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Results for “deleterious mutation”

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PubMed2001

How many deleterious mutations are there in the human genome?

An estimate of the number of deleterious mutations in the human genome is made using data on the frequency of rare recessive disease in cousin marriages and in the general population. Sexual reproduction ensures that deleterious mutations are distributed at random in zygotes with an approximate Poisson distribution. The mean of this distribution is the sum of the mean number of deleterious mutations in zygotes which contribute to the next generation (Y) and the mean number of new mutations which arise in each human generation (X). The estimates are that X is between 1 and 2.6 and Y is between 12 and 32. A mathematical model based on redundancy is then used to predict how zygote survival will vary with the number of deleterious mutations. The form of this relationship is the same as that seen in experiments on cell survival following radiation-induced mutational damage and this provides independent support for this theoretical approach. The zygotes that survive to contribute to the next generation have a skewed distribution with a mean of Y. It is argued that the number of deleterious mutations in the genome is an important variable in health and disease.

Genes, Recessive↗

PubMedDate not supplied

Selection on a modifier of recombination rate due to linked deleterious mutations.

Several models have been suggested to explain the origin and maintenance of recombination. Here I present the results from computer simulations of multilocus haploid and diploid genotypes in small populations. Each chromosome consisted of 1001 loci where deleterious mutations occurred. At "equilibrium" for mutation-selection-genetic drift balance a single recombination variant was introduced to the population in the middle of a chromosome. On average 75,000 replicates for each combination of parameters were followed to fixation or loss of the modifier allele. The results show that, in a small population, increased recombination can be selected, even in the absence of epistasis or beneficial mutations. The effect of the mutation rate for deleterious mutations depends on the ploidy level and the recessiveness of deleterious mutations. A higher deleterious mutation rate is required for an increase in recombination rate to be favored in haploid populations. Increased recombination could not evolve in the case of strong associative overdominance.

Computer Simulation↗

PubMed1999

Spontaneous deleterious mutation in Arabidopsis thaliana.

The frequency and selective impact of deleterious mutations are fundamental parameters in evolutionary theory, yet they have not been directly measured in a plant species. To estimate these quantities, we allowed spontaneous mutations to accumulate for 10 generations in 1,000 inbred lines of the annual, self-fertilizing plant Arabidopsis thaliana and assayed fitness differences between generations 0 and 10 in a common garden. Germination rate, fruit set, and number of seeds per fruit each declined by less than 1% per generation in the mutation lines, and total fitness declined by 0.9% per generation. Among-line variances increased in the mutation lines for all traits. Application of an equal-effects model suggests a downwardly biased genomic deleterious mutation rate of 0.1 and a upwardly biased effect of individual mutations on total fitness of 20%. This genomic deleterious mutation rate is consistent with estimates of nucleotide substitution rates in flowering plants, the genome size of Arabidopsis, and the equilibrium inbreeding depression observed in this highly selfing plant species.

Arabidopsis↗

PubMed1998

Some evolutionary consequences of deleterious mutations.

Most mutations with observable phenotypic effects are deleterious. Studies of Drosophila and inbred plant populations suggest that a new individual may have a mean number of new deleterious mutations that exceeds one-half. Most of these have relatively small homozygous effects and reduce fitness by 1-2% when heterozygous. Several striking features of present-day organisms have apparently evolved in response to the constant input of deleterious alleles by recurrent mutation. For example, the adaptations of hermaphroditic organisms for outcrossing have been widely interpreted in terms of the benefits of avoiding the reduced fitness of inbred progeny, which is partly due to deleterious mutations. Population genetic models of modifiers of the breeding system in the presence of genome-wide deleterious mutation are reviewed and their predictions related to genetic and comparative data. The evolution of degenerate Y chromosomes is a phenomenon that may be caused by the accumulation of deleterious mutations. The population genetic mechanisms that can drive this degenerations are reviewed and their significance assessed in the light of available data.

Animals↗

PubMed2003

Testing for epistasis between deleterious mutations in a parasitoid wasp.

Determining the way in which deleterious mutations interact to effect fitness is crucial to numerous areas in evolutionary biology. For example, if each additional mutation leads to a greater decrease in log fitness than the last, termed synergistic epistasis, then sex and recombination provide an advantage because they enable deleterious mutations to be eliminated more efficiently. However, there is a severe shortage of relevant empirical data, especially of the form that can help test mutational explanations for the widespread occurrence of sex. Here, we test for epistasis in the parasitic wasp Nasonia vitripennis, examining the fitness consequences of chemically induced deleterious mutations. We examine two components of fitness, both of which are thought to be important in natural populations of parasitic wasps: longevity and egg production. Our results show synergistic epistasis for longevity, but not for egg production.

Animals↗

PubMed1999

The dynamics of infinitesimally rare alleles, applied to the evolution of mutation rates and the expression of deleterious mutations.

