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Results for “deleterious mutation”

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PubMed2005

Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women.

PURPOSE: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a function of race. METHODS: After IRB approved informed consent, 170 white women and 30 African American women with known breast cancer diagnosed at a young age (45 years or less) underwent complete sequencing of the BRCA1 and BRCA2 genes. Each cohort represented approximately 40% of women of the same ethnic background aged 45 years or younger in a breast cancer database. RESULTS: Of the 200 patients tested, 131 (65%) had wild type mutations, 34 (17%) had deleterious mutations, and 35 (18%) had variants of uncertain significance. There were no significant differences between the white and African American cohorts regarding the percentage of deleterious mutations (17% v 17%). However, most African American patients had mutations in BRCA2 (4/5, 80%), while most mutations in the white cohort were in BRCA1 (20/29, 69%). In addition, 46% of the African American women had variants of uncertain significance, compared to only 12% of the white cohort. CONCLUSIONS: Young African American women with breast cancer have a similar frequency of deleterious mutations as white women, but have a significantly higher frequency of variants of uncertain significance. Review of these variants revealed that the majority were unlikely to be associated with disease risk or were likely to be polymorphisms. The implications for genetic testing and counselling in young women with breast cancer are discussed.

Adult↗

PubMed2000

Low variability in a Y-linked plant gene and its implications for Y-chromosome evolution.

Sex chromosomes have evolved independently in several different groups of organisms, but they share common features, including genetic degeneration of the Y chromosome. Suppression of recombination between ancestral proto-X and proto-Y chromosomes is thought to have led to their gradual divergence, and to degeneration of the Y chromosome, but the evolutionary forces responsible are unknown. In non-recombining Y chromosomes, deleterious mutations may be carried to fixation by linked advantageous mutations ("selective sweeps"). Occurrence of deleterious mutations may drive "Muller's ratchet" (stochastic loss of chromosomes with the fewest mutations). Selective elimination of deleterious mutations, causing "background selection" may accelerate stochastic fixation of mildly detrimental mutations. All these processes lower effective population sizes, and therefore reduce variability of genes in evolving Y chromosomes. We have studied DNA diversity and divergence in a recently described X- and Y-linked gene pair (SLX-1 and SLY-1) of the plant Silene latifolia to obtain evidence about the early stages of Y degeneration. Here we show that DNA polymorphism in SLY-1 is 20-fold lower than in SLX-1, but the pattern of polymorphism does not suggest a selective sweep.

Animals↗

PubMed2004

Sexual selection, redundancy and survival of the most beautiful.

A model is described of a highly redundant complex organism that has overlapping banks of genes such that each vital function is specified by several different genetic systems. This generates a synergistic profile linking probability of survival to the number of deleterious mutations in the genome. Computer models show that there is a dynamic interaction between the mean number of new deleterious mutations per generation (X), the mean number of deleterious mutations in the genome of the population (Y) and percentage zygote survival (Zs). Increased X leads to increased Y and a fall in Zs but it takes several generations before a new equilibrium is reached. If sexual attraction is influenced by the number of deleterious mutations in the genome of individuals then Y is reduced and Zs increased for any given value of X. This fall in Y and rise in Zs is more marked in polygamous than monogamous mating systems. The model is specified such that deleterious mutations can occur without any observable or measurable effect on function. Thus sexual selection, in this organism, for low levels of deleterious mutations cannot be based on assessment of performance. Instead it is based on a simple symmetrical surface pattern that is flawlessly reproduced by organisms with no deleterious mutations, but is less than perfect, and therefore less attractive, if genetic systems have been deleted. A complex vital task requires a system with a high level of redundancy that acts so that the loss of one component has no observable effect and therefore cannot be used for sexual selection. The reproduction of a beautiful surface pattern also requires a low error, high redundancy genetic system; however, in this case there is advantage if a single deleterious mutation produces a recognisable change. This leads to the conclusion that sexual selection and sexual attraction should be based on beauty rather than utility, and explains the common observation in nature that it is the most beautiful that survive.

Animals↗

PubMed2001

Sexual selection and the maintenance of sexual reproduction.

The maintenance of sexual reproduction is a problem in evolutionary theory because, all else being equal, asexual populations have a twofold fitness advantage over their sexual counterparts and should rapidly outnumber a sexual population because every individual has the potential to reproduce. The twofold cost of sex exists because of anisogamy or gamete dimorphism-egg-producing females make a larger contribution to the zygote compared with the small contribution made by the sperm of males, but both males and females contribute 50% of the genes. Anisogamy also generates the conditions for sexual selection, a powerful evolutionary force that does not exist in asexual populations. The continued prevalence of sexual reproduction indicates that the 'all else being equal' assumption is incorrect. Here I show that sexual selection can mitigate or even eliminate the cost of sex. If sexual selection causes deleterious mutations to be more deleterious in males than females, then deleterious mutations are maintained at lower equilibrium frequency in sexual populations relative to asexual populations. The fitness of sexual females is higher than asexuals because there is no difference in the fecundity of sexual females and asexuals of the same genotype, but the equilibrium frequency of deleterious mutations is lower in sexual populations. The results are not altered by synergistic epistasis in males.

