonucleotides blocked at their 3' termini with acyclonucleotides in which a 2-hydroxyethoxymethyl group substitutes for the 2'-deoxyribofuranosyl sugar. Type II archeon DNA polymerases Vent (exo-) and Pfu (exo-) can be utilized for PAP or a bidirectional form of PAP with acyclonucleotide-blocked oligonucleotides, but not with dideoxynucleotide-blocked oligonucleotides. In contrast, a Type I DNA polymerase, TaqFS, can utilize either acyclonucleotide-blocked or dideoxynucleotide-blocked oligonucleotides. These findings expand the potential of nascent PAP technology.

Alleles↗

PubMed1988

Evolution of bacterial transformation: is sex with dead cells ever better than no sex at all?

Computer simulations of bacterial transformation are used to show that, under a wide range of biologically reasonable assumptions, transforming populations undergoing deleterious mutation and selection have a higher mean fitness at equilibrium than asexual populations. The source of transforming DNA, the amount of DNA taken up by each transforming cell, and the relationship between number of mutations and cell viability (the fitness function) are important factors. When the DNA source is living cells, transformation resembles meiotic sex. When the DNA source is cells killed by selection against mutations, transformation increases the average number of mutations per genome but can nevertheless increase the mean fitness of the population at equilibrium. In a model of regulated transformation, in which the most fit cells of a transforming population do not transform, transforming populations are always fitter at equilibrium than asexual populations. These results show that transformation can reduce mutation load.

Models, Biological↗

PubMed2003

Numerical and exact solutions for continuum of alleles models.

Two results are presented for problems involving alleles with a continuous range of effects. The first result is a simple yet highly accurate numerical method that determines the equilibrium distribution of allelic effects, moments of this distribution, and the mutational load. The numerical method is explicitly applied to the mutation-selection balance problem of stabilising selection. The second result is an exact solution for the distribution of allelic effects under weak stabilising selection for a particular distribution of mutant effects. The exact solution is shown to yield a distribution of allelic effects that, depending on the mutation rate, interpolates between the "House of Cards" approximation and the Gaussian approximation. The exact solution is also used to test the accuracy of the numerical method.

Alleles↗

PubMedDate not supplied

Classification of hypotheses on the advantage of amphimixis.

A classification of hypotheses on the advantage of amphimixis over apomixis is presented. According to "Immediate Benefit" hypotheses, amphimixis is advantageous regardless of reciprocal gene exchange, because either it directly increases fitness of the progeny, reduces the deleterious mutation rate, or makes selection more efficient. In contrast, "Variation and Selection" hypotheses attribute the advantage of amphimixis to the reciprocal gene exchange that alters genetic variability and response to selection among the progeny. Most such hypotheses assume that amphimixis increases variability and efficiency of selection, but some claim that amphimixis decreases response to selection. Variation and Selection hypotheses require that some factor, either random drift or epistatic selection, makes distributions of different alleles nonindependent, while another factor, either changes of the genotype fitnesses or deleterious mutations, makes overrepresented genotypes non-optimal. Numerous Variation and Selection hypotheses, dealing with either unstructured or spatially structured populations, are reviewed. Two of them seem most plausible: better responsiveness of the amphimictic population to widely fluctuating selection, and lower mutation load in the amphimictic population under synergistic selection against deleterious mutations. In both cases the large advantage of amphimixis requires rather stringent conditions, which could be falsified by careful experiment. Further progress in understanding the evolution of amphimixis will depend mostly on such experimental work.

Environment↗

PubMed2006

Negative environmental perturbations may improve species persistence.

Among the factors proximally involved in the extinction of small isolated populations, genetic deterioration and temporal variation in environmental quality have been the subjects of intensive research in ecological and evolutionary sciences. However, previous theoretical studies and population viability assessments generally assumed a strict dichotomy between these two types of threat. Yet a number of empirical studies have recently suggested that the effects of genetic deterioration and environmental variation should not be considered independently, by demonstrating that the main effect of inbreeding depression lies with its tendency to exacerbate the deleterious consequences of environmental stress. Capitalizing on these results, I developed a stochastic model to examine the impact of random environmental perturbations on the persistence time of small isolated populations subject to inbreeding depression and mutation accumulation. The model assumes that spontaneous deleterious mutations have more severe effects when perturbations occur, which results in more efficient purging of the mutation load. Under this assumption, I find that negative perturbations may paradoxically improve middle- and long-term species persistence for realistic frequency of occurrence and severity distribution.

