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PubMed1998

Quantitative genetics of ovariole number in Drosophila melanogaster. II. Mutational variation and genotype-environment interaction.

The rare alleles model of mutation-selection balance (MSB) hypothesis for the maintenance of genetic variation was evaluated for two quantitative traits, ovariole number and body size. Mutational variances (VM) for these traits, estimated from mutation accumulation lines, were 4.75 and 1.97 x 10(-4) times the environmental variance (VE), respectively. The mutation accumulation lines were studied in three environments to test for genotype x environment interaction (GEI) of new mutations; significant mutational GEI was found for both traits. Mutations for ovariole number have a quadratic relationship with competitive fitness, suggesting stabilizing selection for the trait; there is no significant correlation between mutations for body size and competitive fitness. Under MSB, the ratio of segregating genetic variance, VG, to mutational variance, VM, estimates the inverse of the selection coefficient against a heterozygote for a new mutation. Estimates of VG/VM for ovariole number and body size were both approximately 1.1 x 10(4). Thus, MSB can explain the level of variation, if mutations affecting these traits are under very weak selection, which is inconsistent with the empirical observation of stabilizing selection, or if the estimate of VM is biased downward by two orders of magnitude. GEI is a possible alternative explanation.

Analysis of Variance↗
PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗
PubMed1999

Beta-catenin accumulation and mutation of the CTNNB1 gene in hepatoblastoma.

Hepatoblastoma is a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years. Epidemiologic studies have shown an increased frequency of this tumor type in families affected by adenomatous polyposis coli. In addition to the epidemiologic data, molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential. In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, we observed increased beta-catenin levels in the cytoplasm and in the nuclei of three investigated hepatoblastomas. Sequencing of exon 3 of the beta-catenin gene (CTNNB1) revealed an activating mutation in one of the tumor samples. Our data indicate for the first time that beta-catenin accumulation may play a role in the development of hepatoblastoma and that activating mutations of the beta-catenin gene may substitute biallelic APC inactivation in this tumor type. Genes Chromosomes Cancer 25:399-402, 1999.

Cadherins↗
PubMedDate not supplied

Cancer, aging and cellular senescence.

Normal cells do not divide indefinitely due to a process termed cellular or replicative senescence. Several lines of evidence suggest that replicative senescence evolved to protect higher eukaryotes, particularly mammals, from developing cancer. Senescent cells differ from their presenescent counterparts in three way: 1) they arrest growth and cannot be stimulated to reenter the cell cycle by physiological mitogens; 2) they become resistant to apoptotic cell death; 3) they acquire altered differentiated functions. Replicative senescence occurs because, owing to the biochemistry of DNA replication, cells acquire one or more critically short telomere. The mechanism by which a short telomere induces the senescent phenotype is unknown. Recent findings suggest that certain types of DNA damage and inappropriate mitogenic signals can also cause cells to adopt a senescent phenotype. Thus, cells respond to a number of potentially oncogenic stimuli by adopting a senescent phenotype. These findings suggest that the senescence response is a fail-safe mechanism that protects cells from tumorigenic transformation. Despite the protection from cancer conveyed by cellular senescence and other mechanisms that suppress tumorigenesis, the development of cancer is almost inevitable as mammalian organisms age. Why is this the case? Certainly, aging predisposes cells to accumulate mutations, several of which are necessary before malignant transformation occurs, particularly in humans. However, many benign or relatively well-controlled tumors may also harbor many potentially oncogenic mutations, suggesting that the tissue microenvironment can suppress the expression of many malignant phenotypes. Although the idea remains controversial, cellular senescence has also been proposed to contribute to organismal aging. Senescent cells have recently been shown to accumulate with age in human tissues. One possibility is that the tissue microenvironment is disrupted by the accumulation of dysfunctional senescent cells. Thus, mutation accumulation may synergize with the accumulation of senescent cells, leading to increasing risk for developing cancer that is a hallmark of mammalian aging.

Aging↗
PubMed2003

Rapid fitness recovery in mutationally degraded lines of Caenorhabditis elegans.

Deleterious mutation accumulation has been implicated in many biological phenomena and as a potentially significant threat to human health and the persistence of small populations. The vast majority of mutations with effects on fitness are known to be deleterious in a given environment, and their accumulation results in mean population fitness decline. However, whether populations are capable of recovering from negative effects of prolonged genetic bottlenecks via beneficial or compensatory mutation accumulation has not previously been tested. To address this question, long-term mutation-accumulation lines of the nematode Caenorhabditis elegans, previously propagated as single individuals each generation, were maintained in large population sizes under competitive conditions. Fitness assays of these lines and comparison to parallel mutation-accumulation lines and the ancestral control show that, while the process of fitness restoration was incomplete for some lines, full recovery of mean fitness was achieved in fewer than 80 generations. Several lines of evidence indicate that this fitness restoration was at least partially driven by compensatory mutation accumulation rather than a result of a generic form of laboratory adaptation. This surprising result has broad implications for the influence of the mutational process on many issues in evolutionary and conservation biology.

