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PubMed2005

The scale of mutational variation in the murid genome.

Mutation rates vary across mammalian genomes, but little is known about the scale over which this variation occurs. Knowledge of the magnitude and scale of mutational variation is required to understand the processes that drive mutation, and is essential in formulating a robust null hypothesis for comparative genomics studies. Here we estimate the scale of mutational variation in the murid genome by calculating the spatial autocorrelation of nucleotide substitution rates in ancestral repeats. Such transposable elements are good candidates for neutrally evolving sequence and therefore well suited for the study of mutation rate variation. We find that the autocorrelation coefficient decays to a value close to zero by approximately 15 Mb, with little apparent variation in mutation rate under 100 kb. We conclude that the primary scale over which mutation rates vary is subchromosomal. Furthermore, our analysis shows that within-chromosome mutational variability exceeds variation among chromosomes by approximately one order of magnitude. Thus, differences in mutation rate between different regions of the same chromosome frequently exceed differences both between whole autosomes and between autosomes and the X-chromosome. Our results indicate that factors other than the time spent in the male germ line are important in driving mutation rates. This raises questions about the biological mechanism(s) that produce new mutations and has implications for the study of male-driven evolution.

Animals↗
PubMed2000

Long-term mutation rates in the hepatitis B virus genome.

Mutations in the hepatitis B virus (HBV) genome have so far been investigated in cross-sectional or short-term longitudinal studies. Information about long-term changes is lacking due to the difficulty of sampling over long observation periods. In this study, a retrospective approach was used that allowed the analysis of changes in the viral genome from transmission to late stages of infection without the requirement for sampling early during this period. The entire viral genome was sequenced from serum samples of three mothers and their 10 adult children, who presumably had been infected vertically. The emergence of mutations between birth and sampling (mean 26.5 years) was assessed by comparing the individual sequences with the sequence of the strain assumed to have been transmitted. The mean differences from this sequence were 0.02 and 0. 28% in seven asymptomatic and one symptomatic hepatitis B e antigen (HBeAg)-positive carriers, respectively, and 0.62 % in five HBeAg-negative carriers. Mutations occurred throughout the genome and 88% of the mutations caused amino acid substitutions spread over all genes. In HBeAg-negative carriers, the number of nucleotide and amino acid changes was independent of the severity of liver disease and, except the (1762)AGG(1764)-->TGA changes, no specific mutation was associated with liver disease. In conclusion, by using a novel method it was found that the entire HBV genome is extremely stable over long periods of time during the HBeAg-positive phase if the immune response (inflammation) is weak, whereas an average of 20 mutations emerged after development of hepatitis and/or loss of HBeAg without association with clinical outcome.

Adult↗
PubMed2006

Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma.

Although mantle cell lymphoma (MCL) frequently harbors inactivated ataxia telangiectasia mutated (ATM) and p53 alleles, little is known about the molecular phenotypes caused by these genetic changes. We identified point mutations and genomic deletions in these genes in a series of cyclin D1-positive MCL cases and correlated genotype with gene expression profiles and overall survival. Mutated and/or deleted ATM and p53 alleles were found in 56% (40/72) and 26% (21/82) of the cases examined, respectively. Although MCL patients with inactive p53 alleles showed a significant reduction in median overall survival, aberrant ATM status did not predict for survival. Nevertheless, specific gene expression signatures indicative of the mutation and genomic deletion status of each gene were identified that were different from wild-type cases. These signatures were comprised of a select group of genes related to apoptosis, stress responses, and cell cycle regulation that are relevant to ATM or p53 function. Importantly, we found the molecular signatures are different between cases with mutations and deletions, because the latter are characterized by loss of genes colocalized in the same chromosome region of ATM or p53. This information on molecular phenotypes may provide new areas of investigation for ATM function or may be exploited by designing specific therapies for MCL cases with p53 aberrations.

