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Results for “deleterious mutation”

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PubMed1988

Deleterious mutations and the evolution of sexual reproduction.

The origin and maintenance of sexual reproduction continues to be an important problem in evolutionary biology. If the deleterious mutation rate per genome per generation is greater than 1, then the greater efficiency of selection against these mutations in sexual populations may be responsible for the evolution of sex and related phenomena. In modern human populations detrimental mutations with small individual effects are probably accumulating faster than they are being eliminated by selection.

Animals↗

PubMed1988

Deleterious mutations as an evolutionary factor. III. Mating preference and some general remarks.

This paper is concerned with the evolution of female mating choice under truncation selection against deleterious mutations. It is shown that with genome degradation rates necessary to maintain crossing-over, the advantage of choice is of the order of several per cent, which is in good accord with some experimental data. Some other consequences of intensive selection against mutations are also discussed.

Animals↗

PubMed1999

BRCA1 IVS16+6T-->C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site.

Results and conclusions are presented that characterize BRCA1 IVS16+6T-->C as a deleterious mutation. BRCA1 transcripts from peripheral blood mononuclear cells of a breast cancer patient with the transition IVS16+6T-->C show the loss of a heterozygous base within codon 871. Additionally, an aberrant RNA splicing product which incorporates 69 bases of the 5' end of intron 16 at the junction of exons 16 and 17 is produced solely from the allele with IVS16+6T-->C. This insertion contains two in-frame stop codons and encodes a protein truncated at residue 1662 (plus 13 residues encoded by the intron). The aberrant transcript is specifically associated with the intronic variant since it was contained within the insertion. Furthermore, sequence analysis of the heterozygous base within codon 871 demonstrates that the two RNA products, productive mRNA and aberrantly spliced RNA, are contributed to exclusively by separate alleles. Finally, the aberrant transcript is produced by the activation of a cryptic splice site which has greater homology with the primate consensus splice sequence than the mutated exon 16 donor site.

Adult↗

PubMed1999

Effect of selection against deleterious mutations on the decline in heterozygosity at neutral loci in closely inbreeding populations.

Transition matrices for selfing and full-sib mating were derived to investigate the effect of selection against deleterious mutations on the process of inbreeding at a linked neutral locus. Selection was allowed to act within lines only (selection type I) or equally within and between lines (type II). For selfing lines under selection type I, inbreeding is always retarded, the retardation being determined by the recombination fraction between the neutral and selected loci and the inbreeding depression from the selected locus, irrespective of the selection coefficient (s) and dominance coefficient (h) of the mutant allele. For selfing under selection type II or full-sib mating under both selection types, inbreeding is delayed by weak selection (small s and sh), due to the associative overdominance created at the neutral locus, and accelerated by strong selection, due to the elevated differential contributions between alternative alleles at the neutral locus within individuals and between lines (for selection type II). For multiple fitness loci under selection, stochastic simulations were run for populations with selfing, full-sib mating, and random mating, using empirical estimates of mutation parameters and inbreeding load in Drosophila. The simulations results are in general compatible with empirical observations.

Animals↗

PubMed1998

Inferences on genome-wide deleterious mutation rates in inbred populations of Drosophila and mice.

A theoretical analysis was carried out on the mutation load observed in long-maintained inbred lines from two experiments with Drosophila and mice. The rate of decline in fitness and its sampling distribution were predicted for both experiments using Monte Carlo simulation with a range of mutational parameters and models. The predicted rates of change in fitness were compared to the empirical observed rates, which were close to zero. The classical hypothesis of many deleterious mutations (about one event per genome per generation) of small effect (1-2%) resulting in a mutation pressure for fitness of about 1% per generation is incompatible with the data. Recent estimates suggesting an overall mutation pressure for fitness traits of about 0.1% are, however, compatible with the observed load.

Animals↗

PubMed1992

Deleterious mutations and the origin of the meiotic ploidy cycle.

A population genetical model is investigated in which the organism either alternates between diploid and haploid states or lives entirely in the haploid state. The behavior of the organism is determined by the genotype at a modifier locus. At an independent locus deleterious mutations occur at a low but constant frequency. It is found that the haploid behavior is always an evolutionarily attainable stable trait, while the ploidy-cyclic behavior is an evolutionarily attainable stable trait only when a certain condition holds. This condition depends on the strength of selection, the degree of "sheltering" given by the heterozygote state, and the degree of linkage between the modifier locus and the locus under selection. The last result leads to the speculation that the eukaryotes are derived from an organism which first developed more than one chromosome before it evolved the ploidy cycle.

Genetics, Population↗

PubMed2003

A conservative test of genetic drift in the endosymbiotic bacterium Buchnera: slightly deleterious mutations in the chaperonin groEL.