Animals↗

PubMed2003

Patterns of inbreeding depression and architecture of the load in subdivided populations.

Inbreeding depression is a general phenomenon that is due mainly to recessive deleterious mutations, the so-called mutation load. It has been much studied theoretically. However, until very recently, population structure has not been taken into account, even though it can be an important factor in the evolution of populations. Population subdivision modifies the dynamics of deleterious mutations because the outcome of selection depends on processes both within populations (selection and drift) and between populations (migration). Here, we present a general model that permits us to gain insight into patterns of inbreeding depression, heterosis, and the load in subdivided populations. We show that they can be interpreted with reference to single-population theory, using an appropriate local effective population size that integrates the effects of drift, selection, and migration. We term this the "effective population size of selection" (NS(e)). For the infinite island model, for example, it is equal to NS(e) = N1 + m/hs, where N is the local population size, m the migration rate, and h and s the dominance and selection coefficients of deleterious mutation. Our results have implications for the estimation and interpretation of inbreeding depression in subdivided populations, especially regarding conservation issues. We also discuss the possible effects of migration and subdivision on the evolution of mating systems.

Animals↗

PubMed1999

An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy.

A novel heteroplasmic 7587T-->C mutation in the mitochondrial genome which changes the initiation codon of the gene encoding cytochrome c oxidase subunit II (COX II), was found in a family with mitochondrial disease. This T-->C transition is predicted to change the initiating methionine to threonine. The mutation load was present at 67% in muscle from the index case and at 91% in muscle from the patient's clinically affected son. Muscle biopsy samples revealed isolated COX deficiency and mitochondrial proliferation. Single-muscle-fiber analysis revealed that the 7587C copy was at much higher load in COX-negative fibers than in COX-positive fibers. After microphotometric enzyme analysis, the mutation was shown to cause a decrease in COX activity when the mutant load was >55%-65%. In fibroblasts from one family member, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II. This new mutation constitutes a new mechanism by which mtDNA mutations can cause disease-defective initiation of translation.

Adult↗

PubMed1999

Mutational analysis of loading of iron into rat liver ferritin by ceruloplasmin.

Site-directed mutagenesis was used to investigate the loading of iron into rat liver ferritin by ceruloplasmin. Changes were made in the H chain to investigate the role of tyrosines involved in an inherent ferroxidase activity thought to be involved in the self-loading of iron into ferritin. Mutation Y34F affected the rate of iron loading by ceruloplasmin and incorporation of the oxidized iron into the core. Mutation Y29R (making it analogous to the L chain) had no effect on iron oxidation but slightly decreased core formation. A double mutation in the L chain, to open the alpha-helix bundle channel, and R25Y, making the protein more analogous to the H chain, increased the amount of iron incorporated into the core, again suggesting that this Tyr is involved in ligand exchange for core formation. Additional changes in the L chain involving the BC loop suggest that the entire BC loop is involved in the association of ferritin with ceruloplasmin, increasing its ferroxidase activity and the rate of iron loading into ferritin.

Amino Acid Sequence↗

PubMed2002

Diet activity, and lifestyle associations with p53 mutations in colon tumors.

