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PubMed2000

Evolutionary origin and consequences of uniparental mitochondrial inheritance.

In the great majority of sexual organisms, cytoplasmic genomes such as the mitochondrial genome are inherited (almost) exclusively through only one, usually the maternal, parent. This rule probably evolved to minimize the potential spread of selfish cytoplasmic genomic mutations through a species. Maternal inheritance creates an asymmetry between the sexes from which several evolutionary consequences follow. Because natural selection on mitochondria operates only in females, mitochondrial mutations may have more deleterious effects in males than in females. Strictly uniparental inheritance creates asexual mitochondrial lineages that are vulnerable to mutation accumulation (Muller's ratchet). There is evidence that over evolutionary time mitochondrial genomes have indeed accumulated slightly deleterious mutations. Mutation accumulation in animal mitochondrial genomes is probably slowed down mainly by two processes: a severe reduction in germline mitochondrial genome copy number at some point in the life cycle, enabling more effective elimination of mutations by natural selection, and occasional recombination between maternal and paternal mitochondrial genomes following paternal leakage.

DNA Repair↗
PubMed2005

Genomic buffering mitigates the effects of deleterious mutations in bacteria.

The relationship between the number of randomly accumulated mutations in a genome and fitness is a key parameter in evolutionary biology. Mutations may interact such that their combined effect on fitness is additive (no epistasis), reinforced (synergistic epistasis) or mitigated (antagonistic epistasis). We measured the decrease in fitness caused by increasing mutation number in the bacterium Salmonella typhimurium using a regulated, error-prone DNA polymerase (polymerase IV, DinB). As mutations accumulated, fitness costs increased at a diminishing rate. This suggests that random mutations interact such that their combined effect on fitness is mitigated and that the genome is buffered against the fitness reduction caused by accumulated mutations. Levels of the heat shock chaperones DnaK and GroEL increased in lineages that had accumulated many mutations, and experimental overproduction of GroEL further increased the fitness of lineages containing deleterious mutations. These findings suggest that overexpression of chaperones contributes to antagonistic epistasis.

Adaptation, Physiological↗
PubMed1999

Beta-catenin accumulation and mutation of exon 3 of the beta-catenin gene in hepatocellular carcinoma.

A study was conducted to clarify the contribution of beta-catenin accumulation and mutation of the beta-catenin gene to hepatocarcinogenesis. Beta-catenin accumulation was examined immunohistochemically in 38 paired samples of hepatocellular carcinoma (HCC) and corresponding non-cancerous liver tissue. Gene mutation was analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing using intronic primers encompassing exon 3. Neither accumulation nor mutation was detected in non-cancerous liver tissues that showed no remarkable histological features, chronic hepatitis or liver cirrhosis. Accumulation of beta-catenin was seen in the nucleus, cytoplasm or cell membrane in 15 of 38 (39%) HCC samples, and gene mutation was seen in 9 of 38 (24%) HCC samples. Although there was a significant correlation between accumulation and mutation (P<0.01), six HCCs without mutation also showed accumulation. Samples of early HCC showed neither accumulation nor mutation, and accumulation and mutation were each correlated significantly with portal vein tumor involvement (P<0.05). The present results indicate that (1) mutation of exon 3 of the beta-catenin gene can lead to beta-catenin accumulation, although other mechanisms of accumulation may also operate in HCC, and (2) beta-catenin accumulation and mutation of the beta-catenin gene are not early events in hepatocarcinogenesis, and may be associated with the malignant progression of HCC.

Adult↗
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↗
PubMed2002

Evolution of late-life mortality in Drosophila melanogaster.