Apoptosis↗
PubMed2000

Estimation of spontaneous genome-wide mutation rate parameters: whither beneficial mutations?

Empirical estimates of genome-wide mutation rates and of the distribution of mutational effects are needed to illuminate various topics ranging from evolutionary biology to conservation. Methods for inferring genome-wide mutation parameters are presented, and results stemming from these studies are reviewed. It is argued that, although most if not all mutations detected in mutation accumulation experiments are deleterious, the question of the rate of favourable mutations (and their effects) is still a matter for debate.

Animals↗
PubMed1995

Theoretical basis of one-dimensional genome scanning: a direct method to identify the site of a mutation.

Genome scanning is a technique designed to uncover a net genetic difference between otherwise identical DNA samples. As such, it can be used to directly identify the site of a gene mutation, facilitating the cloning of DNA fragments from that site. Unlike other conventional positional cloning methods, one-dimensional genome scanning does not require prior knowledge of the location of the gene or mutation nor does it require closely linked markers. Rather, this method can directly identify the site of a net genomic change, such as a deletion or duplication caused by a mutation. Thus, the genome scanning method can be used in place of classic positional cloning strategies because prior positioning or mapping of the objective gene is unnecessary. By using this approach, we have identified and cloned a DNA fragment duplicated in the p(un) mutation of the mouse pink-eyed dilution locus (Brilliant et al., Science 1991, 252, 566-569). However, no other similar attempt using one-dimensional genome scanning has been reported so far, in spite of the simplicity of the procedure and its success in identifying and ultimately characterizing the pink-eyed dilution gene of the mouse. The lack of other reports of its success are perhaps not because of the practical difficulties of this method, but may be due to the false presumption that the probability for directly identifying the mutation site using genome scanning is extremely low. The theoretical probability was calculated and is presented here.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome.

Mutations have pivotal functions in the onset of genetic diseases and are the fundamental substrate for evolution. However, present estimates of the spontaneous mutation rate and spectrum are derived from indirect and biased measurements. For instance, mutation rate estimates for Caenorhabditis elegans are extrapolated from observations on a few genetic loci with visible phenotypes and vary over an order of magnitude. Alternative approaches in mammals, relying on phylogenetic comparisons of pseudogene loci and fourfold degenerate codon positions, suffer from uncertainties in the actual number of generations separating the compared species and the inability to exclude biases associated with natural selection. Here we provide a direct and unbiased estimate of the nuclear mutation rate and its molecular spectrum with a set of C. elegans mutation-accumulation lines that reveal a mutation rate about tenfold higher than previous indirect estimates and an excess of insertions over deletions. Because deletions dominate patterns of C. elegans pseudogene variation, our observations indicate that natural selection might be significant in promoting small genome size, and challenge the prevalent assumption that pseudogene divergence accurately reflects the spontaneous mutation spectrum.

Animals↗
PubMed2006

Mutator transposon in maize and MULEs in the plant genome.

Mutator (Mu) is by far the most mutagenic plant transposon. The high frequency of transposition and the tendency to insert into low copy sequences for such transposon have made it the primary means by which genes are mutagenized in maize (Zea mays L.). Mus like elements (MULEs) are widespread among angiosperms and multiple-diverged functional variants can be present in a single genome. MULEs often capture genetic sequences. These Pack-MuLEs can mobilize thousands of gene fragments, which may have had a significant impact on host genome evolution. There is also evidence that MULEs can move between reproductively isolated species. Here we present an overview of the discovery, features and utility of Mu transposon. Classification of Mu elements and future directions of related research are also discussed. Understanding Mu will help us elucidate the dynamic genome.

DNA Transposable Elements↗
PubMed2003

Ligation of high-melting-temperature 'clamp' sequence extends the scanning range of rare point-mutational analysis by constant denaturant capillary electrophoresis (CDCE) to most of the human genome.