Inactivation of the p53 tumor suppressor gene is a common event in the development of colon cancer. We use data collected as part of a multicenter case-control study of colon cancer to evaluate associations between p53 mutations and diet and lifestyle factors. p53 mutational status was determined for 1458 incident cases of colon cancer using single-strand conformational polymorphism/sequencing of exons 5-8. We determined associations among those with and without mutations compared with population-based controls (N = 2410) and to cases with p53 mutations compared with cases without p53 mutations. Associations also were examined by location and function of specific types of p53 mutations. p53 mutations were identified in tumors in 47.1% of cases; 81.9% of people with mutations had a missense mutation. Cases with a p53 mutation were more likely to consume a Western-style diet, compared with controls [odds ratio (OR), 2.03; 95% confidence interval (CI), 1.53-2.69], than were cases who were p53 wild type (Wt), compared with controls (OR, 1.57;95% CI, 1.20-2.06). Specific components of the Western-style diet, including diets with a high glycemic load (mutation versus control: OR, 1.48; 95% CI, 1.11-1.98 and Wt versus control: OR, 0.98; 95% CI, 0.75-1.28) and diets high in red meat, fast food, and trans-fatty acid (mutation versus control: OR, 1.92; 95% CI, 1.47-2.50 and Wt versus control: OR, 1.39; 95% CI, 1.08-1.80) appeared to be most strongly associated with p53 mutations. Diets with a high glycemic load (relative to lowest intake) were significantly associated with missense mutations (OR, 1.69; 95% CI, 1.23-2.33 comparing p53+ to controls and OR, 1.72; 95% CI, 1.19-2.50 comparing cases p53+ to cases p53 Wt), as were diets high in red meat, fast food, and trans-fatty acids (OR, 1.92; 95% CI, 1.14-2.56 comparing p53+ to controls and OR, 1.40; 95% CI, 1.00-1.98 comparing cases p53+ to cases p53 Wt). Physical inactivity, large body mass index, cigarette smoking, using aspirin/nonsteroidal anti-inflammatory drugs, and other dietary factors appeared to be comparably associated with colon cancer in those with and without p53 mutations. These data suggest that components of a Western-style diet such as high consumption of red meat and foods that increase glycemic load are associated with a p53 disease pathway.

Adult↗

PubMed1994

Advantages of sexual reproduction.

Despite the obvious efficiencies of many forms of asexual reproduction, sexual reproduction abounds. Asexual species, for the most part, are relatively short-lived offshoots of sexual ancestors. From the nineteenth century, it has been recognized that, since there is no obvious advantage to the individuals involved, the advantages of sexual reproduction must be evolutionary. Furthermore, the advantage must be substantial; for example, producing males entails a two-fold cost, compared to dispensing with them and reproducing by parthenogenetic females. There are a large number of plausible hypotheses. To me the most convincing of these are two. The first hypothesis, and the oldest, is that sexual reproduction offers the opportunity to produce recombinant types that can make the population better able to keep up with changes in the environment. Although the subject of a great deal of work, and despite its great plausibility, the hypothesis has been very difficult to test by critical observations or experiments. Second, species with recombination can bunch harmful mutations together and eliminate several in a single "genetic death." Asexual species, can eliminate them only in the same genotype in which they occurred. If the rate of occurrence of deleterious mutations is one or more per zygote, some mechanism for eliminating them efficiently must exist. A test of this mutation load hypothesis for sexual reproduction, then, is to find whether deleterious mutation rates in general are this high--as Drosophila data argue. Unfortunately, although molecular and evolutionary studies can give information on the total mutation rate, they cannot determine what fraction are deleterious. In addition, there are short discussions of the advantages of diploidy, anisogamy, and separate sexes.

Adaptation, Physiological↗

PubMed2005

Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing.

Disease-causing mutations in mitochondrial DNA (mtDNA) are typically heteroplasmic and therefore interpretation of genetic tests for mitochondrial disorders can be problematic. Detection of low level heteroplasmy is technically demanding and it is often difficult to discriminate between the absence of a mutation or the failure of a technique to detect the mutation in a particular tissue. The reliable measurement of heteroplasmy in different tissues may help identify individuals who are at risk of developing specific complications and allow improved prognostic advice for patients and family members. We have evaluated Pyrosequencing technology for the detection and estimation of heteroplasmy for six mitochondrial point mutations associated with the following diseases: Leber's hereditary optical neuropathy (LHON), G3460A, G11778A, and T14484C; mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), A3243G; myoclonus epilepsy with ragged red fibers (MERRF), A8344G, and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)/Leighs: T8993G/C. Results obtained from the Pyrosequencing assays for 50 patients with presumptive mitochondrial disease were compared to those obtained using the commonly used diagnostic technique of polymerase chain reaction (PCR) and restriction enzyme digestion. The Pyrosequencing assays provided accurate genotyping and quantitative determination of mutational load with a sensitivity and specificity of 100%. The MELAS A3243G mutation was detected reliably at a level of 1% heteroplasmy. We conclude that Pyrosequencing is a rapid and robust method for detecting heteroplasmic mitochondrial point mutations.

Base Sequence↗