Animals↗

PubMed2003

The role of somatic and germline mutations in aging and a mutation interaction model of aging.

Mutations with a deleterious effect that is expressed after the average reproductive period are not effectively selected against and can accumulate in the germline. A conservative estimate is that at least 1-2% of new deleterious mutations affect some aspect of DNA replication, repair, or chromosome segregation. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate. This can have an interactive effect, in that it may increase the rate of somatic mutation during an individual's lifetime. The aging individual therefore becomes increasingly mosaic for somatic mutations, which in turn could potentially contribute to the gradual deterioration of biological processes and influence what we experience as senescence. Interventions that reduce somatic and germ cell mutations should, therefore, reduce the aging process in present and future generations.

Aging↗

PubMed2006

Characterization of compensated mutations in terms of structural and physico-chemical properties.

The study of the evolution of compensatory mechanisms among amino acids is paramount to our understanding of intramolecular epistatic interactions. It has been addressed from different points of view, for example much effort has been devoted to establish the number of compensatory mutations required per deleterious mutation. However, we still do not know how the nature of the compensated mutation determines the existence of compensatory mutations. Within this context, recent studies have produced several instances of an interesting phenomenon: human disease-associated residues may sometimes appear as wild-type residues in non-human proteins. This can be explained in terms of compensatory mutations, present in the non-human protein, which would neutralize the damage caused by the disease-associated residue. Therefore, comparison between these compensated mutations and non-compensated pathological mutations provides a simple approach to understand how the nature of the compensated deleterious mutation determines the existence of compensatory mutations. To address this issue, we have obtained a large set of compensated mutations and characterised them with a series of different properties. When comparing the resulting distributions with those from pathological mutations we find that in general compensated mutations are milder than pathological mutations. More precisely, we find that the probability that a compensatory mutation will evolve is directly related (i) to the location in the protein structure and (ii) to changes in physico-chemical properties (e.g. amino acid volume or hydrophobicity) of the compensated mutation.

Animals↗

PubMed1980

A test of evolutionary theories of senescence.

Senescence is the post-maturation decline in survivorship and fecundity that accompanies advancing age. Two main evolutionary theories have been proposed to account for senescence. (1) The mutation-accumulation theory. Deleterious mutations exerting their effects only late in life would tend to accumulate, because of their minimal effects on fitness. More precisely, exclusively late-acting deleterious mutations will attain higher equilibrium frequencies under mutation--selection balance than will mutations that act early, resulting in lower mean values for fitness components late in life (ref. 3, p. 218). Medawar emphasized the possibility that this effect would be enhanced by selection of modifiers that postpone the age of onset of genetic diseases. (2) The pleiotropy theory. Williams suggested that many of the genes with beneficial effects on early fitness components have pleiotropic deleterious effects on late fitness components, but are nevertheless favoured by natural selection. (These theories are based on the decline with age in the effect of age-specific fitness-component changes on total fitness (ref. 3, pp. 206--214 and refs 4, 5). Either or both of these theories could apply in any particular population.) Selection experiments in Drosophila and Tribolium support the pleiotropy theory, although one such experiment gave results that only bordered on significance, but the mutation--accumulation theory has never been tested. The present results provide evidence for the pleiotropy theory, but do not support the mutation--accumulation theory.

Aging↗

PubMed2000

Mutation and sex in a competitive world.

How do deleterious mutations interact to affect fitness? The answer to this question has substantial implications for a variety of important problems in population biology, including the evolution of sex, the rate of adaptation and the conservation of small populations. Here we analyse a mathematical model of competition for food in which deleterious mutations affect competitive ability. We show that, if individuals usually compete in small groups, then competition can easily lead to a type of genetic interaction known as synergistic epistasis. This means that a deleterious mutation is most damaging in a genome that already has many other deleterious mutations. We also show that competition in small groups can produce a large advantage for sexual populations, both in mean fitness and in ability to resist invasion by asexual lineages. One implication of our findings is that experimental efforts to demonstrate synergistic epistasis may not succeed unless the experiments are redesigned to make them much more naturalistic.

Animals↗

PubMed2024

Nonlethal deleterious mutation-induced stress accelerates bacterial aging.