Mutations cause or influence the prevalence of many diseases. In human tissues, somatic point mutations have been observed at fractions at or below 4/10,000 and 5/100,000 in mitochondrial and nuclear DNA, respectively. In human populations, fractions for the multiple alleles that code for recessive deleterious syndromes are not expected to exceed 5 x 10(-4). Both nuclear and mitochondrial point mutations have been measured in human cells and tissues at fractions approaching 10(-6) using constant denaturant capillary electrophoresis (CDCE) coupled with high-fidelity PCR (hifiPCR). However, this approach is only applicable to those target sequences (approximately 100 bp) juxtaposed with a 'clamp', a higher-melting-temperature sequence, in genomic DNA; such naturally clamped targets represent approximately 9% of the human genome. To open up most of the human genome to rare point-mutational analysis, a high-efficiency DNA ligation procedure was recently developed so that a clamp could be attached to any target of interest. We coupled this ligation procedure with prior CDCE/hifiPCR and achieved a sensitivity of 2 x 10(-5) in human cells for the first time using an externally attached clamp. At this sensitivity, somatic mutations, each representing an anatomically distinct cluster of cells (turnover unit) derived from a mutant stem cell, may be detected in a series of tissue samples, each containing as many as 5 x 10(4) turnover units. Additionally, rare inherited mutations may be scanned in pooled DNA samples, each derived from as many as 10(5) persons.

Cell Line↗
PubMed2004

Codon usage between genomes is constrained by genome-wide mutational processes.

Analysis of genome-wide codon bias shows that only two parameters effectively differentiate the genome-wide codon bias of 100 eubacterial and archaeal organisms. The first parameter correlates with genome GC content, and the second parameter correlates with context-dependent nucleotide bias. Both of these parameters may be calculated from intergenic sequences. Therefore, genome-wide codon bias in eubacteria and archaea may be predicted from intergenic sequences that are not translated. When these two parameters are calculated for genes from nonmammalian eukaryotic organisms, genes from the same organism again have similar values, and genome-wide codon bias may also be predicted from intergenic sequences. In mammals, genes from the same organism are similar only in the second parameter, because GC content varies widely among isochores. Our results suggest that, in general, genome-wide codon bias is determined primarily by mutational processes that act throughout the genome, and only secondarily by selective forces acting on translated sequences.

Animals↗
PubMed1983

Molecular Engineering of the Autographa californica Nuclear Polyhedrosis Virus Genome: Deletion Mutations Within the Polyhedrin Gene.

We describe a method to introduce site-specific mutations into the genome of Autographa californica nuclear polyhedrosis virus. Specifically, the A. californica nuclear polyhedrosis virus gene for polyhedrin, the major protein that forms viral occlusions in infected cells, was mutagenized by introducing deletions into the cloned DNA fragment containing the gene. The mutagenized polyhedrin gene was transferred to the intact viral DNA by mixing fragment and viral DNAs, cotransfecting Spodoptera frugiperda cells, and screening for viral recombinants that had undergone allelic exchange. Recombinant viruses with mutant polyhedrin genes were obtained by selecting the progeny virus that did not produce viral occlusions in infected cells (occlusion-negative mutants). Analyses of occlusion-negative mutants demonstrated that the polyhedrin gene was not essential for the production of infectious virus and that deletion of certain sequences within the gene did not alter the control, or decrease the level of expression, of polyhedrin. An early viral protein of 25,000 molecular weight was apparently not essential for virus replication in vitro, as the synthesis of this protein was not detected in cells infected with a mutant virus.

Journal Article↗
PubMed1999

High genomic deleterious mutation rates in hominids.

It has been suggested that humans may suffer a high genomic deleterious mutation rate. Here we test this hypothesis by applying a variant of a molecular approach to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

Animals↗
PubMed2000

The evolution of mutation rates: separating causes from consequences.