A new method is presented for analysing the dynamics of a classical model where infinitesimally rare alleles segregate at an infinite number of unlinked loci, and where the alleles at different loci have equivalent effects. The dynamics of the distribution of the number of rare alleles per individual (the "phenotypic distribution") can be followed without knowing the frequencies of individual genotypes. Meiosis and random union of gametes have a very simple effect on the factorial cumulants of the phenotypic distribution which are consequently the natural set of variables to follow. An exact solution is presented for the dynamics of rare alleles under mutation and multiplicative selection. This solution has a simple representation in terms of the factorial cumulants. Unlike the QLE (quasi-linkage equilibrium) solution, this solution applies even when the population is far from linkage equilibrium. This approach is extended to analyse the joint dynamics of infinitesimally rare alleles at an infinite number of unlinked loci, together with a locus (with arbitrary allele frequencies) with which they interact. This more general method is used to investigate (1) the joint dynamics of a modifier of the mutation rate, together with deleterious alleles under mutation and multiplicative selection, and (2) the fate of an allele that ameliorates or exacerbates the fitness effects of deleterious alleles. When a new modifier allele causes a large change in the mutation rate, strong linkage disequilibrium is generated during its progress. However, using this new approach based on factorial cumulants, it is found that a remarkably simple invasion condition applies to alleles at the modifier locus, even when strong linkage disequilibrium is generated.

Alleles↗

PubMed2005

Deleterious mutation in related species of the plant genus Amsinckia with contrasting mating systems.

Theory for the evolution of modifiers of the rate of mutation suggests that a lower rate of mutation may evolve after the breakdown of mechanisms that enforce outcrossing. Mutation accumulation (MA) experiments were conducted to compare deleterious mutation parameters in two closely related species of the plant genus Amsinckia, a group that exhibits wide variation in the mating system. One of the two species studied (A. douglasiana) is predominantly outcrossed in natural populations, where as the other species (A. gloriosa) is predominantly self-pollinated. Progeny assays of flower number per plant from generation 1 lines (control) and generation 11 lines (MA treatment) were conducted in both species. Dry weight measurements of progeny from the control and MA treatment in A. douglasiana also were made. Estimation of mutation parameters was conducted using maximum likelihood under the assumption of a gamma distribution of mutational effects. The two species exhibited similar rates and effects of deleterious mutation affecting flower number. Estimates of mutation rate for dry weight in A. douglasiana are close to those for flower number. Overall, the estimates of mutation parameters observed in these species are intermediate within the range reported for fitness components in other eukaryotes. The results are discussed within the context of evolutionary change in deleterious mutation accompanying mating system evolution and with respect to previous estimates of mutation parameters based on assays of inbreeding depression and the assumption of mutation-selection equilibrium.

Amsinckia↗

PubMed2026

High levels of mitotic gene conversion are needed to effectively purge deleterious mutations in asexual organisms.

Self-fertilisation and asexual reproduction are both hypothesised to cause long-term extinction due to inefficient selection against deleterious mutations. Self-fertilisation can counter these effects through creating homozygous genotypes and purging deleterious mutations. Although complete asexuality lacks meiotic gene exchange, mitotic gene conversion creates homozygous regions that could limit deleterious mutation accumulation in an analogous manner. We compare mutation accumulation in self-fertilising and facultative sexual populations subject to mitotic gene conversion, and quantify the efficacy of purging in the latter. We first show analytically that purging is most effective with high levels of asexuality and gene conversion, and when deleterious mutations are recessive. We further show using simulations that, when mitotic gene conversion becomes sufficiently high in obligate asexuals, there is a reduction in the mutation count and a jump in homozygosity, reflecting purging. However, this mechanism is not necessarily as efficient at purging under high self-fertilisation, and elevated rates of mitotic gene conversion seem to be needed for widespread purging compared to empirical estimates. If gene conversion rates are allowed to evolve, then elevated rates that increase mean fitness can arise, but only if there is sufficient variance in the gene conversion rate. Conversely, if gene conversion rates are already high and rates are not constrained then they will slightly decrease, reducing mean fitness.

Self-fertilisation↗

PubMed1996

Estimation of deleterious-mutation parameters in natural populations.

The rate and average effects of spontaneous deleterious mutations are important determinants of the evolution of breeding systems and of the vulnerability of small populations to extinction. Nevertheless, few attempts have been made to estimate the properties of such mutations, and those studies that have been performed have been extremely labor intensive, relying on long-term, laboratory mutation-accumulation experiments. We present an alternative to the latter approach. For populations in which the genetic variance for fitness is a consequence of selection-mutation balance, the mean fitness and genetic variance of fitness in outbred generations can be expressed as simple functions of the genomic mutation rate, average homozygous effect and average dominance coefficient of new mutations. Using empirical estimates for the mean and genetic variance of fitness, these expressions can then be solved to obtain joint estimates of the deleterious-mutation parameters. We employ computer simulations to evaluate the degree of bias of the estimators and present some general recommendations on the application of the technique. Our procedures provide some hope for obtaining estimates of the properties of deleterious mutations from a wide phylogenetic range of species as well as a mechanism for testing the validity of alternative models for the maintenance of genetic variance for fitness.