Analysis of Variance↗
PubMed2004

Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defective Arabidopsis.

During the many cell divisions that precede formation of plant gametes, their apical-meristem and floral antecedents are continually exposed to endogenous and environmental mutagenic threats. Although some deleterious recessive mutations may be eliminated during growth of haploid gametophytes and functionally haploid early embryos ("haplosufficiency quality-checking"), the multiplicity of plant genome-maintenance systems suggests aggressive quality control during prior diploid growth. To test in Arabidopsis a hypothesis that prior mismatch repair (MMR) is paramount in defense of plant genetic fidelity, we propagated in parallel 36 MMR-defective (Atmsh2-1) and 36 wild-type lines. The Atmsh2-1 lines rapidly accumulated a wide variety of mutations: fifth-generation (G5) plants showed abnormalities in morphology and development, fertility, germination efficiency, seed/silique development, and seed set. Only two Atmsh2-1, but all 36 wild-type lines, appeared normal at G5. Analyses of insertion/deletion mutation at six repeat-sequence (microsatellite) loci showed each Atmsh2-1 line to have evolved its own "fingerprint," the results of as many as 10 microsatellite mutations in a single line. Thus, MMR during diploid growth is essential for plant genomic integrity.

Arabidopsis↗
PubMed2002

Long-term Helicobacter pylori infection in Japanese monkeys induces atrophic gastritis and accumulation of mutations in the p53 tumor suppressor gene.

BACKGROUND: Helicobacter pylori is accepted as a definite human gastric carcinogen from an epidemiological point of view despite insufficient experimental data. Although we previously showed that the number of p53 immunopositive cells in the atrophic gastric mucosa of H. pylori-infected Japanese monkeys gradually increased over time, data on p53 gene mutations were not obtained in that study. To obtain direct evidence of carcinogenesis associated with H. pylori infection, we investigated whether p53 gene mutations are present in the gastric mucosa of a nonhuman primate model susceptible to H. pylori. MATERIALS AND METHODS: Using the DNA from gastric tissues obtained from six H. pylori-uninfected monkeys of different ages, nucleotide sequence of the wild-type p53 gene was determined by amplification of exons (Ex) 5, 6, 7 and 8 and sequencing. Gastric specimens obtained from eight Japanese monkeys that had been infected with H. pylori for different lengths of time (1.5-7.5 years), were analyzed for mutations in exons 5-8 of p53. RESULTS: In the six H. pylori-uninfected monkeys, nucleotide sequences of p53 Ex 5-8 were completely common and no mutations were noted. However, among the monkeys that were infected with H. pylori over various periods of time, there was an accumulation of p53 nucleotide (amino acid) substitutions as the gastric atrophy score increased. CONCLUSIONS: We conclude that the appearance of p53 gene mutation may be closely associated with the degree of gastric mucosal atrophy, which depends on the duration of H. pylori infection. Searching for p53 gene mutations may be useful for studying the progression of gastric carcinogenesis associated with H. pylori.

Animals↗
PubMed2004

Vesicular stomatitis virus evolution during alternation between persistent infection in insect cells and acute infection in mammalian cells is dominated by the persistence phase.

Vesicular stomatitis virus has the potential for very rapid evolution in the laboratory, but like many other arboviruses, it evolves at a relatively slow rate in the natural environment. Previous work showed that alternating replication in different cell types does not promote stasis. In order to determine whether other factors promote stasis, we compared the fitness trajectories of populations evolving during acute infections in mammalian cells, populations evolving during persistent infections in insect cells, and populations evolving during alternating acute and persistent infection cycles. Populations evolving under constant conditions increased in fitness in the environment in which they replicated. An asymmetric trade-off was observed such that acute infection had no cost for persistence but persistent replication had a dramatic cost for acute infection in mammalian cells. After an initial period of increase, fitness remained approximately constant in all the populations that included persistent replication, but fitness continuously increased in populations evolving during acute infections. Determination of the consensus sequence of the genes encoding the N, P, M, and G proteins showed that the pattern of mutation accumulation was coherent with fitness changes during persistence so that once fitness reached a maximum, the rate of mutation accumulation dropped. Persistent replication dominated both the genetic and the phenotypic evolution of the populations that alternated between acute infection of mammalian cells and persistence in insect cells, and fitness loss was observed in the mammalian environment despite periodic replication in mammalian cells. These results show that stasis can be achieved without good levels of adaptation to both the mammalian and the insect environments.