The obligate endosymbiotic bacterium Buchnera aphidicola shows elevated rates of sequence evolution compared to free-living relatives, particularly at nonsynonymous sites. Because Buchnera experiences population bottlenecks during transmission to the offspring of its aphid host, it is hypothesized that genetic drift and the accumulation of slightly deleterious mutations can explain this rate increase. Recent studies of intraspecific variation in Buchnera reveal patterns consistent with this hypothesis. In this study, we examine inter- and intraspecific nucleotide variation in groEL, a highly conserved chaperonin gene that is constitutively overexpressed in Buchnera. Maximum-likelihood estimates of nonsynonymous substitution rates across Buchnera species are strikingly low at groEL compared to other loci. Despite this evidence for strong purifying selection on groEL, our intraspecific analysis of this gene documents reduced synonymous polymorphism, elevated nonsynonymous polymorphism, and an excess of rare alleles relative to the neutral expectation, as found in recent studies of other Buchnera loci. Comparisons with Escherichia coli generally show patterns predicted by their differences in N(e). The sum of these observations is not expected under relaxed or balancing selection, selective sweeps, or increased mutation rate. Rather, they further support the hypothesis that drift is an important force driving accelerated protein evolution in this obligate mutualist.

Buchnera↗

PubMed2003

Sex slows down the accumulation of deleterious mutations in the homothallic fungus Aspergillus nidulans.

Coexistence of sexual and asexual reproduction within the same individual is an intriguing problem, especially when it concerns homothallic haplonts, like the fungus Aspergillus nidulans. In this fungus asexual and sexual offspring have largely identical genotypes. This genetic model organism is an ideal tool to measure possible fitness effects of sex (compared to asex) resulting from causes other than recombination. In this article we show that slightly deleterious mutations accumulate at a lower rate in the sexual pathway than in the asexual pathway. This secondary sex advantage may contribute to the persistence of sexual spores in this fungus. We propose that this advantage results from intra-organismal selection of the fittest gametes or zygotes, which is more stringent in the costly sexual pathway.

Aspergillus nidulans↗

PubMed2004

Enhanced detection of deleterious mutations by TTGE analysis of mother and child's DNA side by side.

Mitochondrial DNA (mtDNA) disorders represent a group of heterogeneous diseases that are caused by mutations in mtDNA. We examined 45 pairs of mother and the affected child, by screening the entire mitochondrial genome with temporal temperature gradient gel electrophoresis (TTGE), using 32 pairs of overlapping primers. TTGE is an effective method of mutation detection. It detects and distinguishes heteroplasmic mutations from homoplasmic mutations. By running the mother and child's DNA samples side by side and sequencing only the DNA fragments showing different TTGE patterns, excessive sequencing can be avoided, particularly because most sequence variations represent benign polymorphisms. Mutations identified by sequencing were further confirmed by PCR/ASO (allele-specific oligonucleotide) dot blot analysis or PCR/RFLP (restriction fragment length polymorphism). A total of seven differences in sequence between mother and child pairs were identified: A189G, T5580C, G5821A, C5840T, A8326G, G12207A, and G15995A. All but two mutations were novel. The most significant are the A8326G, G12207A, and G15595A mutations. The A8326G is located at the anticodon region of tRNA(Lys), right next to the first nucleotide of the triplet codon, and it is highly conserved throughout evolution. The G12207A mutation is located at the first base of tRNA(ser) (AGY). The G15995A mutation occurs at a stem region that results in the disruption of the first base pair at the anticodon loop of tRNA(Pro) and is highly conserved throughout evolution from sea urchins to mammals. Running TTGE side by side with DNAs from mother and the affected child is a novel method to detect deleterious mutations.

Child↗

PubMed2002

Genome-wide deleterious mutation favors dispersal and species integrity.

Here I develop the idea that ubiquitous harmful genome-wide mutation with local differentiation favors dispersal, even though migration reduces average fitness. Historical contingency of the mutational process means that demes (sub-populations) differentiate from one another. Deleterious or lethal partially recessive mutations carried by migrants then do not encounter similar mutations in the recipient deme. Migrant offspring have higher fitness than offspring of residents, because migrant offspring are heterozygous rather than homozygous for harmful mutations. The advantage is inversely related to local inbreeding depression. Genome-wide deleterious mutation favors the evolution of dispersal, which in turn enhances the genetic integrity of the species.

Animals↗

PubMedDate not supplied

Mating structure and the cost of deleterious mutation: I. Postponing inbreeding.

