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Results for “deleterious mutation”

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PubMed2005

Deleterious mutations in exon 1 of MECP2 in Rett syndrome.

The MECP2 gene is responsible for 80-85% of typical cases of Rett syndrome with deleterious mutations affecting exons 3 and 4. Recently, an alternate transcript including exon 1 was discovered with a new protein isoform (MeCP2_e1) much more abundant in brain. We screened exon 1 of MECP2 for mutations and for large rearrangements in a panel of 212 typical cases of Rett syndrome and one family case with atypical Rett syndrome. We identified two deleterious mutations (c.48_55dup and c.62+2_62+3del) and four large rearrangements encompassing exon 1 of MECP2. We also identified the c.16_21dup alteration formerly reported as c.3_4insGCCGCC and give additional support to classify this sequence variation as polymorphic. In our large panel of typical Rett, mutations affecting exon 1 of MECP2 represent 1% of the deleterious alleles. This study confirms that mutations in exon 1 of MECP2 are a rare cause of Rett syndrome.

Child, Preschool↗

PubMed2001

Selection intensity against deleterious mutations in RNA secondary structures and rate of compensatory nucleotide substitutions.

A two-locus model of reversible mutations with compensatory fitness interactions is presented; single mutations are assumed to be deleterious but neutral in appropriate combinations. The expectation of the time of compensatory nucleotide substitutions is calculated analytically for the case of tight linkage between sites. It is shown that selection increases the substitution time dramatically when selection intensity Ns > 1, where N is the diploid population size and s the selection coefficient. Computer simulations demonstrate that recombination increases the substitution time, but the effect of recombination is small when selection is weak. The amount of linkage disequilibrium generated in the process of compensatory substitution is also investigated. It is shown that significant linkage disequilibrium is expected to be rare in natural populations. The model is applied to the mRNA secondary structure of the bicoid 3' untranslated region of Drosophila. It is concluded that average selection intensity Ns against single deleterious mutations is not likely to be much larger than 1.

3' Untranslated Regions↗

PubMed1998

Deleterious mutation accumulation in organelle genomes.

It is well established on theoretical grounds that the accumulation of mildly deleterious mutations in nonrecombining genomes is a major extinction risk in obligately asexual populations. Sexual populations can also incur mutational deterioration in genomic regions that experience little or no recombination, i.e., autosomal regions near centromeres, Y chromosomes, and organelle genomes. Our results suggest, for a wide array of genes (transfer RNAs, ribosomal RNAs, and proteins) in a diverse collection of species (animals, plants, and fungi), an almost universal increase in the fixation probabilities of mildly deleterious mutations arising in mitochondrial and chloroplast genomes relative to those arising in the recombining nuclear genome. This enhanced width of the selective sieve in organelle genomes does not appear to be a consequence of relaxed selection, but can be explained by the decline in the efficiency of selection that results from the reduction of effective population size induced by uniparental inheritance. Because of the very low mutation rates of organelle genomes (on the order of 10(-4) per genome per year), the reduction in fitness resulting from mutation accumulation in such genomes is a very long-term process, not likely to imperil many species on time scales of less than a million years, but perhaps playing some role in phylogenetic lineage sorting on time scales of 10 to 100 million years.

Animals↗

PubMed2006

RDMAS: a web server for RNA deleterious mutation analysis.

BACKGROUND: The diverse functions of ncRNAs critically depend on their structures. Mutations in ncRNAs disrupting the structures of functional sites are expected to be deleterious. RNA deleterious mutations have attracted wide attentions because some of them in cells result in serious disease, and some others in microbes influence their fitness. RESULTS: The RDMAS web server we describe here is an online tool for evaluating structural deleteriousness of single nucleotide mutation in RNA genes. Several structure comparison methods have been integrated; sub-optimal structures predicted can be optionally involved to mitigate the uncertainty of secondary structure prediction. With a user-friendly interface, the web application is easy to use. Intuitive illustrations are provided along with the original computational results to facilitate quick analysis. CONCLUSION: RDMAS can be used to explore the structure alterations which cause mutations pathogenic, and to predict deleterious mutations which may help to determine the functionally critical regions. RDMAS is freely accessed via http://biosrv1.bmi.ac.cn/rdmas.

Databases, Nucleic Acid↗

PubMed2002

Deleterious mutations in a hybrid zone: can mutational load decrease the barrier to gene flow?