Gene Deletion↗

PubMed2003

Deleterious mutations and the genetic variance of male fitness components in Mimulus guttatus.

Deleterious mutations are relevant to a broad range of questions in genetics and evolutionary biology. I present an application of the "biometric method" for estimating mutational parameters for male fitness characters of the yellow monkeyflower, Mimulus guttatus. The biometric method rests on two critical assumptions. The first is that experimental inbreeding changes genotype frequencies without changing allele frequencies; i.e., there is no genetic purging during the experiment. I satisfy this condition by employing a breeding design in which the parents are randomly extracted, fully homozygous inbred lines. The second is that all genetic variation is attributable to deleterious mutations maintained in mutation-selection balance. I explicitly test this hypothesis using likelihood ratios. Of the three deleterious mutation models tested, the first two are rejected for all characters. The failure of these models is due to an excess of additive genetic variation relative to the expectation under mutation-selection balance. The third model is not rejected for either of two log-transformed male fitness traits. However, this model imposes only "weak conditions" and is not sufficiently detailed to provide estimates for mutational parameters. The implication is that, if biometric methods are going to yield useful parameter estimates, they will need to consider mutational models more complicated than those typically employed in experimental studies.

Analysis of Variance↗

PubMed2000

Deleterious mutations and the evolution of sex.

It has been suggested that sexual reproduction is maintained because it reduces the load imposed by recurrent deleterious mutations. If rates of deleterious mutation per diploid genome per generation (U) exceed 1, and mutations interact synergistically, then sexuals can overcome their inherent twofold disadvantage. We have tested this hypothesis by estimating genomic point mutation rates for protein-coding genes in a range of animal taxa. We find a positive linear relationship between U and generation time. In species with short generation times, U is predicted to be far below 1, suggesting that sex is not maintained by its capacity to purge the genome of deleterious mutations.

Animals↗

PubMed2023

Utilizing evolutionary conservation to detect deleterious mutations and improve genomic prediction in cassava.

INTRODUCTION: Cassava (Manihot esculenta) is an annual root crop which provides the major source of calories for over half a billion people around the world. Since its domestication ~10,000 years ago, cassava has been largely clonally propagated through stem cuttings. Minimal sexual recombination has led to an accumulation of deleterious mutations made evident by heavy inbreeding depression. METHODS: To locate and characterize these deleterious mutations, and to measure selection pressure across the cassava genome, we aligned 52 related Euphorbiaceae and other related species representing millions of years of evolution. With single base-pair resolution of genetic conservation, we used protein structure models, amino acid impact, and evolutionary conservation across the Euphorbiaceae to estimate evolutionary constraint. With known deleterious mutations, we aimed to improve genomic evaluations of plant performance through genomic prediction. We first tested this hypothesis through simulation utilizing multi-kernel GBLUP to predict simulated phenotypes across separate populations of cassava. RESULTS: Simulations showed a sizable increase of prediction accuracy when incorporating functional variants in the model when the trait was determined by<100 quantitative trait loci (QTL). Utilizing deleterious mutations and functional weights informed through evolutionary conservation, we saw improvements in genomic prediction accuracy that were dependent on trait and prediction. CONCLUSION: We showed the potential for using evolutionary information to track functional variation across the genome, in order to improve whole genome trait prediction. We anticipate that continued work to improve genotype accuracy and deleterious mutation assessment will lead to improved genomic assessments of cassava clones.

cassava (Manihot esculenta)↗

PubMed2003

How are deleterious mutations purged? Drift versus nonrandom mating.

Accumulation of deleterious mutations has important consequences for the evolution of mating systems and the persistence of small populations. It is well established that consanguineous mating can purge a part of the mutation load and that lethal mutations can also be purged in small populations. However, the efficiency of purging in natural populations, due to either consanguineous mating or to reduced population size, has been questioned. Consequences of consanguineous mating systems and small population size are often equated under "inbreeding" because both increase homozygosity, and selection is though to be more efficient against homozygous deleterious alleles. I show that two processes of purging that I call "purging by drift" and "purging by nonrandom mating" have to be distinguished. Conditions under which the two ways of purging are effective are derived. Nonrandom mating can purge deleterious mutations regardless of their dominance level, whereas only highly recessive mutations can be purged by drift. Both types of purging are limited by population size, and sharp thresholds separate domains where purging is either effective or not. The limitations derived here on the efficiency of purging are compatible with some experimental studies. Implications of these results for conservation and evolution of mating systems are discussed.

