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PubMed2002

The mathematical basis of sexual attraction.

Computer programs have been written to study the dynamic interaction in humans between environmental mutagenesis, the genomic load of deleterious mutations and the probability of zygote survival. The human genome is complex and highly redundant and as a consequence deleterious mutations accumulate. The computer programs are based on a model of the human genome in which deleterious mutations interact synergistically causing impaired performance in individual systems and this leads to a positive correlation between the total number of deleterious mutations in the genome and impaired performance across the whole spectrum of biological capability. This includes performance in intellectual tasks, sporting ability, the ability to fight disease and preserve health and the development of a symmetrical physical form. Sexual reproduction distributes deleterious mutations unequally amongst zygotes and the model predicts that zygote survival will correlate negatively with zygote mutational load. The computer simulation shows that rising environmental mutagenesis will lead to a rise in the human genomic mutational load and to decreased zygote survival, although the full effect would take several generations. If this occurred the health of future generations would suffer and methods to monitor environmental mutagenesis are required. The model also shows that a marked rise in environmental mutagenesis would lead to species extinction if mate choice were random, i.e., unrelated to the genomic mutational load. The biological imperfections caused by mutations, however, in health, intelligence and physical symmetry are all, to varying degrees, related to sexual attraction. The model shows that if mates are chosen in response to sexual attraction the species can be maintained in the presence of high environmental mutagenesis. A polygamous pattern in which females mate with a minority of males has the most marked effect in reducing the number of deleterious mutations in the next generation. The model also shows that as environmental mutagenesis falls the number of eligible males would increase and a species would change from a polygamous to a monogamous pattern of mating. These results imply that we are not attracted by good genes, but by a lack of bad genes. Sexual attraction is a force which counteracts genomic degradation.

Female↗

PubMed2006

Quantitative detection of p53 mutations in plasma DNA from tobacco smokers.

In lung tumors, the p53 tumor suppressor gene is commonly mutated with a characteristic mutation spectrum. The amount of and alterations in plasma DNA, such as mutations in p53, were associated with several cancers. Few studies used quantitative methods of high sensitivity. Previously, we observed p53 mutations in the noncancerous tissue that differed from those in lung tumors using the highly sensitive p53 mutation load assay. Based on our observation of an increased p53 mutation load in nontumorous lung tissue in smokers, we hypothesized that plasma DNA may contain mutant p53 indicative of tobacco smoke exposure and will be an effective biomarker of lung cancer or smoking exposure. We modified the p53 mutation load assay to detect mutations at p53 codons 248 and 249, common mutations in lung cancer, in plasma DNA samples with a sensitivity of 1:5,000. The assay was applied to a set of lung cancer cases (n = 39), hospital controls (n = 21), and population controls (n = 20) from a larger study. Controls were selected to consist of equal numbers of both ever and never smokers. The p53 mutation load (mutated p53 copies per total number of p53 copies) was associated with smoking (P = 0.06), but not with lung cancer (P = 0.59). Most of the individuals with p53 mutations observed in plasma DNA were ever smokers and the p53 mutation load was higher in those who smoked for longer durations (P = 0.04). In summary, we were able to detect p53 mutations in plasma DNA from healthy individuals and our data suggest that p53 mutations in plasma DNA may be a marker of carcinogen exposure from tobacco smoke.

Baltimore↗

PubMed2026

Large-scale simulation of coverage and error rate tradeoffs for cancer detection in cell-free DNA whole-genome sequencing.

MOTIVATION: Cell-free DNA (cfDNA) whole-genome sequencing (WGS) is a promising approach for detecting cancer recurrence. It enables cancer detection by identifying all tumor-derived cfDNA (ctDNA) molecules carrying somatic single nucleotide variants (sSNVs). While ideally, a sequencing platform should be highly accurate for reliable ctDNA detection, in reality, all sequencing platforms introduce sequencing errors that generate false positives indistinguishable from true SNVs. Understanding how sequencing parameters influence ctDNA detection sensitivity at low tumor fractions (TFs) in cfDNA samples is essential for guiding sequencing strategies in clinical contexts. To model cfDNA sequencing for tumor detection, which contains asymmetric noise and multiple interacting parameters, analytical modeling is intractable, motivating large-scale parallelized simulation. RESULTS: We developed a simulation framework to generate in silico cfDNA data across 10 cancer types. In total, 480 million cfDNA samples were simulated from tumor WGS profiles. Overall, the lowest detectable TF differs substantially between cancer types under identical sequencing conditions due to variations in mutational load. For cancers with high mutational load, 3× coverage with low-error techniques reliably detects TFs below 0.1%. In contrast, cancers with low mutational load require at least six-fold higher coverage to achieve comparable detection thresholds. Increasing sequencing quality scores from Q30 to Q55 at 30× coverage further enhances sensitivity, enabling detection of TFs as low as 1 × 10-5. This study provides a comprehensive framework for optimizing sequencing parameters, offering valuable guidance for tailoring future technology development for specific cancer types and clinical applications. AVAILABILITY AND IMPLEMENTATION: The code is publicly available at https://github.com/UMCUGenetics/cfdetect/tree/main.