The aim of this paper is to investigate the effect of deleterious mutations in a hybrid zone maintained by selection against hybrids. In such zones, linkage disequilibria among hybrid depression loci, resulting from a balance between migration and selection, are crucial in maintaining the barrier because they allow each locus, in addition to its own selection coefficient, to cumulate indirect selective effects from other loci. Deleterious alleles produce heterosis and increase by this means the effective migration rate in structured populations. In a hybrid zone, they therefore contribute to decrease linkage disequilibria as well as the barrier to gene flow imposed by hybrid depression. However, deleterious mutations have no effect: (i) when selection against hybrids is weak, because linkage disequilibria are small even without heterosis in this case, or (ii) when selection against hybrids is so strong that it overwhelms heterosis. On the other hand, with moderate selection against hybrids, the decrease in the strength of the barrier due to heterosis may reach detectable levels, although it requires relatively small population sizes and/or migration rates. The effect is expected to be small and only within small genomes where loci are tightly linked can it become strong. Nevertheless, neglecting mutational load may to some extent obscure the estimations of selective parameters based either on artificial F1 crosses or on cline characteristics.

Computer Simulation↗

PubMed1999

The effect of overdominance on characterizing deleterious mutations in large natural populations.

Alternatives to the mutation-accumulation approach have been developed to characterize deleterious genomic mutations. However, they all depend on the assumption that the standing genetic variation in natural populations is solely due to mutation-selection (M-S) balance and therefore that overdominance does not contribute to heterosis. Despite tremendous efforts, the extent to which this assumption is valid is unknown. With different degrees of violation of the M-S balance assumption in large equilibrium populations, we investigated the statistical properties and the robustness of these alternative methods in the presence of overdominance. We found that for dominant mutations, estimates for U (genomic mutation rate) will be biased upward and those for h (mean dominance coefficient) and s (mean selection coefficient), biased downward when additional overdominant mutations are present. However, the degree of bias is generally moderate and depends largely on the magnitude of the contribution of overdominant mutations to heterosis or genetic variation. This renders the estimates of U and s not always biased under variable mutation effects that, when working alone, cause U and s to be underestimated. The contributions to heterosis and genetic variation from overdominant mutations are monotonic but not linearly proportional to each other. Our results not only provide a basis for the correct inference of deleterious mutation parameters from natural populations, but also alleviate the biggest concern in applying the new approaches, thus paving the way for reliably estimating properties of deleterious mutations.

Animals↗

PubMed2006

Elimination of deleterious mutations in plastid genomes by gene conversion.

Asexual reproduction is believed to be detrimental, mainly because of the accumulation of deleterious mutations over time, a hypothesis known as Muller's ratchet. In seed plants, most asexually reproducing genetic systems are polyploid, with apomictic species (plants forming seeds without fertilization) as well as plastids and mitochondria providing prominent examples. Whether or not polyploidy helps asexual genetic systems to escape Muller's ratchet is unknown. Gene conversion, particularly when slightly biased, represents a potential mechanism that could allow asexual genetic systems to reduce their mutation load in a genome copy number-dependent manner. However, direct experimental evidence for the operation of gene conversion between genome molecules to correct mutations is largely lacking. Here we describe an experimental system based on transgenic tobacco chloroplasts that allows us to analyze gene conversion events in higher plant plastid genomes. We provide evidence for gene conversion acting as a highly efficient mechanism by which the polyploid plastid genetic system can correct deleterious mutations and make one good genome out of two bad ones. Our finding that gene conversion can be biased may provide a molecular link between asexual reproduction, high genome copy numbers and low mutation rates.

Base Sequence↗

PubMed2005

Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.

This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.

Alleles↗

PubMed2000

Inbreeding depression due to mildly deleterious mutations in finite populations: size does matter.

We studied the effects of population size on the inbreeding depression and genetic load caused by deleterious mutations at a single locus. Analysis shows how the inbreeding depression decreases as population size becomes smaller and/or the rate of inbreeding increases. This pattern contrasts with that for the load, which increases as population size becomes smaller but decreases as inbreeding rate goes up. The depression and load both approach asymptotic limits when the population size becomes very large or very small. Numerical results show that the transition between the small and the large population regimes is quite rapid, and occurs largely over a range of population sizes that vary by a factor of 10. The effects of drift on inbreeding depression may bias some estimates of the genomic rate of deleterious mutation. These effects could also be important in the evolution of breeding systems in hermaphroditic organisms and in the conservation of endangered populations.

Genetics, Population↗

PubMed1997

Deleterious mutations, variable epistatic interactions, and the evolution of recombination.