Aging appears to cease at late ages, when mortality rates roughly plateau in large-scale demographic studies. This anomalous plateau in late-life mortality has been explained theoretically in two ways: (1) as a strictly demographic result of heterogeneity in life-long robustness between individuals within cohorts, and (2) as an evolutionary result of the plateau in the force of natural selection after the end of reproduction. Here we test the latter theory using cohorts of Drosophila melanogaster cultured with different ages of reproduction for many generations. We show in two independent comparisons that populations that evolve with early truncation of reproduction exhibit earlier onset of mortality-rate plateaus, in conformity with evolutionary theory. In addition, we test two population genetic mechanisms that may be involved in the evolution of late-life mortality: mutation accumulation and antagonistic pleiotropy. We test mutation accumulation by crossing genetically divergent, yet demographically identical, populations, testing for hybrid vigor between the hybrid and nonhybrid parental populations. We found no difference between the hybrid and nonhybrid populations in late-life mortality rates, a result that does not support mutation accumulation as a genetic mechanism for late-life mortality, assuming mutations act recessively. Finally, we test antagonistic pleiotropy by returning replicate populations to a much earlier age of last reproduction for a short evolutionary time, testing for a rapid indirect response of late-life mortality rates. The positive results from this test support antagonistic pleiotropy as a genetic mechanism for the evolution of late-life mortality. Together these experiments comprise the first corroborations of the evolutionary theory of late-life mortality.

Aging↗
PubMed1998

Mutation and senescence: where genetics and demography meet.

Two evolutionary genetic models-mutation accumulation and antagonistic pleiotropy-have been proposed to explain the origin and maintenance of senescence. In this paper, we focus our attention on the mutation accumulation model. We re-examine previous evidence for mutation accumulation in light of new information from large-scale demographic experiments. After discussing evidence for the predictions that have been put forth from models of mutation accumulation, we discuss two critical issues at length. First, we discuss the possibility that classical fruit fly stock maintenance regimes may give rise to spurious results in selection studies of aging. Second, we consider evidence for the assumptions underlying evolutionary models of aging. These models assume that mutations act additively on age-specific survival rate, that there exist mutations whose effects are confined to late age-classes, and that all mutations have equal effects. Recent empirical evidence suggests that each of these three assumptions is unlikely to be true. On the basis of these results, we do not conclude that mutation accumulation is no longer a valid explanation for the evolution of aging. Rather, we suggest that we now need to begin developing more biologically realistic genetic models for the evolution of aging.

Aging↗
PubMed2000

Age-specific effects of novel mutations in Drosophila melanogaster I. Mortality.

Theories for the evolution of aging rest on the assumption that at least some deleterious mutations have effects that are limited to certain ages. Many mutation accumulation studies have tried to measure the number and magnitude of deleterious mutations, but few studies have tried to determine the extent to which the effects of mutations are limited to particular ages. Here we estimate the age-specific effect of deleterious mutations on mortality rate in an outbred population of the fruit fly, Drosophila melanogaster. We used the 'middle class neighborhood' approach to accumulation mutations in populations of flies that had recently been obtained from the wild. There are mutations that increase mortality rates, but whose effects are limited to specific ages. The age-specificity of mutational effects differs between the sexes, between virgin and mated flies, and over time. After 10 and 20 generations of mutation accumulation, there were clear age-specific effects of mutations. After 30 generations, however, the degree of age-specificity decreased. In addition, mutation accumulation led to a steady increase in larval mortality and a small but significant increase in the sex ratio of eclosing flies. We discuss the implications of these results for models of aging, and suggest approaches that future studies should take to obtain accurate information on the age-specificity of novel mutations.

Aging↗
PubMed2004

Molecular basis of fitness loss and fitness recovery in vesicular stomatitis virus.

Viral populations subjected to repeated genetic bottleneck accumulate deleterious mutations in a process known as Muller's ratchet. Asexual viruses, such as vesicular stomatitis virus (VSV) can recover from Muller's ratchet by replication with large effective population sizes. However, mutants with a history of bottleneck transmissions often show decreased adaptability when compared to non-bottlenecked populations. We have generated a collection of bottlenecked mutants and allowed them to recover by large population passages. We have characterized fitness changes and the complete genomes of these strains. Mutations accumulated during the operation of Muller's ratchet led to the identification of two potential mutational hot spots in the VSV genome. As in other viral systems, transitions were more common than transversions. Both back mutation and compensatory mutations contributed to recovery, although a significant level of fitness increase was observed in nine of the 13 bottlenecked strains with no obvious changes in the consensus sequence. Additional replication of three strains resulted in the fixation of single point mutations. Only two mutations previously found in non-bottlenecked, high-fitness populations that had been adapting to the same environment were identified in the recovered strains.

Animals↗
PubMed2003

Relationship between E-cadherin gene mutation and p53 gene mutation, p53 accumulation, Bcl-2 expression and Ki-67 staining in diffuse-type gastric carcinoma.