Whole Genome Sequencing↗

PubMed1988

Evolution of sex in RNA viruses.

The distribution of deleterious mutations in a population of organisms is determined by the opposing effects of two forces, mutation pressure and selection. If mutation rates are high, the resulting mutation-selection balance can generate a substantial mutational load in the population. Sex can be advantageous to organisms experiencing high mutation rates because it can either buffer the mutation-selection balance from genetic drift, thus preventing any increases in the mutational load (Muller, 1964: Mut. Res. 1, 2), or decrease the mutational load by increasing the efficiency of selection (Crow, 1970: Biomathematics 1, 128). Muller's hypothesis assumes that deleterious mutations act independently, whereas Crow's hypothesis assumes that deleterious mutations interact synergistically, i.e., the acquisition of a deleterious mutation is proportionately more harmful to a genome with many mutations than it is to a genome with a few mutations. RNA viruses provide a test for these two hypotheses because they have extremely high mutation rates and appear to have evolved specific adaptations to reproduce sexually. Population genetic models for RNA viruses show that Muller's and Crow's hypotheses are also possible explanations for why sex is advantageous to these viruses. A re-analysis of published data on RNA viruses that are cultured by undiluted passage suggests that deleterious mutations in such viruses interact synergistically and that sex evolved there as a mechanism to reduce the mutational load.

Models, Genetic↗

PubMedDate not supplied

[The genetic consequences of the radioactive contamination of populations of Arabidopsis thaliana growing in a 30-kilometer area of the accident at the Chernobyl Atomic Electric Power Station].

Annually during six years since 1986 dynamics of the mutation load in Arabidopsis populations was studied. Frequency of the embryonic lethal mutations was studied with Muller embryonic test. First two years after the accident an increase of mutation load in Arabidopsis populations was observed at all levels of radioactive contamination. In the areas with contamination up to 10 mR/h the mutation load decreased to the control level by 1990. In the areas with contamination up to 130 mR/h the mutation load exceeds the control by 4-8 times.

Arabidopsis↗

PubMed2004

The opportunity for canalization and the evolution of genetic networks.

There has been a recent revival of interest in how genetic interactions evolve, spurred on by an increase in our knowledge of genetic interactions at the molecular level. Empirical work on genetic networks has revealed a surprising amount of robustness to perturbations, suggesting that robustness is an evolved feature of genetic networks. Here, we derive a general model for the evolution of canalization that can incorporate any form of perturbation. We establish an upper bound to the strength of selection on canalization that is approximately equal to the fitness load in the system. This method makes it possible to compare different forms of perturbation, including genetic, developmental, and environmental effects. In general, load that arises from mutational processes is low because the mutation rate is itself low. Mutation load can create selection for canalization in a small network that can be achieved through dominance evolution or gene duplication, and in each case selection for canalization is weak at best. In larger genetic networks, selection on genetic canalization can be reasonably strong because larger networks have higher mutational load. Because load induced through migration, segregation, developmental noise, and environmental variance is not mutation limited, each can cause strong selection for canalization.

Evolution, Molecular↗

PubMed2006

Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations.

We retrospectively analyzed the clinical, histological, and biochemical data of 11 children, five of which carried the maternally-inherited mitochondrial T8993C and six carrying the T8993G point mutations in the ATP synthase 6 gene. The percentage of heteroplasmy was 95% or higher in muscle and in blood. All patients had an early clinical presentation with muscle hypotonia, severe extrapyramidal dysfunction and Leigh disease demonstrated by the cranial MRI. A slower clinical progression and more frequent sensory-neuronal involvement were noted in the patients carrying the T8993C mutation in a high mutation load in muscle and blood. No histological abnormality was found. In 9 out of 11 patients a decreased ATP production was detected, and complex V activity was deficient in all children. The activities of the respiratory enzyme complexes II and IV were normal, whereas an associated combined complex I and III deficiency were present in two patients. No obvious difference was found between the biochemical parameters of the two patient groups harboring different mutations in the same gene. No correlation was found between the degree of complex V enzyme deficiency and the severity of the phenotype. We confirmed an impaired assembly/stability of complex V in our patients. This is the first report of decreased activity and impaired assembly/stability of complex V in patients with T8993C mutations measured in muscle tissue.

