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PubMed1998

Tracing cell fates in human colorectal tumors from somatic microsatellite mutations: evidence of adenomas with stem cell architecture.

Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. In contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy.

Adenoma↗
PubMed1997

Transgenic mouse models for studying mutations in vivo: applications in aging research.

To study mutation accumulation in the DNA of somatic cells and tissues during aging in vivo, a transgenic mouse model has been constructed. The model harbors plasmid vectors, containing the lacZ reporter gene, integrated head to tail at various chromosomal locations. Procedures have been worked out to efficiently recover the plasmids into E. coli host cells. A positive selection system, permitting only E. coli cells with a lacZ mutated plasmid to grow, allows for the accurate determination of mutation frequencies as the ratio of mutant colonies versus the total number of transformants, i.e., the total number of plasmid copies recovered. Results obtained from a life span study of plasmid mice with vector clusters on chromosome 3 and 4 indicated age-related mutation accumulation in the liver, but not in the brain. Comparison of the mutational spectra revealed a significantly larger proportion of large size-change mutations in liver than in brain.

Aging↗
PubMed1997

Transgenic mouse models for studying mutations in vivo: applications in aging research.

To study mutation accumulation in the DNA of somatic cells and tissues during aging in vivo, a transgenic mouse model has been constructed. The model harbors plasmid vectors, containing the lacZ reporter gene, integrated head to tail at various chromosomal locations. Procedures have been worked out to efficiently recovery the plasmids into E. coli host cells. A positive selection system, permitting only E. coli cells with a lacZ mutated plasmid to grow, allows for the accurate determination of mutation frequencies as the ratio of mutant colonies versus the total number of transformants, i.e., the total number of plasmid copies recovered. Results obtained from a life span study of plasmid mice with vector clusters on chromosome 3 and 4 indicated age-related mutation accumulation in the liver, but not in the brain. Comparison of the mutational spectra revealed a significantly larger proportion of large size-change mutations in liver than in brain.

Aging↗
PubMed2006

Ameiotic recombination in asexual lineages of Daphnia.

Despite the enormous theoretical attention given to the evolutionary consequences of sexual reproduction, the validity of the key assumptions on which the theory depends rarely has been evaluated. It is often argued that a reduced ability to purge deleterious mutations condemns asexual lineages to an early extinction. However, most well characterized asexual lineages fail to exhibit the high levels of neutral allelic divergence expected in the absence of recombination. With purely descriptive data, it is difficult to evaluate whether this pattern is a consequence of the rapid demise of asexual lineages, an unusual degree of mutational stability, or recombination. Here, we show in mutation-accumulation lines of asexual Daphnia that the rate of loss of nucleotide heterozygosity by ameiotic recombination is substantially greater than the rate of introduction of new variation by mutation. This suggests that the evolutionary potential of asexual diploid species is not only a matter of mutation accumulation and reduced efficiency of selection, and [corrected] it underscores the limited utility of using neutral allelic divergence as an indicator of ancient asexuality.

Animals↗
PubMed2002

Detection of genetically divergent clone mates in apomictic dandelions.

This study aims to identify genetically diverged clone mates in apomictic dandelions. Clone mates are defined as individuals that may have diverged as a result of mutation accumulation and that have undergone only clonal reproduction since their most recent common ancestor. Based on distinctive morphology and an aberrant and rare chloroplast haplotype, northwest European individuals of Taraxacum section Naevosa are well suited for the detection of clonal lineages in which mutation has occurred. In the case of strictly clonal reproduction, nuclear genetic variability was expected to be hierarchically organized. Nucleotide polymorphisms in internal transcribed spacer (ITS) sequences, however, were incompatible with a clonal structure of the Norwegian individuals, probably due to persistent ancestral polymorphisms that pre-date the origin of the Naevosa clone. This interpretation is supported by the presence of ITS variants in section Naevosa that were also found in distantly related dandelions. In contrast to the ITS sequence data, amplified fragment length polymorphisms (AFLPs), isozymes and microsatellites strongly supported the contention of prolonged clonal reproduction and mutation accumulation in Norwegian Naevosa. Because these markers are generally considered to be more variable and more rapidly evolving than ITS sequences, mutations in these markers probably evolved after the origin of the clone. Within the Norwegian clone, a surprising number of markers distinguished the clone mates. As a consequence, incorporation of mutation in the detection of clone mates is anticipated to have a big impact on estimates of size, geographical range and age of clones as well as on experimental designs of studies of clonal plants.

Asteraceae↗
PubMedDate not supplied

The location of a mutator factor in a strain of Drosophila melanogaster by assaying male recombination.