Adaptation, Physiological↗
PubMed1997

The rate of mitochondrial mutagenesis is faster in mice than humans.

We have investigated mitochondrial DNA (mtDNA) mutagenesis in the laboratory mouse. Using a nested PCR method for quantification, the absolute frequency, tissue distribution and rate of increase of mitochondrial deletion mutations was determined. Multiple deletions arise in brain, cardiac muscle and kidney tissues: deletions occur most frequently at regions of directly repeated mtDNA homology. Deletion frequencies rose by 2.5 x 10(5), 6300- and 4000-fold in heart, brain and kidney, respectively, between young and old mice. The rates of mtDNA mutation accumulation in mouse and human hearts are modeled well by exponential equations, with r-values of 0.96 and 0.97, and mutations rose much faster in mouse than human mtDNA per unit time. Thus, maintenance of the human mitochondrial genome is much better than that of mice, consistent with the higher rate and final extent of total DNA repair in humans than mice, that has been observed by others and consistent with the predictions of the disposable soma model of aging. A comparison of mtDNA mutagenesis from cardiocytes vs. whole heart tissue was undertaken. Deletion mutations were observed to be 100-fold lower in DNA prepared from isolated cardiocytes than from whole heart homogenates, consistent with a model of uneven mtDNA mutation accumulation.

Adolescent↗
PubMed2006

The ovotestis: an underdeveloped organ of evolution.

In animals that have separate sexes (gonochorists), many sperm are produced to fertilise a few eggs. As the male germline undergoes more mitoses, so the accumulated mutation frequency is elevated in sperm compared with ova, and evolution is 'male-driven'. In contrast, in many hermaphroditic animals, a single organ--the ovotestis--produces both ova and sperm. Since self-renewing cells in the ovotestis may give rise to both cell types throughout life, ova in hermaphrodites could in theory have undergone as many cell divisions as sperm. Here, I consider some possible effects of the ovotestis on evolution. In particular, I hypothesise that the accumulated mutation frequency of nuclear genes in hermaphrodites (including species that change sex) may reach twice that compared with gonochorists. There may be an even greater increase in the mitochondrial mutation frequency. Further developmental studies and the accumulation of comparative data should allow hypothesis testing. If the prediction is correct, then it may provide the most-straightforward explanation for the extraordinary diversity of mitochondrial DNA in some hermaphrodites, especially molluscs.

Animals↗
PubMed2005

The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans.

The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences.

Animals↗
PubMed2004

[Survival of Drosophila melanogaster progeny after prolonged suppression of pairing and recombination in autosome 3].

Two laboratory strains of Drosophila melanogaster carrying autosome 3 with a meiotic mutation c(3)G, that is maintained since 1985 in various balancer chromosomes, were used to study progeny survival. The conditions of maintenance of these strains and the effect of c(3)G mutation completely suppress pairing and crossing over in autosome 3. In addition, selection pressure was reduced because of permanent heterozygosity, mediating mutation accumulation in the studied chromosome. In both strains, all homozygotes for autosome 3 (c(3)G/c(3)G) perished. The hybrid homozygotes carrying chromosomes with c(3)G mutation from different strains survived in 0.4 of the progeny. Higher viability was observed after normal pairing and meiotic recombination of the studied chromosome with the chromosome from the wild-type line. The possible nature of mutations accumulated after prolonged suppression of chromosome pairing and recombination is discussed.

Animals↗
PubMed2004

Spontaneous mutations in diploid Saccharomyces cerevisiae: more beneficial than expected.

We performed a 1012-generation mutation-accumulation (MA) experiment in the yeast, Saccharomyces cerevisiae. The MA lines exhibited a significant reduction in mean fitness and a significant increase in variance in fitness. We found that 5.75% of the fitness-altering mutations accumulated were beneficial. This finding contradicts the widely held belief that nearly all fitness-altering mutations are deleterious. The mutation rate was estimated as 6.3 x 10(-5) mutations per haploid genome per generation and the average heterozygous fitness effect of a mutation as 0.061. These estimates are compatible with previous estimates in yeast.

Likelihood Functions↗
PubMed2004

Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing.