Adenosine Triphosphate↗

PubMed2003

Somatic hypermutation does not require Rad54 and Rad54B-mediated homologous recombination.

Secondary diversification of immunoglobulin (Ig) genes occurs through somatic hypermutation (SHM) in B cells of the germinal center (GC). The GC reaction is associated with a high frequency of DNA double-strand breaks (DSB) in the hypermutation domain of Ig genes. Homologous recombination (HR) is a prominent DSB repair pathway. Among the proteins involved in HR are the Rad-54 paralogues, Rad54 and Rad54B. To investigate whether Rad54/Rad54B-mediated HR is involved in SHM, we determined the ratio of mutated versus non-mutated Vlambda PCR products from memory (IgM-, IgD-, Vlambda1+) and GC (PNA(high), Vlambda1+) B cells, the mutation load, the mutation frequency, the base exchange pattern and the distribution of somatic mutations along the rearranged Vlambda light chain (VlambdaLC) genes. All these parameters of SHM were unaltered in memory and GC B cells lacking one or both Rad54 paralogues. Thus, our data indicate that Rad54 and Rad54B-mediated HR is not essential for SHM. In addition, the finding that the ablation of RAD51 paralogues causes an increase in SHM argues against a direct involvement of HR in promoting SHM.

Animals↗

PubMed2003

Inbreeding depression in fecundity and inbred line extinction in the bulb mite, Rhizoglyphus robini.

This study investigated the magnitude of inbreeding depression in fecundity, and whether the depression is purged during six generations of sib mating in the bulb mite, Rhizoglyphus robini. The progeny resulting from a single generation of brother-sister mating suffered significant inbreeding depression in fecundity. During the following six generations of continuous sib-mating, 58% lines were lost, 45% because of sterility and 13% because of preadult mortality. The lines were then outcrossed, and their inbreeding depression compared with that of the base population. The inbreeding depression for the outcrossed population was 0.15, and for the base population 0.19, but the difference was not significant. The lack of significant purging of inbreeding depression indicates that it was caused either by detrimental genes of small effect, or by the breaking down of overdominant relations between alleles. However, the large proportion of extinct lines points to the former mechanism as a predominant cause of inbreeding depression. Theory predicts that the probability of line extinction with inbreeding increases with its load of mutations. If phenotypic variation in fecundity was partly because of differences in numbers of mutations carried by individuals, the fecundity of the line founder could be expected to correlate with the probability that the line derived from it will survive long-term inbreeding. Indeed, fecundity of founder females was significantly associated with line survival, which suggests that line extinction rate may be used as a method to study individual mutational loads, for example, in studies of sexual selection.

Animals↗

PubMed2005

The transmission of OXPHOS disease and methods to prevent this.

Diseases owing to defects of oxidative phosphorylation (OXPHOS) affect approximately 1 in 8,000 individuals. Clinical manifestations can be extremely variable and range from single-affected tissues to multisystemic syndromes. In general, tissues with a high energy demand, like brain, heart and muscle, are affected. The OXPHOS system is under dual genetic control, and mutations in both nuclear and mitochondrial genes can cause OXPHOS diseases. The expression and segregation of mitochondrial DNA (mtDNA) mutations is different from nuclear gene defects. The mtDNA mutations can be either homoplasmic or heteroplasmic and in the latter case disease becomes manifest when the mutation exceeds a tissue-specific threshold. This mutation load can vary between tissues and often an exact correlation between mutation load and phenotypic expression is lacking. The transmission of mtDNA mutations is exclusively maternal, but the mutation load between embryos can vary tremendously because of a segregational bottleneck. Diseases by nuclear gene mutations show a normal Mendelian inheritance pattern and often have a more constant clinical manifestation. Given the prevalence and severity of OXPHOS disorders and the lack of adequate therapy, existing and new methods for the prevention of transmission of OXPHOS disorders, like prenatal diagnosis (PND), preimplantation genetic diagnosis (PGD), cytoplasmic transfer (CT) and nuclear transfer (NT), are technically and ethically evaluated.

Animals↗

PubMed2000

Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals.