In a set of "mutation accumulation lines," of Drosophila melanogaster that had originated from two different wild-caught lethal-carrying second chromosomes (Yamaguchi and Mukai 1974; Mukai and Cockerham 1977; Voelker, Schaffer and Mukai 1980) a correlation exists between high rates of reverse mutation at two visible loci and the ability to induce male recombination (Scobie and Schaffer 1982). The second and third chromosomes were extracted from the lines demonstrating these phenomena and tested for independent ability to induce male recombination. When the wild chromosome being tested was of male origin extracted second chromosome lines were found to induce moderate to high levels of male recombination and reduced transmission frequency of the wild chromosome (the k value). The recombinants recovered in these crosses also demonstrated a high level of double-crossover recombination without the recovery of the reciprocal double-recombinant types. In addition, identifiable portions of extracted second chromosomes of male origin have been placed on very similar, marked genetic backgrounds and tested for their ability to induce male recombination. Results of this procedure have identified two regions of the second chromosome that induce male recombination and reduce k values. These results are consistent with the hypothesis that there exist two mutator factors and the second chromosome, each associated with a "mutation accumulation line" with an unstable locus.

Animals↗
PubMed2003

From the stress theory of aging to energetic and evolutionary expectations for longevity.

Stress targets energy carriers. Genes for stress resistance are selected that convey high metabolic efficiency enabling adaptation to the energetically restrictive and hence stressful environments of natural populations. Data from experimental organisms and from humans are consistent with a primary role for stress resistance underlying life span, which provides a hitherto neglected procedure for assaying longevity in natural populations. Taking into account the metabolic consequences of stressful environments, the free-radical theory of aging becomes a general stress theory of aging. A recent derivative, the deprivation-syndrome theory of aging, highlights resource and hence energy shortages. Energy balances under the stress theory of aging are primary for an understanding of the evolutionary limits of longevity of organisms in their habitats. In contrast, well-nourished humans of the modern era, and laboratory, domesticated and island populations are exposed to more benign conditions which appear to provide the background for other evolutionary theories of aging, especially the mutation accumulation and antagonistic pleiotropy theories. In modern human populations where selection for stress resistance is relaxed compared with earlier harsher conditions, substantial future evolutionary extensions to maximum life span may be difficult to attain because of the mutation accumulation process. However there is an urgent need for comparative empirical studies of life-history traits including longevity under benign and harsh environments.

Aging↗
PubMed1999

Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation.

Inappropriate activation of the Wnt pathway resulting from beta-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivo effects of mutated beta-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the beta-catenin gene, and the expression and subcellular localization of beta-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in beta-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of beta-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of beta-catenin was significantly associated with the presence of mutations in the beta-catenin gene (P < 0.005). Moreover, nuclear beta-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P < 0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/beta-catenin pathway in HCC results mainly from somatic mutations in the beta-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.

Adult↗
PubMed2006

An ageing question: do embryonic stem cells protect their genomes?

Many physiological and cellular processes contribute to the ageing of individuals. One hypothesis argues that the genomes of somatic cells accumulate mutations, which, in turn, alter the metabolism of the cells and contribute to the ageing process. The frequency of somatic mutation approaches 10(-4) and the majority of mutagenic events at heterozygous loci is due to loss of heterozygosity as a consequence of mitotic recombination. A corollary to the argument that somatic cells accumulate mutations is that cells of the germ line and ES cells have a greater requirement for maintaining the integrity of their genomes. In the former case, a high somatic mutation frequency predicts an increase in somatic disease, which limits our lifespan. The corollary is that cells of the germline and ES cells must minimize the mutational burden to limit the frequency of congenital disease and to ensure the proper transmission of undamaged DNA to the gene pool. This report describes two mechanisms utilized by murine ES cells to minimize DNA damage within the proliferative pool. In the first case, murine ES cells display a frequency of mutation and mitotic recombination that is about 100-fold lower than that observed in somatic cells. Second, ES cells lack a G1 checkpoint following DNA damage. When subjected to ionizing radiation, the fraction of apoptotic cells increases to about 40%. Ectopic expression of Chk2 is sufficient to establish a G1 arrest and the concomitant protection from cell death.

Aging↗
PubMed2000

p53 protein accumulation and mutations in normal and benign breast tissue.