Random mutagenesis, including when it leads to loss of gene function, is a key mechanism enabling microorganisms' long-term adaptation to new environments. However, loss-of-function mutations are often deleterious, triggering, in turn, cellular stress and complex homeostatic stress responses, called "allostasis," to promote cell survival. Here, we characterize the differential impacts of 65 nonlethal, deleterious single-gene deletions on Escherichia coli growth in three different growth environments. Further assessments of select mutants, namely, those bearing single adenosine triphosphate (ATP) synthase subunit deletions, reveal that mutants display reorganized transcriptome profiles that reflect both the environment and the specific gene deletion. We also find that ATP synthase α-subunit deleted (ΔatpA) cells exhibit elevated metabolic rates while having slower growth compared to wild-type (wt) E. coli cells. At the single-cell level, compared to wt cells, individual ΔatpA cells display near normal proliferation profiles but enter a postreplicative state earlier and exhibit a distinct senescence phenotype. These results highlight the complex interplay between genomic diversity, adaptation, and stress response and uncover an "aging cost" to individual bacterial cells for maintaining population-level resilience to environmental and genetic stress; they also suggest potential bacteriostatic antibiotic targets and -as select human genetic diseases display highly similar phenotypes, - a bacterial origin of some human diseases.

Escherichia coli↗

PubMed1997

Before crossing over: the advantages of eukaryotic sex in genomes lacking chiasmatic recombination.

Non-recombining populations should suffer from four classic population genetic disadvantages: (1) they cannot reverse Muller's Ratchet, the accumulation of deleterious mutations caused by genetic drift and mutation; (2) whenever the fix a favourable mutation they lose all unlinked favourable variants; (3) they tend to lose favourable mutations that are linked to deleterious mutations; and (4) their genetic loads can be quite high when deleterious mutations have synergistic effects. It is commonly assumed that inter-chromosomal recombination (independent assortment) can counter these phenomena, but this has been studied only for the genetic load case. In contrast, many studies have shown that recombination via crossing over can counter these phenomena. Here we first show that segregation alone can strongly decelerate Muller's Ratchet in diploids, i.e. that recombination is not the only way to do so. We then show that inter-chromosomal recombination can indeed deal with phenomena (1) to (3) above very effectively if the genome consists of a moderate number of chromosomes. Therefore, if the above advantages of genetic recombination played a large role in the initial success of eukaryotic sex, the crucial moment in the origin of sex might have been the evolution of inter-chromosomal recombination, i.e. the evolution of genome segmentation, segregation, and syngamy. Crossing over might have become established as a major recombinational device only later, eliminating the disadvantages of extensively segmented genomes.

Crossing Over, Genetic↗

PubMed1998

On the three methods for estimating deleterious genomic mutation parameters.

Due to the tremendous cost of the traditional mutation-accumulation approach (the Bateman-Mukai technique), data are rare for deleterious mutation parameters such as genomic mutation rate, selection and dominance coefficients. Two alternative approaches have been developed (the Morton-Charlesworth and Deng-Lynch techniques). Except for the Deng-Lynch method, the statistical properties (bias and sampling variance) of these techniques are poorly understood; therefore we investigated them using computer simulation. With constant fitness effects of mutations, the Bateman-Mukai (assuming additive effects) and Deng-Lynch (assuming multiplicative effects) techniques are unbiased; the Morton-Charlesworth technique (assuming multiplicative effects) is very biased if fitness is used in the regression to estimate h, but slightly biased if the logarithm of fitness is used. With variable fitness effects, all techniques are biased. The Deng-Lynch technique is statistically better than the others except when fitness is used to estimate the average degree of dominance in selfing populations with the Morton-Charlesworth technique. If fitness effects are multiplicative but additivity is assumed, the Bateman-Mukai technique is biased under constant fitness effects, and less biased under variable fitness effects relative to when fitness effects are additive (as assumed by the technique). Our study not only quantifies the degree of bias under the biologically plausible situations investigated, thus forming a basis for correct inference of the true parameters by using these techniques, but also provides insights into the relative efficiencies of these techniques when the same number of genotypes are handled experimentally.

Computer Simulation↗

PubMed2001

Rapid mutational declines of viability in Drosophila.

High rates of mildly deleterious mutation could cause the extinction of small populations, reduce neutral genetic variation and provide an evolutionary advantage for sex. In the first attempts to estimate the rate of mildly deleterious mutation, Mukai and Ohnishi allowed spontaneous mutations to accumulate on D. melanogaster second chromosomes shielded from recombination and selection. Viability of the shielded chromosomes appeared to decline rapidly, implying a deleterious mutation rate on the order of one per zygote per generation. These results have been challenged, however; at issue is whether Mukai and Ohnishi may have confounded viability declines caused by mutation with declines resulting from environmental changes or other extraneous factors. Here, using a method not sensitive to non-mutational viability changes, I reanalyse the previous mutation-accumulation (MA) experiments, and report the results of a new one. I show that in each of four experiments, including Mukai's two experiments, viability declines due to mildly deleterious mutations were rapid. The results give no support for the view that Mukai overestimated the declines. Although there is substantial variation in estimates of genomic mutation rates from the experiments, this variation is probably due to some combination of sampling error, strain differences and differences in assay conditions, rather than to failure to distinguish mutational and non-mutational viability changes.