Dyskerin is a nucleolar protein present in small nucleolar ribonucleoprotein particles that modify specific uridine residues of rRNA by converting them to pseudouridine. Dyskerin is also a component of the telomerase complex. Point mutations in the human gene encoding dyskerin cause the skin and bone marrow failure syndrome dyskeratosis congenita (DC). To test the extent to which disruption of pseudouridylation or telomerase activity may contribute to the pathogenesis of DC, we introduced two dyskerin mutations into murine embryonic stem cells. The A353V mutation is the most frequent mutation in patients with X-linked DC, whereas the G402E mutation was identified in a single family. The A353V, but not the G402E, mutation led to severe destabilization of telomerase RNA, a reduction in telomerase activity, and a significant continuous loss of telomere length with increasing numbers of cell divisions during in vitro culture. Both mutations caused a defect in overall pseudouridylation and a small but detectable decrease in the rate of pre-rRNA processing. In addition, both mutant embryonic stem cell lines showed a decrease in the accumulation of a subset of H/ACA small nucleolar RNAs, correlating with a significant decrease in site-specific pseudouridylation efficiency. Interestingly, the H/ACA snoRNAs decreased in the G402E mutant cell line differed from those affected in A353V mutant cells. Hence, our findings show that point mutations in dyskerin may affect both the telomerase and pseudouridylation pathways and the extent to which these functions are altered can vary for different mutations.

Animals↗
PubMed2000

Estimation of microsatellite mutation rates in Drosophila melanogaster.

Microsatellite mutations were studied in a set of 175 mutation accumulation lines, all of them independently derived from a completely homozygous population of Drosophila melanogaster and maintained under strong inbreeding during 80 generations. We assayed 28 microsatellites and detected two mutations. One mutation consisted of a single addition of a dinucleotide repeat and the other was a deletion of five trinucleotide repeats. The average mutation rate was 5.1 x 10(-6), in full agreement with previous estimates from two different sets of mutation accumulation lines.

Animals↗
PubMed2005

Contribution of de novo point mutations to the overall mutational burden in mitochondrial DNA of adult rats.

This study analyzed the incidence of point mutations in mitochondrial DNA of brain and muscle tissues from young (6-month) and old (24-month) male F344 rats. Coding sequence mutations in subunit 5 of the NADH dehydrogenase gene were detected after high-fidelity PCR amplification and cloning by denaturing gradient gel electrophoresis (DGGE) assay followed by sequencing of detected mutants. In total, almost a thousand individual clones were analyzed both in brain and muscle samples. On average, mtDNA from brain tissue showed a 66% increase with age in mutation frequencies (2.3+/-1.9 vs. 3.8+/-4.5 x 10(-4) mutations/bp, mean+/-SD), which failed to reach statistical significance (p=0.45). Muscle tissues yielded substantially fewer mutants with average mutant frequencies for both young and old rats almost 10 times lower than the corresponding values in the brain tissue (0.3+/-0.4 and 0.5+/-0.6 x 10(-4), respectively). The difference in mutation accumulation between muscle and brain was highly significant in both the younger group (Chi-squared=9.7, p < or = 0.01) and in older animals (Chi-squared=10.9, p < or = 0.001). Molecular analysis of the mutated sequences revealed that almost half were identical sequences recurring in different samples and tissues. Our findings indicate that the process of mutation accumulation in mitochondria begins in the germ-line and/or during earlier stages of life, contributing up to half of the total mutational burden, whereas de novo spontaneous formation of point mutations in adulthood is far less than was anticipated.

Aging↗
PubMed2003

A nuclear restorer-of-fertility mutation disrupts accumulation of mitochondrial ATP synthase subunit alpha in developing pollen of S male-sterile maize.

Mitochondrial biogenesis and function depend upon the interaction of mitochondrial and nuclear genomes. Forward genetic analysis of mitochondrial function presents a challenge in organisms that are obligated to respire. In the S-cytoplasmic male sterility (CMS-S) system of maize, expression of mitochondrial open reading frames (orf355-orf77) conditions collapse of developing haploid pollen. Nuclear restorer-of-fertility mutations that circumvent pollen collapse are often homozygous lethal. These spontaneous mutations potentially result from disruption of nuclear genes required for mitochondrial gene expression, in contrast to homozygous-viable restorer-of-fertility alleles that function to block or compensate for the expression of mitochondrial CMS genes. Consistent with this hypothesis, the homozygous-lethal restoring allele historically designated RfIII was shown to be recessive in diploid pollen produced by tetraploid CMS-S plants. Accordingly, the symbol for this allele has been changed to restorer-of-fertility lethal 1 (rfl1). In haploid rfl1 pollen, orf355-orf77 transcripts and mitochondrial transcripts encoding the alpha-subunit of the ATP synthase (ATPA) were decreased in abundance. Haploid rfl1 pollen failed to accumulate wild-type levels of ATPA protein, indicating that functional requirements for mitochondrial protein accumulation are relaxed in maize pollen. The CMS-S system and rfl mutations therefore allow for the selection of nuclear mutations disrupting mitochondrial biogenesis in a multicellular eukaryote.

Alleles↗
PubMed1996

Nature of deleterious mutation load in Drosophila.

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

Animals↗