In this paper, we examine the conditions that allow increased recombination to evolve in the presence of recurrent deleterious mutation. We focus on a three-locus model first studied by Feldman et al. (1980), which follows the dynamics of a modifier locus that alters the recombination rate between two loci subject to deleterious mutation. Although Feldman et al. (1980) indicated that increased recombination might be favored if there is diminishing-returns epistasis, we show that alleles that increase the recombination rate can only invade if there is synergistic epistasis between the loci under selection. Even with synergistic epistasis, evolution at the modifier locus will lead to decreased recombination if the modifier locus is loosely linked and epistasis is strong. Using the multi-locus analysis of Barton (1995), we show that variability among loci in the sign and strength of epistasis further decreases the parameter space over which increased recombination may evolve. We conclude that, even with negative epistasis, increased recombination may only be favored when linkage is tight, especially if, as seems likely, epistatic interactions are highly variable among loci.

Animals↗

PubMed2000

The X chromosome and the rate of deleterious mutations in humans.

Monosomy for the X chromosome in humans creates a genetic Achilles' heel for nature to deal with. We report that the human X chromosome appears to have one-third the density of the coding sequence of the autosomes and, because of partial shielding from the high mutation rate of the male sex, that it should also have a lower mutation rate than the autosomes (i.e.,.73). Hence, the X chromosome should contribute one quarter (.33x.73=.24) of the deleterious mutations expected from its DNA content. In this way, selection has possibly moderated risks from mutation in X-linked genes that are thought to have been fixed in their syntenic state since the onset of the mammalian lineage. The unexpected difference in the density of coding sequences indicates that our recent, hemophilia B-based estimate of the rate of deleterious mutations per zygote should be increased from 1.3 to 4 (1.3x3).

Base Composition↗

PubMed1994

Selection against deleterious mutations and the maintenance of biparental sex.

The mutational deterministic hypothesis postulates an advantage to sexual over asexual reproduction when mutation rates are on the order of 1.0 per genome per generation, provided that selection takes the form of a synergistic epistasis. While the efficacy of this mechanism has been investigated for infinite populations, its ability to protect sex in finite populations exhibiting stochastic dynamics remains untested. Stochastic processes have the potential to undermine protection for sex in two ways: (1) asexual lineages derived from sexual ancestors may, by chance, be founded by individuals bearing fewer than the equilibrium mean number of mutations, and (2) once established, such lineages will undergo random perturbations in the rates at which they grow and accumulate mutations. In the present study, I show using computer simulation that sexual populations of as many as 10,000 individuals are susceptible to invasion by asexual lineages for mutation rates higher than predicted under the mutational deterministic hypothesis. My simulations differ from previous investigations in that they model the progress of asexual lineages into sexual populations as both stochastic and deterministic processes for various mutation rates, selection regimes, and population sizes. It is suggested that ecological factors, such as parasitism or release from competition, could interact with selection against deleterious mutations to protect sex. To provide the sole explanation for sex, however, may require that selection against deleterious mutations be accompanied by mutation rates on the order of 2.0 per genome per generation.

Animals↗

PubMed2003

Male-biased transmission of deleterious mutations to the progeny in Arabidopsis thaliana.

The extent and cause of male-biased mutation rates, the higher number of mutations in sperm than in eggs, is currently an active and controversial subject. Recent evidence indicates that this male (sperm) bias not only occurs in animals but also in plants. The higher mutation rate in plant sperm was inferred from rates of evolution of neutral DNA regions, and the results were confined to the mitochondria and chloroplasts of gymnosperms. However, the relative transmission rates of deleterious mutations, which have substantial evolutionary consequences, have rarely been studied. Here, an investigation is described by using the hermaphroditic self-compatible flowering plant Arabidopsis thaliana, in which we artificially increased the rate of mutation in pollen (i.e., sperm donor) and maternal (i.e., egg donor) parents, by using two kinds of UV irradiation in parallel and separate experiments, and assessed the deleterious effects on fitness of the F(2) generation. The results show that more deleterious induced mutations are transmitted to the progeny by a sperm than by an egg. These findings provide the first experimental evidence that more deleterious mutations are inherited from sperm than from an egg in any organism. Possible causes underlying this male bias are discussed.

Arabidopsis↗

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↗

PubMed2001

The influence of neighborhood size and habitat shape on the accumulation of deleterious mutations.