The mutation load of the pathogenic LHON (Leber hereditary optic neuropathy) mtDNA mutation at nucleotide 3460 has been followed over time in the WBC/platelet fraction from members of a matrilineal pedigree. Longitudinal analysis over a sampling period of five to six years indicates that, in all five heteroplasmic family members, the mutation load decreases at a mean overall rate of approximately 1% per year. There was no change in mutation load in homoplasmic wildtype or in homoplasmic mutant individuals. For the purposes of comparison, a longitudinal analysis of a silent mtDNA polymorphism at nucleotide 14560 was also carried out for members of a second matrilineal pedigree. In contrast to the results for the pathogenic mtDNA mutation, there was no change in the proportion of the silent polymorphism in the WBC/platelet fraction of four family members over a period of seven years. These results indicate that the pathogenic 3460 LHON mutation segregates under negative selection in these cell populations. One possible mechanism through which selection may operate is that, in heteroplasmic individuals, the hematopoietic stem cells are generally homoplasmic, either for the wildtype or for the mutant allele. The homoplasmic mutant stem cells, because of their mitochondrial respiratory chain defect, produce fewer mature WBCs and platelets over time than do the wildtype stem cells. Alternatively, the stem cells may be heteroplasmic and selection may act to favor proliferation of mitochondria with lower levels of the pathogenic mutation in the WBC/platelet cell populations.

DNA Mutational Analysis↗

PubMed2006

Antagonistic coevolution with parasites increases the cost of host deleterious mutations.

The fitness consequences of deleterious mutations are sometimes greater when individuals are parasitized, hence parasites may result in the more rapid purging of deleterious mutations from host populations. The significance of host deleterious mutations when hosts and parasites antagonistically coevolve (reciprocal evolution of host resistance and parasite infectivity) has not previously been experimentally investigated. We addressed this by coevolving the bacterium Pseudomonas fluorescens and a parasitic bacteriophage in laboratory microcosms, using bacteria with high and low mutation loads. Directional coevolution between bacterial resistance and phage infectivity occurred in all populations. Bacterial population fitness, as measured by competition experiments with ancestral genotypes in the absence of phage, declined with time spent coevolving. However, this decline was significantly more rapid in bacteria with high mutation loads, suggesting the cost of bacterial resistance to phage was greater in the presence of deleterious mutations (synergistic epistasis). As such, resistance to phage was more costly to evolve in the presence of a high mutation load. Consistent with these data, bacteria with high mutation loads underwent less rapid directional coevolution with their phage populations, and showed lower levels of resistance to their coevolving phage populations. These data suggest that coevolution with parasites increases the rate at which deleterious mutations are purged from host populations.

Directed Molecular Evolution↗

PubMed2001

Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?

Leber hereditary optic neuropathy (LHON) is a major cause of inherited blindness in young males. Approximately 1 in 7 individuals with LHON harbor a mixture of mutated and wild-type (normal) mtDNA (heteroplasmy), and the risks of developing blindness in heteroplasmic LHON individuals are not well characterized. MtDNA is inherited exclusively down the maternal line, and although the risks of a relative within a homoplasmic LHON pedigree are relatively well established, the risks of transmission in heteroplasmic LHON pedigrees have not been studied in detail. We analyzed 17 independent pedigrees that harbor the most prevalent LHON mutation: G11778A. The pedigrees were influenced by incomplete ascertainment bias, which was reduced by omitting the affected probands from the analysis. We made the following observations: (1) The frequency of blindness in males was related to the mutation load in that individual's blood. (2) Mothers with < or = 80% mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift in these pedigrees. This study provides insights into the mutation load, or threshold, necessary for expression of the optic neuropathy, the relationship between mutation load in the mother and the risk of blindness in her children, and the complex inheritance of heteroplasmic mtDNA defects.

DNA, Mitochondrial↗

PubMed1979

'Our load of mutation': reappraisal of an old problem.

H. J. Muller, in a paper in 1950 entitled 'Our load of mutation', predicted the genetic decay of the human species due to increasing mutation pressure combined with relaxation of natural selection. In the meantime, much information on spontaneous and induced mutations in humans has been accumulated, and a reappraisal of Muller's conclusions gives a much less gloomy overall picture. However, a certain increase of malformation and disease can be predicted as a result of ionizing radiation and chemical mutagens. On the other hand, genetic counselling and antenatal diagnosis of genetic anomalies may help to keep the genetic risks within tolerable limits. Research on the biological conditions for the untoward effects of mutagenic chemicals considered necessary for the wellbeing of humans may also help to reduce genetic risks. The extent and kind of the risks as well as possibilities for prevention are discussed with a few examples.

Animals↗

PubMed2002

Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation.