E-cadherin mutations are found in 50% of diffuse-type gastric carcinoma, but not in intestinal gastric carcinoma. Because cell-cell adhesion mediated by E-cadherin plays an important role in epithelial cell survival, E-cadherin mutations could alter the apoptotic behavior of tumor cells. p53 and Bcl-2 family members are also important regulators of cellular apoptosis. This is the first study that investigates the relationship between E-cadherin gene mutation and p53 gene mutation, p53 accumulation, Bcl-2 expression, and Ki-67 expression in diffuse-type gastric carcinoma (24 cases, E-cadherin mutation status: wild-type in 8 patients and mutant in 16 patients). The mutation status of exons 5-8 of p53 was analyzed by denaturing high pressure liquid chromatography (DHPLC) in formalin-fixed, paraffin-embedded tumor sections, followed by direct sequencing of cases with aberrant chromatographic patterns. p53 mutations were found in 1 of 8 tumors without E-cadherin mutation (12.5%) and in 1 of 16 tumors with E-cadherin mutation (6.3%), a difference that was not statistically significant (p = 1.00). p53 accumulation was found in 8 of 24 tumors (33.3%) by immunohistochemical staining. p53 accumulation was significantly more frequent in tumors without E-cadherin mutations (5 of 8 tumors, 62.5%) than in gastric carcinoma tissues with E-cadherin mutations (3 of 16 tumors, 18.8%, p = 0.03). Bcl-2 staining was not observed in gastric carcinoma cells without E-cadherin mutations, but was detectable in 5 of 16 tumors with E-cadherin mutations (31.3%), a difference that was not statistically significant (p = 0.13). No relationship was observed between Ki-67 staining and the E-cadherin mutation status (p = 1.00). These data suggest that the presence of E-cadherin mutations can significantly alter the accumulation of the apoptosis-regulating p53 protein, whereas no correlation with the p53 mutation status or with Ki-67 staining was observed.

Adenocarcinoma↗
PubMed2006

Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells?

Mitochondrial DNA (mtDNA) mutations accumulate in the skeletal muscle of patients with mtDNA disease, and also as part of healthy ageing. Simulations of human muscle fibres suggest that, over many decades, the continuous destruction and copying of mtDNA (relaxed replication) can lead to dramatic changes in the percentage level of mutant mtDNA in non-dividing cells through random genetic drift. This process should apply to both pathogenic and neutral mutations. To test this hypothesis we sequenced the entire mitochondrial genome for 20 muscle fibres from a healthy elderly 85-year-old individual, chosen because of the low frequency of cytochrome c oxidase negative fibres. Phenotypically neutral single base substitutions were detected in 15% of the healthy fibres, supporting the hypothesis that positive selection is not essential for the clonal expansion of mtDNA point mutations during human life. Treatments that enhance mtDNA replication, such as vigorous excercise, could amplify this process, with potentially detrimental long-term consequences.

Aged, 80 and over↗
PubMed1974

Variation of spontaneous occurrence rates of chromosomal aberrations in the second chromosomes of Drosophila melanogaster.

After accumulating mutations by the aid of marked inversions, spontaneous occurrence rates of chromosome aberrations were estimated for 1148 chromosome lines that originated from five stem line second chromosomes of Drosophila melanogaster. In chromosome lines originating from three stem chromosomes (CH, PQ, and RT), mutations were accumulated for 7550, 7252, and 7256 chromosome generations, respectively, but no structural change was detected. For the chromosome lines that originated from the other two stem chromosomes, the situation was different: Twenty aberrations (19 paracentric inversions and 1 translocation between the second and the third chromosomes) during 45990 chromosome generations took place in the 500 chromosome lines derived from stem line chromosome (AW), and 92 aberrations (83 paracentric inversions, 6 pericentric inversions, 2 translocations between the second and the third chromosomes and 1 transposition) arose during 45006 chromosome generations in the 500 chromosome lines derived from stem line chromosome (JH). For the AW group the occurrence rate becomes 0.00043 per chromosome per generation for all aberrations and 0.00041 for inversions. For the JH group the corresponding rates are 0.00204 and 0.00198, respectively.-A non-random distribution of the breakpoint on the salivary gland chromosome was observed and the breakpoints were concentrated in the regions 26, 29, 33, and 34.-The cytoplasms and the chromosomes (other than the second chromosomes) were made approximately uniform throughout the experiments. Thus, this remarkable variability in the occurrence rate is most probably due to the differences in one or more chromosomal elements on the original five stem chromosomes. The mutable chromosomes (AW and JH) appear to carry a kind of mutator factor such as hi (Ives 1950).