To examine the impact of genetic neighborhood size and habitat shape on genetic load and the accumulation of deleterious mutation, individual-based simulations were performed in continuously distributed habitats. The risk of extinction increased as both the area of the habitat and the neighborhood size decreased. When the neighborhood area became smaller than the habitat area, habitat shape also began to influence the risk of extinction by mutation loads, expected time to extinction being shorter in longer and narrower habitats than in a square habitat. Both the number of homozygous deleterious loci per individual and the mutation load in the population increased as the neighborhood size and total population size decreased. Neighborhood size and total population size both independently affected the average number of homozygous deleterious loci per individual. In addition, as the ratio of the long to the short side of the rectangle of a habitat increased, the average number of homozygous deleterious loci increased. When the areas of the habitats were held constant, the average number of homozygous loci and the mutation loads were smallest for a regular square and largest for the longest, narrowest habitat. These results suggest that the spatial genetic structure of an individual is an important factor in the accumulation of deleterious mutations and the risk of extinction by mutation meltdown.

Animals↗

PubMed2003

Deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria.

The primary genetic form of trimethylaminuria (TMAU) is caused by inherited defects in the flavin-containing monooxygenase 3 (FMO3) gene. Defective FMO3 has a decreased ability to catalyze the N-oxygenation of the dietary-derived malodourous amine, trimethylamine. We report two novel deleterious mutations identified in two unrelated individuals affected by the disorder. Sequence analysis of the FMO3 coding exons amplified from genomic DNA revealed that the mutation from individual 1 was heterozygous for a G>A missense mutation in exon 2 of the FMO3 gene. The mutation changed a GAG encoding Glu at codon 32 to AAG encoding Lys. Wild-type and mutant E32K FMO3 were expressed in Escherichia coli as maltose binding-fusion proteins and assayed for their ability to catalyze oxygenation of various FMO3 substrates. The results showed that the E32K mutation abrogated the catalytic activity of the enzyme. Individual 2 was identified as heterozygous for the P153L mutation. In addition, individual 2 was also heterozygous for a novel single nucleotide deletion of A191 in exon 3 at codon 64. The deletion resulted in a frame shift and caused premature termination of the FMO3 gene immediately after codon 65. Family pedigree analysis revealed that the P153L and the deletion mutation were carried on different alleles for this individual. Therefore, both alleles of the FMO3 gene for individual 2 were affected by mutations abolishing the catalytic activity of the enzyme, explaining the severe TMAU condition. The two deleterious mutations reported herein were rare mutations with estimated allelic frequencies of less than 1%.

Amino Acid Sequence↗

PubMed2006

Interference among deleterious mutations favours sex and recombination in finite populations.

Sex and recombination are widespread, but explaining these phenomena has been one of the most difficult problems in evolutionary biology. Recombination is advantageous when different individuals in a population carry different advantageous alleles. By bringing together advantageous alleles onto the same chromosome, recombination speeds up the process of adaptation and opposes the fixation of harmful mutations by means of Muller's ratchet. Nevertheless, adaptive substitutions favour sex and recombination only if the rate of adaptive mutation is high, and Muller's ratchet operates only in small or asexual populations. Here, by tracking the fate of modifier alleles that alter the frequency of sex and recombination, we show that background selection against deleterious mutant alleles provides a stochastic advantage to sex and recombination that increases with population size. The advantage arises because, with low levels of recombination, selection at other loci severely reduces the effective population size and genetic variance in fitness at a focal locus (the Hill-Robertson effect), making a population less able to respond to selection and to rid itself of deleterious mutations. Sex and recombination reveal the hidden genetic variance in fitness by combining chromosomes of intermediate fitness to create chromosomes that are relatively free of (or are loaded with) deleterious mutations. This increase in genetic variance within finite populations improves the response to selection and generates a substantial advantage to sex and recombination that is fairly insensitive to the form of epistatic interactions between deleterious alleles. The mechanism supported by our results offers a robust and broadly applicable explanation for the evolutionary advantage of recombination and can explain the spread of costly sex.

Alleles↗

PubMed2002

Deleterious mutation and the evolution of eusociality.

Certain arguments concerning the evolution of eusociality form a classic example of the application of the principles of kin selection. These arguments center on the different degrees of relatedness of potential beneficiaries of an individual's efforts, for example a female's higher relatedness to her sisters than to her daughters in a haplodiploid system. This type of reasoning is insufficicnt to account for the evolution and maintainence of sexual reproduction, because parthenogenic females produce offspring that are more closely related to them than are offspring produced sexually. Among the forces invoked to explain sexual reproduction is deleterious mutation. This factor can be shown to favor eusociality as well, because siblings produced by helping carry fewer deleterious alleles on average than would offspring. The strength of this effect depends on the genomewide deleterious mutation rate, U, and on the selection coefficient, s, associated with deleterious alleles. For small s, the effect depends approximately on the product Us. This phenomenon illustrates that an assumption implicit in some analyses-that the relatedness of an individual to an actor is all that matters to its value to that actor-can fail for the evolution of eusociality as it does for the evolution of sex.

Animals↗