Animals↗

PubMed1997

Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans.

Theory concerning the evolution of sex and recombination and mutation load relies on information on rates and distributions of effects of deleterious mutations. Direct information on the genomic mutation rate in Drosophila implies that an accumulation of mildly deleterious mutations reduces viability of populations by at least 1% per generation. We carried out an experiment to measure the deleterious mutation rate in Caenorhabditis elegans, in which independent sublines were maintained with one hermaphrodite parent per generation, conditions that minimize the opportunity for natural selection and lead to random fixation of deleterious mutations. After 60 generations of mutation accumulation, negligible changes in mean reproductive output and lifespan occurred, but the genetic variance increased at rates typical for life history traits in other species. The estimated deleterious mutation rate per haploid genome for fitness, U, was 0.0026, a figure two orders of magnitude smaller than previously measured for viability in Drosophila.

Animals↗

PubMed2006

JADE: a distributed Java application for deleterious genomic mutation (DGM) estimation.

SUMMARY: The characterization of deleterious genomic mutation (DGM) is of central significance for evolutionary biology and genetic studies. Fitness moment method has been developed to efficiently characterize DGM from natural population directly. In order to enable researchers to employ this method for theoretical and empirical research on characterizing DGM, we here present a distributed Java Application for DGM Estimation (JADE). AVAILABILITY: http://orclinux.creighton.edu/DGM/index.htm.

Biological Evolution↗

PubMed1999

Properties of spontaneous mutations affecting quantitative traits.

Recent mutation accumulation results from invertebrate species suggest that mild deleterious mutation is far less frequent than previously thought, implying smaller expressed mutational loads. Although the rate (lambda) and effect (s) of very slight deleterious mutation remain unknown, most mutational fitness decline would come from moderately deleterious mutation (s approximately 0.2, lambda approximately 0.03), and this situation would not qualitatively change in harsh environments. Estimates of the average coefficient of dominance (h) of non-severe deleterious mutations are controversial. The typical value of h = 0.4 can be questioned, and a lower estimate (about 0.1) is suggested. Estimated mutational parameters are remarkably alike for morphological and fitness component traits (excluding lethals), indicating low mutation rates and moderate mutational effects, with a distribution generally showing strong negative asymmetry and little leptokurtosis. New mutations showed considerable genotype-environment interaction. However, the mutational variance of fitness-component traits due to non-severe detrimental mutations did not increase with environmental harshness. For morphological traits, a class of predominantly additive mutations with no detectable effect on fitness and relatively small effect on the trait was identified. This should be close to that responsible for standing variation in natural populations.

Adaptation, Physiological↗

PubMed2000

Understanding the overdispersed molecular clock.

Rates of molecular evolution at some protein-encoding loci are more irregular than expected under a simple neutral model of molecular evolution. This pattern of excessive irregularity in protein substitutions is often called the "overdispersed molecular clock" and is characterized by an index of dispersion, R(T) > 1. Assuming infinite sites, no recombination model of the gene R(T) is given for a general stationary model of molecular evolution. R(T) is shown to be affected by only three things: fluctuations that occur on a very slow time scale, advantageous or deleterious mutations, and interactions between mutations. In the absence of interactions, advantageous mutations are shown to lower R(T); deleterious mutations are shown to raise it. Previously described models for the overdispersed molecular clock are analyzed in terms of this work as are a few very simple new models. A model of deleterious mutations is shown to be sufficient to explain the observed values of R(T). Our current best estimates of R(T) suggest that either most mutations are deleterious or some key population parameter changes on a very slow time scale. No other interpretations seem plausible. Finally, a comment is made on how R(T) might be used to distinguish selective sweeps from background selection.

Alleles↗

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↗

PubMed2001

The speed of Muller's ratchet with background selection, and the degeneration of Y chromosomes.

The rate of accumulation of deleterious mutations by Muller's ratchet is investigated in large asexual haploid populations, for a range of parameters with potential biological relevance. The rate of this process is studied by considering a very simple model in which mutations can have two types of effect: either strongly deleterious or mildly deleterious. It is shown that the rate of accumulation of mildly deleterious mutations can be greatly increased by the presence of strongly deleterious mutations, and that this can be predicted from the associated reduction in effective population size (the background selection effect). We also examine the rate of the ratchet when there are two classes of mutation of similar but unequal effects on fitness. The accuracy of analytical approximations for the rate of this process is analysed. Its possible role in causing the degeneration of Y and neo-Y chromosomes is discussed in the light of our present knowledge of deleterious mutation rates and selection coefficients.

Animals↗