Animals↗
PubMed2004

Aging as an evolved characteristic - Weismann's theory reconsidered.

Theories of aging have become significantly more important because of discoveries which indicate that aging is not universal or inevitable and which therefore indicate that major medical intervention in aging is possible. Directions of anti-aging research could be significantly influenced by basic theories of aging. Weismann proposed in 1882 that aging was an evolved genetically programmed adaptation that had a species benefit. Since then this idea has been largely replaced by various theories in which aging is not an adaptation but results from accumulated adverse mutations or is an adverse side effect of some essential process. Arguments are presented to the effect that aging is an evolved beneficial characteristic and is therefore likely to result from a more complex and structured mechanism than if it resulted from more random processes such as mutation accumulation. Further, aging appears to be one of a number of related and interactive life-cycle characteristics including age-at-puberty suggesting that it might be controlled by similar biological mechanisms.

Adaptation, Biological↗
PubMed2003

The role of mutators in the emergence of antibiotic-resistant bacteria.

Bacteria contain a number of error prevention and error correction systems that maintain genome stability. However, strains exhibiting elevated mutation frequencies have recently been reported amongst natural populations of pathogenic Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa, Neisseria meningitidis, Helicobacter pylori and Streptococcus pneumoniae. The majority of naturally occurring, strong mutators contain defects in the methyl-directed mismatch repair (MMR) system, with mutations in mutS predominating. MMR-deficient strains possess superior genetic backgrounds for the selection of some antibiotic-resistance mutations since mutation frequencies up to 1000-fold higher than normal strains have been reported, and resistance levels achieved in mutators can be greater than those arising in non-mutator hosts. MMR is a major constraint to interspecies recombination events. Removal of this barrier, as in the case of MMR defective mutators, also enhances the frequency of horizontal gene transfer, which is an important mechanism of acquired drug resistance in bacteria. Permanent global mutator status is associated with loss of fitness as mutators accumulate deleterious mutations more frequently than non-mutators. Fitness limitations of mutators may be overcome simply by the high bacterial cell densities that can be achieved during acute infection or by the adoption of transient mutator status. Mutators are a risk factor during the treatment of bacterial infections as they appear to enhance the selection of mutants expressing high- and low-level antibiotic resistance and have the capacity to refine existing plasmid-located resistance determinants.

Animals↗
PubMed2000

Rates of movement of transposable elements on the second chromosome of Drosophila melanogaster.

The rates of movement of 11 families of transposable elements of Drosophila melanogaster were studied by means of in situ hybridization of probes to polytene chromosomes of larvae from a long-term mutation accumulation experiment. Replicate mutation-accumulation lines carrying second chromosomes derived from a single common ancestral chromosome were maintained by backcrosses of single males heterozygous for a balancer chromosome and a wild-type chromosome, and were scored after 116 generations. Twenty-seven transpositions and 1 excision were detected using homozygous viable and fertile second chromosomes, for a total of 235,056 potential sources of transposition events and a potential 252,880 excision events. The overall transposition rate per element per generation was 1.15 x 10(-4) and the excision rate was 3.95 x 10(-6). The single excision (of a roo element) was due to recombination between the element's long terminal repeats. A survey of the five most active elements among nine homozygous lethal lines revealed no significant difference in the estimates of transposition and excision rates from those from viable lines. The excess of transposition over excision events is in agreement with the results of other in situ hybridization experiments, and supports the conclusion that replicative increase in transposable element copy number is opposed by selection. These conclusions are compared with those from other studies, and with the conclusions from population surveys of element frequencies.

Animals↗
PubMed1999

The evolutionary genetics of ageing and longevity.