OBJECTIVE: To investigate the correlation between biochemical and clinical phenotype in 6 patients from 3 unrelated families with different mutation loads (heteroplasmy) of the T8993G mitochondrial DNA mutation associated with neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome. METHODS: We studied adenosine triphosphate (ATP) synthase activity (synthesis and hydrolysis) in platelet-derived submitochondrial particles and assessed mutant loads both in platelets used for biochemical analysis and in other available tissues. Biochemical and molecular results were correlated with clinical features. RESULTS: The rate of ATP hydrolysis was normal, but ATP synthesis was severely impaired (30% to 4% of residual activity) in patients harboring 34% to 90% mutant mitochondrial DNA, without any evidence of a threshold for the expression of this defect. There was little variation in heteroplasmy among tissues from each patient, but wider variability was detected in 2 mothers. Correlation of heteroplasmy and clinical and biochemical features suggested that ATP synthesis is defective at mutant loads as low as 34% and is extremely reduced at mutant loads above 80% when the phenotype is neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome. CONCLUSIONS: This study indicates a close relationship between tissue heteroplasmy, expression of the biochemical defect in platelets, and clinical involvement. The biochemical defect was greater than previously reported, and we found no evidence of a biochemical threshold. The uniform distribution of high mutant loads among our patients' tissues suggests a differential tissue-specific reliance on mitochondrial ATP synthesis.

Adenosine Triphosphate↗

PubMed2006

Most spontaneous tumors in a mouse model of Li-Fraumeni syndrome do not have a mutator phenotype.

Mutations are the substrate of cancer. Yet, little is known about the degree and nature of mutations in tumors because measurement of mutation load in tumors and normal tissues was generally not possible until the advent of transgenic mouse mutation detection systems. Herein, we present the first analysis of mutation frequency and pattern in thymic tumors from a mouse model of Li-Fraumeni syndrome (p53+/- murine model) using the Big Blue assay with sequencing of all mutants. We also make the first characterization of mutation frequency and pattern in p53-deficient extra-thymic cancers. The data more than triple the literature on all non-mismatch repair deficient tumors for which mutations are identified by sequence analysis, allowing mutation frequency and pattern to be determined. Most tumors had a normal mutation frequency and a normal mutation pattern. Five tumors showed modest increases in mutation frequency (2.3-fold or less). Alterations in mutation patterns were uncommon, tumor-specific and not necessarily associated with increases in mutation frequency. Given the data from two spontaneous tumors (normal mutation frequency with an abnormal pattern in a p53-/- mouse and low mutation frequency in a p53+/+ control mouse), we hypothesize that tumors sometimes can carry a low mutation load. The study was not without certain caveats: mutation load could not be compared between tumor and normal tissue from the same animal; sample sizes for extra-thymic tumor types were small, and only point mutations and deletions, insertions and indels up to 2 kb were detected. However, the data clearly show key differences in tumors from p53+/- mice compared with mismatch repair deficient tumors; a lack of dramatic increase in mutation frequency and absence of a signature of mutation.

Animals↗

PubMed2003

Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents.

Selection against deleterious mutations imposes a mutation load on populations because individuals die or fail to reproduce. In vertebrates, estimates of genomic rates of deleterious mutations in protein-coding genes imply the existence of a substantial mutation load, but many functionally important regions of the genome are thought to reside in noncoding DNA, and the contribution of noncoding DNA to the mutation load has been unresolved. Here, we infer the frequency of deleterious mutations in noncoding DNA of rodents by comparing rates of substitution at noncoding nucleotides with rates of substitution at the fastest evolving intronic sites of adjacent genes sampled from the whole genome sequences of mouse and rat. We show that the major elements of selectively constrained noncoding DNA are within 2,500 bp upstream and downstream of coding sequences and in first introns. Our estimate of the genomic deleterious point mutation rate for noncoding DNA (0.22 per diploid per generation) is similar to that for coding DNA. Mammalian populations therefore experience a substantial genetic load associated with selection against deleterious mutations in noncoding DNA. Deleterious mutations in noncoding DNA have predominantly quantitative effects and could be an important source of the burden of complex genetic disease variation in human populations.

Animals↗

PubMed1997

Radiation damage accumulation over large time intervals: a descriptive model.

A simple model of DNA damage (mutation load) accumulation is considered. For time intervals exceeding average life duration, the kinetics of mutation load is determined. The major process determining these kinetics is shown to be natural selection (or any equivalent process of removal of the most affected lines). The characteristic time of this process (which is around three generations) is the approximate time of integration of the dose rate for determination of radiation damage. The conclusion is made that the maximum permissible dose should be established for this characteristic time, as it determines the remote effects of prolonged exposure to radiation. After this, the accumulated genetic damage presents "dose rate-effect" rather than "dose-effect" dependence. Dependence of mutation load on dose rate and parameters of selection processes is examined for different types of mutations. The cases of stable and exponentially decreasing dose rate are considered. The applicability of the model to human population is discussed.

DNA Damage↗