Biological Evolution↗

PubMed2006

Selective pressures at a codon-level predict deleterious mutations in human disease genes.

Deleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.

Amino Acid Sequence↗

PubMed2005

The effect of antagonistic pleiotropy on the estimation of the average coefficient of dominance of deleterious mutations.

We investigate the impact of antagonistic pleiotropy on the most widely used methods of estimation of the average coefficient of dominance of deleterious mutations from segregating populations. A proportion of the deleterious mutations affecting a given studied fitness component are assumed to have an advantageous effect on another one, generating overdominance on global fitness. Using diffusion approximations and transition matrix methods, we obtain the distribution of gene frequencies for nonpleiotropic and pleiotropic mutations in populations at the mutation-selection-drift balance. From these distributions we build homozygous and heterozygous chromosomes and assess the behavior of the estimators of dominance. A very small number of deleterious mutations with antagonistic pleiotropy produces substantial increases on the estimate of the average degree of dominance of mutations affecting the fitness component under study. For example, estimates are increased three- to fivefold when 2% of segregating loci are over-dominant for fitness. In contrast, strengthening pleiotropy, where pleiotropic effects are assumed to be also deleterious, has little effect on the estimates of the average degree of dominance, supporting previous results. The antagonistic pleiotropy model considered, applied under mutational parameters described in the literature, produces patterns for the distribution of chromosomal viabilities, levels of genetic variance, and homozygous mutation load generally consistent with those observed empirically for viability in Drosophila melanogaster.

Computer Simulation↗

PubMed2001

The effects of deleterious mutations in cyclically parthenogenetic organisms.

Cyclically parthenogenetic organisms experience benefits of both sexual and asexual reproductive modes in a constant environment. Sexual reproduction generates new genotypes and may facilitate the purging of deleterious mutations whereas asexuality has a two-fold advantage and enables maintenance of well-fitted genotypes. Asexual reproduction can have a drawback as increased linkage may lead to the accumulation of deleterious mutations. This study presents the results of Monte Carlo simulations of small and infinite diploid populations, with deleterious mutations occurring at multiple loci. The recombination rate and the length of the asexual period, interrupted by sexual reproduction, are allowed to vary. Here I show that the fitness of cyclical parthenogenetic population is dependent on the length of the asexual period. Increased length of the asexual period can lead both to increased segregational load following sexual reproduction and to a stronger effect of deleterious mutations on variation at a linked neutral marker, either by reducing or increasing the variation.

Animals↗

PubMed1993

The effect of deleterious mutations on neutral molecular variation.

Selection against deleterious alleles maintained by mutation may cause a reduction in the amount of genetic variability at linked neutral sites. This is because a new neutral variant can only remain in a large population for a long period of time if it is maintained in gametes that are free of deleterious alleles, and hence are not destined for rapid elimination from the population by selection. Approximate formulas are derived for the reduction below classical neutral values resulting from such background selection against deleterious mutations, for the mean times to fixation and loss of new mutations, nucleotide site diversity, and number of segregating sites. These formulas apply to random-mating populations with no genetic recombination, and to populations reproducing exclusively asexually or by self-fertilization. For a given selection regime and mating system, the reduction is an exponential function of the total mutation rate to deleterious mutations for the section of the genome involved. Simulations show that the effect decreases rapidly with increasing recombination frequency or rate of outcrossing. The mean time to loss of new neutral mutations and the total number of segregating neutral sites are less sensitive to background selection than the other statistics, unless the population size is of the order of a hundred thousand or more. The stationary distribution of allele frequencies at the neutral sites is correspondingly skewed in favor of rare alleles, compared with the classical neutral result. Observed reductions in molecular variation in low recombination genomic regions of sufficiently large size, for instance in the centromere-proximal regions of Drosophila autosomes or in highly selfing plant populations, may be partly due to background selection against deleterious mutations.

Animals↗

PubMed2001

Deleterious mutations and genetic variation for flower size in Mimulus guttatus.

Mimulus guttatus is a wildflower that exhibits substantial genetic variation in flower size. Here, we test the hypothesis that this variation is caused by deleterious mutations maintained through mutation-selection balance. The deleterious-mutation model predicts that rare, partially recessive alleles will be the primary source of variation. We test this prediction by measuring the change in the mean flower size (deltaM) and the directional dominance of flower size (deltaB) within a selection experiment. If variation is due to rare (partially) recessive alleles, deltaB/deltaM is expected to be positive and exceed one. However, we obtain negative values for deltaB/deltaM from three independent selection lines. This result is statistically inconsistent with the deleterious-mutation model.

Alleles↗