Evolutionary theories of ageing are based on the observation that the efficacy of natural selection decreases with age. This is because, even without ageing, individuals will die of environmental causes, such as predation, disease and accidents. Ageing is thought to have evolved as the result of optimising fitness early in life. A second process, namely the progressive accumulation of mutations with effects late in life, will reinforce this result. Longevity of a species is therefore determined by the amount of environmental mortality caused by the ecology of a species. The experimental data concerning the relative roles of both processes are reviewed here. Recent discoveries of the levelling of mortality curves, and of age specific mutations in mutation accumulation lines of Drosophila melanogaster, require adjustments to the original models of the evolution of ageing and species longevity. These adjustments do not invalidate the underlying rationale of evolutionary theories of ageing. With current developments in QTL mapping and genetic association studies, the unravelling of the ageing process has the potential to progress rapidly.

Aging↗
PubMed2002

Rate and pattern of mutation at microsatellite loci in maize.

Microsatellites are important tools for plant breeding, genetics, and evolution, but few studies have analyzed their mutation pattern in plants. In this study, we estimated the mutation rate for 142 microsatellite loci in maize (Zea mays subsp. mays) in two different experiments of mutation accumulation. The mutation rate per generation was estimated to be 7.7 x 10(-4) for microsatellites with dinucleotide repeat motifs, with a 95% confidence interval from 5.2 x 10(-4) to 1.1 x 10(-3). For microsatellites with repeat motifs of more than 2 bp in length, no mutations were detected; so we could only estimate the upper 95% confidence limit of 5.1 x 10(-5) for the mutation rate. For dinucleotide repeat microsatellites, we also determined that the variance of change in the number of repeats (sigma(m)2) is 3.2. We sequenced 55 of the 73 observed mutations, and all mutations proved to be changes in the number of repeats in the microsatellite or in mononucleotide tracts flanking the microsatellite. There is a higher probability to mutate to an allele of larger size. There is heterogeneity in the mutation rate among dinucleotide microsatellites and a positive correlation between the number of repeats in the progenitor allele and the mutation rate. The microsatellite-based estimate of the effective population size of maize is more than an order of magnitude less than previously reported values based on nucleotide sequence variation.

Alleles↗
PubMed1996

Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug.

Inhibitors of the human immunodeficiency virus (HIV) protease are a promising class of antiviral agents that dramatically reduce HIV replication both in culture and in infected patients. However, as for many other antiviral compounds, long-term efficacy of these agents is impeded by the emergence of virus variants with increased resistance to their inhibitory action, following selection of specific mutations in the protease coding sequence. We have studied HIV-1 variants that emerged at different stages of selection in the presence of the C2-symmetrical protease inhibitor ABT-77003. The selection of variants was a gradual process during which mutations accumulated at different sites in the protease, generating virus populations with increasing levels of resistance to the drug. The initially selected viruses had a low level of resistance as well as a markedly reduced replicative capacity. Further accumulation of mutations at secondary sites led to an improvement in both drug resistance and replication. In spite of their reduced infectivity, partially selected virus populations did not readily revert to wild-type when serially passaged in drug-free conditions. Instead, even in the absence of drug, secondary mutations identical to those selected in the presence of the inhibitor continued to emerge. These mutations improved both the intrinsic replicative capacity of the virus and its level of resistance to the inhibitor, suggesting that once committed to drug resistance, readaptation of the enzyme to its natural substrate leads to a reduction of its sensitivity to the inhibitor.

Amino Acid Sequence↗
PubMed2005

Inactivated mariner-like elements (MLE) in pink bollworm, Pectinophora gossypiella.

We isolated multiple copies of mariner-like element (MLE) from the pink bollworm (PBW), Pectinophora gossypiella, a key lepidopteran cotton pest. Although all the MLE sequences contain multiple mutations accumulated in their transposase coding region, the consensus sequence revealed a putative ancestral transposase encoding 339 amino acid residues with a D,D(34)D motif, and 36 bp inverted terminal repeats, belonging to the cecropia subfamily, and most similar to the MLE found in Antheraea species. Examining six different pink bollworm populations, we conclude that the MLE in PBW described in this study are ancient and are undergoing the process of accumulating inactivating mutations. This conclusion is supported by the patterns of polymorphisms revealed by genomic Southern hybridization, transposable element displays, and sequences from multiple MLE.

Amino Acid Sequence↗