Mating structure governs the distribution of alleles in populations and thus the extent to which the phenotypes associated with the alleles are manifested. A mating system which initially achieves more genetic identity within individuals than between individuals enhances the probability that a finite population without reproductive excess will become extinct from a recessive lethal or semidominant lethal mutation; however, such a mating system decreases the number of deaths that will ensue if the population size is maintained by replacement of inviable progeny with individuals engendered from the entire mating pool. This is illustrated with Markov chain models for half-sib and double-first-cousin mating in populations of four individuals and by various techniques for analogous large populations. An appropriate choice of mating strategy can mitigate the effect of deleterious mutations, but the determination of which strategy is appropriate depends on how much reproductive excess is available and on the relative costs assigned to individual deaths and the extinction of a population.

Animals↗

PubMed2006

The accumulation of deleterious mutations in rice genomes: a hypothesis on the cost of domestication.

The extent of molecular differentiation between domesticated animals or plants and their wild relatives is postulated to be small. The availability of the complete genome sequences of two subspecies of the Asian rice, Oryza sativa (indica and japonica) and their wild relatives have provided an unprecedented opportunity to study divergence following domestication. We observed significantly more amino acid substitutions during rice domestication than can be expected from a comparison among wild species. This excess is disproportionately larger for the more radical kinds of amino acid changes (e.g. Cys<-->Tyr). We estimate that approximately a quarter of the amino acid differences between rice cultivars are deleterious, not accountable by the relaxation of selective constraints. This excess is negatively correlated with the rate of recombination, suggesting that 'hitchhiking' has occurred. We hypothesize that during domestication artificial selection increased the frequency of many deleterious mutations.

Crops, Agricultural↗

PubMed2026

Evidence of genome-wide relaxed selection on mildly deleterious mutations in an ancient subterranean catfish.

About one hundred subterranean catfish species have been described, resulting from repeated colonization of cave environments by multiple surface lineages. Most cave-dwelling species are found in the Americas, in particular in South America, but a few species also live in Central and North America. Despite the availability of high-quality genome assemblies for two cave species, the Mexican blind catfish Prietella phreatophila and the Colombian blind catfish Trichomycterus rosablanca, genomic approaches to investigate genetic changes associated with subterranean life or to estimate cave colonization times remain largely unexplored. To fill this gap, we additionally sequenced the genomes of four blind and depigmented subterranean catfishes from Peru (three Trichomycterus and one Astroblepus), as well as the genomes of four close surface relatives. We first extracted a large set of light-related genes, such as phototransduction and crystallin genes, and found contrasting decays of these sequences in different cave species, from 1% of pseudogenes in T. rosablanca to 48% in P. phreatophila. Two independent molecular dating methods gave congruent ages, indicating that these catfishes colonized subterranean habitats at different times, ranging from Early Pliocene to Late Pleistocene, supporting the hypothesis that surface catfishes repeatedly and rapidly adapted to subterranean habitats. The oldest cave species, P. phreatophila, appears to have been thriving in the dark for over 3.5 million years. Moreover, a genome-wide analysis of protein-coding genes suggests weaker purifying selection on mildly deleterious mutations in this cavefish than in other catfish lineages, likely reflecting a long-term small effective population size.

cavefishes↗

PubMed2005

Deleterious mutations in small subunit ribosomal RNA identify functional sites and potential targets for antibiotics.

Many clinically useful antibiotics interfere with protein synthesis in bacterial pathogens by inhibiting ribosome function. The sites of action of known drugs are limited in number, are composed primarily of ribosomal RNA (rRNA), and coincide with functionally critical centers of the ribosome. Nucleotide alterations within such sites are often deleterious. To identify functional sites and potential sites of antibiotic action in the ribosome, we prepared a random mutant library of rRNA genes and selected dominant mutations in 16S rRNA that interfere with cell growth. Fifty-three 16S rRNA positions were identified whose mutation inhibits protein synthesis. Mutations were ranked according to the severity of the phenotype, and the detrimental effect of several mutations on translation was verified in a specialized ribosome system. Analysis of the polysome profiles of mutants suggests that the majority of the mutations directly interfered with ribosome function, whereas a smaller fraction of mutations affected assembly of the small ribosomal subunit. Twelve of the identified mutations mapped to sites targeted by known antibiotics, confirming that deleterious mutations can be used to identify antibiotic targets. About half of the mutations coincided with known functional sites in the ribosome, whereas the rest of the mutations affected ribosomal sites with less clear functional significance. Four clusters of deleterious mutations in otherwise unremarkable ribosomal sites were identified, suggesting their functional importance and potential as antibiotic targets.

Anti-Bacterial Agents↗

PubMed1997

Inbreeding depression and inferred deleterious-mutation parameters in Daphnia.