Mutations in the p53 gene are amongst the most common molecular changes detected in breast cancer, and there are several reports suggesting that changes in p53 may contribute to the pathogenesis of this disease. In a previous case-control study, we demonstrated that p53 protein accumulation detected by immunohistochemistry in normal or benign breast tissue was associated with a 2.5-fold increase in the risk of subsequent breast cancer. In this study, we investigated whether p53 gene mutations were present in the 29 p53 immunopositive normal or benign breast tissue samples and in 15 p53 immunonegative normal or benign breast tissue samples selected randomly from the original study. DNA was extracted from paraffin sections and underwent PCR-SSCP analysis for exons 4 to 10. PCR products that showed abnormal mobility were excised and sequenced. Sixteen (59.2%) of the 27 immunopositive breast tissue samples and 4 (26.7%) of the 15 immunonegative samples had p53 sequence changes. There was no obvious association between the occurrence of these alterations and any specific histopathologic features. Ten cases showed p53 mutations, and they were all missense base substitutions of the transition type. Thirteen other gene changes occurred in 11 breast tissue samples and consisted of 8 silent (no amino acid change), 4 intronic alterations, and 1 indeterminate alteration. One individual had both a mutation and a silent change. In summary, p53 gene alterations can occur in normal or benign breast tissue, but resolution of their role in the pathogenesis of breast cancer will require long-term follow-up studies involving comparisons of breast cancer occurrence in patients with and without p53 mutations as well as functional assays to determine their significance.

Breast↗
PubMed2006

Thermodynamics of neutral protein evolution.

Naturally evolving proteins gradually accumulate mutations while continuing to fold to stable structures. This process of neutral evolution is an important mode of genetic change and forms the basis for the molecular clock. We present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (delta deltaG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins and provides formulas for calculating how fluctuations in stability can overdisperse the molecular clock. It also shows that the structural influences on the rate of sequence evolution observed in earlier simulations can be calculated using just the single-mutation delta deltaG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case the proteins evolve excess mutational robustness that is manifested by extra stability and an increase in the rate of sequence evolution. All our theoretical predictions are confirmed by simulations with lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics shapes the process of evolution.

Computer Simulation↗
PubMed2001

Correspondence re: Y. Yamada et al., frequent beta-catenin gene mutations and accumulations of the protein in the putative preneoplastic lesions lacking macroscopic aberrant crypt foci appearance, in rat colon carcinogenesis. Cancer Res., 60: 3323-3327, 2000; and sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis. Cancer Res., 61: 1874-1878, 2001.

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Animals↗
PubMed2004

[Mitochondrial dysfunction and focal segmental glomerular sclerosis].

Focal segmental glomerular sclerosis (FSGS) is known as one of major renal complication of mitochondrial cytopathies. Glomerular epithelial cells are primary pathogenic sites in FSGS lesions. Glomerular epithelial cells are regarded as terminally differentiated cells and do not proliferate. This characteristic is the same for neuron cells and muscular cells, which are major sites of mitochondrial DNA mutations accumulation. Accumulation of mitochondrial DNA mutations might induce mitochondrial dysfunction and lead to FSGS lesion in glomeruli or these accumulations are only consequences of pathogenic stimuli to glomerular epithelial cells during the disease course of several glomerulopathies. Further investigations are needed to clarify pathogenic role of mitochondria and mitochondrial DNA mutations.

DNA, Mitochondrial↗
PubMedDate not supplied

Novel drug resistance mutations in HIV: recognition and clinical relevance.

During its spread among humans, HIV-1 has developed an extraordinary degree of genetic diversity. The pol region encoding for viral enzymes such as the reverse transcriptase and the protease, and the env region encoding for the viral glycoprotein gp41 are subjected not only to natural variation, but also to the selection pressure imposed by the pharmacologic treatment. Under these conditions in HIV-1 infected people, the virus is able to escape from antiviral drugs by accumulating mutations, either alone or in clusters. The patterns of mutations accumulated by HIV-1 under drug pressure are quite variable, depending on the backbone of virus strains, the level and type of pharmacologic pressure, and the length of therapy. To date, a high number of mutations in protease, reverse transcriptase, and gp41 have been associated with reduced susceptibility to the antiretroviral drugs currently available. However, a number of studies continuously highlight the existence of additional mutations beyond those currently known to be involved in the development of drug resistance in vivo. Most of these so-called "novel" mutations are involved in agonistic correlations with the classical drug resistance mutations on divergent evolutionary pathways, and are associated with an increased resistance to specific drugs. At the same time, the presence of some novel mutations at therapeutic failure has also been significantly associated with an increase of viremia, thus suggesting that they may also play a compensatory role leading to improved viral replication. Interestingly, some natural polymorphisms in drug-naive patients have been significantly associated with the development of drug resistance mutations at failure, thus suggesting their ability to decrease the genetic barrier to the development of drug resistance. In contrast, other novel mutations are negatively associated with specific antiviral treatment, showing negative interactions with relevant drug resistance mutations, and are associated with increased susceptibility to specific drugs. This article reviews the importance of recognition and the clinical relevance of novel mutations involved in resistance to the currently used antiretroviral drugs, discussing in particular the role of novel drug resistance mutations in the reverse transcriptase enzyme. Such novel mutations should be considered for improved prediction of clinical response to antiretroviral drugs and for assessing the efficacy of next-generation drugs.