DENG and LYNCH recently proposed a method for estimating deleterious genomic mutation parameters from changes in the mean and genetic variance of fitness traits upon inbreeding in outcrossing populations. Such observations are readily acquired in cyclical parthenogens. Selfing and life-table experiments were performed for two such Daphnia populations. We observed a significant inbreeding depression and an increase of genetic variance for all traits analyzed. DENG and LYNCH's original procedures were extended to estimate genomic mutation rate (U), mean dominance coefficient (h), mean selection coefficient (s), and scaled genomic mutational variance (Vm/Ve). On average, U, h, s and Vm/Ve (indicates an estimate) are 0.84 [corrected], 0.30, 0.14 and 4.6E-4, respectively. For the true values, the U and h are lower bounds, and s and Vm/Ve upper bounds. The present U, h and Vm/Ve are in general concordance with earlier results. The discrepancy between the present s and that from mutation-accumulation experiments in Drosophila (approximately 0.04) is discussed. It is shown that different reproductive modes do not affect gene frequency at mutation-selection equilibrium if mutational effects on fitness are multiplicative and not completely recessive.

Animals↗

PubMed1998

Inferring Deleterious-Mutation Parameters in Natural Daphnia Populations.

Deng and Lynch (1, 2) proposed to characterize deleterious genomic mutations from changes in the mean and genetic variance of fitness traits upon selfing in outcrossing populations. Such observations can be readily acquired in cyclical parthenogens. Selfing and life-table experiments were performed for two such Daphnia populations. A significant inbreeding depression and an increase of genetic variance for all traits analyzed were observed. Deng and Lynch's (2) procedures were employed to estimate the genomic mutation rate (U), mean dominance coefficient (), mean selection coefficient (), and scaled genomic mutational variance (). On average, and (^ indicates an estimate) are 0.84, 0.30, 0.14 and 4.6E-4 respectively. For the true values, the and are lower bounds, and and upper bounds.

Journal Article↗

PubMed2000

Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma.

Members of the nuclear factor (NF)-kappaB family of transcription factors play a crucial role in cellular activation, immune responses, and oncogenesis. In most cells, they are kept inactive in the cytosol by complex formation with members of the inhibitor of NF-kappaB (IkappaB) family, whose degradation activates NF-kappaB in response to diverse stimuli. In Hodgkin's lymphoma (HL), high constitutive nuclear activity of NF-kappaB is characteristic of the malignant Hodgkin and Reed-Sternberg (H/RS) cells, which occur at low number in a background of nonneoplastic inflammatory cells. In single H/RS cells micromanipulated from histological sections of HL, we detect clonal deleterious somatic mutations in the IkappaBalpha gene in two of three Epstein-Barr virus (EBV)-negative cases but not in two EBV-positive cases (in which a viral oncogene may account for NF-kappaB activation). There was no evidence for IkappaBalpha mutations in two non-HL entities or in normal germinal center B cells. This study establishes deleterious IkappaBalpha mutations as the first recurrent genetic defect found in H/RS cells, indicating a role of IkappaBalpha defects in the pathogenesis of HL and implying that IkappaBalpha is a tumor suppressor gene.

Adult↗

PubMed2000

Estimation of parameters of deleterious mutations in partial selfing or partial outcrossing populations and in nonequilibrium populations.

The Deng-Lynch method was developed to estimate the rate and effects of deleterious genomic mutations (DGM) in natural populations under the assumption that populations are either completely outcrossing or completely selfing and that populations are at mutation-selection (M-S) balance. However, in many plant and animal populations, selfing or outcrossing is often incomplete in that a proportion of populations undergo inbreeding while the rest are outcrossing. In addition, the degrees of deviation of populations from M-S balance are often not known. Through computer simulations, we investigated the robustness and the applicability of the Deng-Lynch method under different degrees of partial selfing or partial outcrossing and for nonequilibrium populations approaching M-S balance at different stages. The investigation was implemented under constant, variable, and epistatic mutation effects. We found that, generally, the estimation by the Deng-Lynch method is fairly robust if the selfing rate (S) is <0.10 in outcrossing populations and if S > 0.8 in selfing populations. The estimation may be unbiased under partial selfing with variable and epistatic mutation effects in predominantly outcrossing populations. The estimation is fairly robust in nonequilibrium populations at different stages approaching M-S balance. The dynamics of populations approaching M-S balance under various parameters are also studied. Under mutation and selection, populations approach balance at a rapid pace. Generally, it takes 400-2000 generations to reach M-S balance even when starting from homogeneous individuals free of DGM. Our investigation here provides a basis for characterizing DGM in partial selfing or outcrossing populations and for nonequilibrium populations.

Genetics, Population↗