Anti-HIV Agents↗
PubMed2000

Proline accumulation by mutation or disruption of the proline oxidase gene improves resistance to freezing and desiccation stresses in Saccharomyces cerevisiae.

We examined the role of intracellular proline under freezing and desiccation stress conditions in Saccharomyces cerevisiae. When cultured in liquid minimal medium, the proline-nonutilizing mutant containing the put1 mutation (proline oxidase-deficient) produced more intracellular proline, and increased the cell survival rate as compared to the wild-type strain after freezing and desiccation. We also constructed two PUT1 gene disruptants. PUT1-disrupted mutants in minimal medium supplemented with external proline at 0.1% accumulated higher proline levels than those of the control strains (17-22-fold). These disruptants also had a 2-5-fold increase in cell viability compared to the control strains after freezing and desiccation stresses. These results indicate that proline has a stress-protective function in yeast.

Adaptation, Physiological↗
PubMed2006

Naturally occurring genetic variation in the age-specific immune response of Drosophila melanogaster.

Immunosenescence, the age-related decline in immune response, is a well-known consequence of aging. To date, most studies of age-related changes in immune response focused on the cellular and physiological bases of this decline; we have virtually no understanding of the genetic basis of age-related changes in the immune system or if indeed such control exists. We used 25 chromosome substitution lines of Drosophila melanogaster derived from a natural population to address three questions: (i) How is the function of the innate immune system influenced by age? (ii) Is there a genetic basis for phenotypic variation in immune response at different ages? (iii) Is there a genetic basis for differences in the way that age influences the immune function? Virgin females from each line were assayed for immune response using clearance of infection with Escherichia coli at 1 and 4 weeks of age. We found significant genetic variation among lines in immune response at each age. Unexpectedly, when averaged across all lines, the immune response actually improved with age. However, there was significant variation in the effect of age on immune response with 11 lines showing improvement, nine lines showing no change and five exhibiting a decline with age. There was no genetic correlation of immune response across ages suggesting that different loci contribute to variation in immune response at each age. The genetic component of the variation in immune response increased with age, a pattern predicted by the mutation accumulation model of senescence. However, this increase in variation resulted in part from the improvement of the immune response in some lines with age. Thus the observed changes in genetic variation in immune function with age are not entirely explained by the mutation accumulation model.

Aging↗
PubMed1997

Nonadaptive mutations occur on the F' episome during adaptive mutation conditions in Escherichia coli.

One of the most studied examples of adaptive mutation is a strain of Escherichia coli, FC40, that cannot utilize lactose (Lac-) but that readily reverts to lactose utilization (Lac+) when lactose is its sole carbon source. Adaptive reversion to Lac+ occurs at a high rate when the Lac- allele is on an F' episome and conjugal functions are expressed. It was previously shown that nonselected mutations on the chromosome did not appear in the Lac- population while episomal Lac+ mutations accumulated, but it remained possible that nonselected mutations might occur on the episome. To investigate this possibility, a second mutational target was created on the Lac- episome by mutation of a Tn1O element, which encodes tetracycline resistance (Tetr), to tetracycline sensitivity (Tets). Reversion rates to Tetr during normal growth and during lactose selection were measured. The results show that nonselected Tetr mutations do accumulate in Lac- cells when those cells are under selection to become Lac+. Thus, reversion to Lac+ in FC40 does not appear to be adaptive in the narrow sense of the word. In addition, the results suggest that during lactose selection, both Lac+ and Tetr mutations are created or preserved by the same recombination-dependent mechanism.

Adaptation, Physiological↗
PubMed2001

Evolutionary theories of ageing applied to long-lived organisms.

Ageing can evolve by mutation accumulation and pleiotropy (trade-offs). The relative prevalence of these two mechanisms is important for determining the likelihood that mechanisms of ageing are homologous in distantly related organisms, and hence the relevance of long-lived organisms to general mechanisms of ageing. Experimental work with Drosophila, examining the properties of standing genetic variation and mutations that accumulate in real time, has provided little evidence in favour of a role for mutation accumulation, but considerable support for the importance of trade-offs, particularly between early fertility and the rate of ageing. Evidence for the roles of these two processes in the evolution of long-livedness can be derived from the response to selection, comparative studies of life history traits and testing for potential trade-offs at the mechanistic level.

Aging↗