Natural selection can adjust the rate of mutation in a population by acting on allelic variation affecting processes of DNA replication and repair. Because mutation is the ultimate source of the genetic variation required for adaptation, it can be appealing to suppose that the genomic mutation rate is adjusted to a level that best promotes adaptation. Most mutations with phenotypic effects are harmful, however, and thus there is relentless selection within populations for lower genomic mutation rates. Selection on beneficial mutations can counter this effect by favoring alleles that raise the mutation rate, but the effect of beneficial mutations on the genomic mutation rate is extremely sensitive to recombination and is unlikely to be important in sexual populations. In contrast, high genomic mutation rates can evolve in asexual populations under the influence of beneficial mutations, but this phenomenon is probably of limited adaptive significance and represents, at best, a temporary reprieve from the continual selection pressure to reduce mutation. The physiological cost of reducing mutation below the low level observed in most populations may be the most important factor in setting the genomic mutation rate in sexual and asexual systems, regardless of the benefits of mutation in producing new adaptive variation. Maintenance of mutation rates higher than the minimum set by this "cost of fidelity" is likely only under special circumstances.

Animals↗
PubMed1999

High genome-wide mutation rates in vegetatively propagated bermudagrass.

A cascade DNA amplification strategy that generates arbitrary signatures from amplification profiles (ASAP) was used to measure genome-wide mutation rates in bermudagrass (Cynodon). ASAP quantified nucleotide changes that were induced by irradiation, genetic instabilities and normal vegetative growth of cultivars and accessions of sterile interspecific hybrids. DNA sequence divergence between cultivar 'Tifway' and its gamma radiation-induced mutant 'Tifway II' (0.70 +/- 0.66%) was comparable to estimates in radiation-induced mutants and spontaneous sports of chrysanthemum (Chrysanthemum morifolium Ramat.). A similar divergence in sequence (0.95 +/- 0.20%) was observed in the pairwise comparison of 17 nondisjunctive 'Tifgreen' and 'Tifdwarf' accessions. Mutation during normal Tifdwarf vegetative growth was evaluated by planting sprigs and sampling their offspring. Somatic sequence divergence levels (0.004 +/- 0.007%) resulted in a mutation rate of 1.05 x 10-8 per nucleotide per generation, assuming that a bermudagrass sprig constitutes a generation of growth. These rates were comparable to those found in germinal cells and individuals of either human or Drosophila melanogaster, supporting the notion that eukaryotic evolution is generation rather than time dependent. The high accumulation of somatic mutations (10 per triploid genome) is consistent with a model whereby mutation load in a population exhibiting obligate vegetative reproduction is substantially higher than in a population under sexual or asexual reproduction. These constraints could be the cause of reported genetic instabilities in the Tifgreen-Tifdwarf complex. Finally, a long-term rate measured across accessions and indicative of the accumulation of mutations in 17 Tifgreen-Tifdwarf populations (µ = 1.02 x 10-8 per nucleotide per generation) was strikingly congruent with the bermudagrass vegetative mutation rate, suggesting absence of evolutionary constraints in the sampled genomic regions. Mutation rates calculated from across-accesions divergence estimates (5.18 +/- 0.53%) indicated that plant material was evolving 100 times faster (3.8 x 10-7 changes per nucleotide per year) than a molecular clock rate estimate for grasses, probably resulting from the compound effect of clonal growth and life span of the hybrid plant material.

Journal Article↗
PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗
PubMed2005

Colorimetric approach to high-throughput mutation analysis.

High-throughput genomic mutation screening for primary tumors has characteristically been expensive, labor-intensive, and inadequate to detect low levels of mutation in a background of wild-type signal. We present a new, combined PCR and colorimetric approach that is inexpensive, simple, and can detect the presence of 1% mutation in a background of wild-type. We compared manual dideoxy sequencing of p53 for eight lung cancer samples to a novel assay combining a primer extension step and an enzymatic colorimetric step in a 96-well plate with covalently attached oligonucleotide sequences. For every sample, we were able to detect the presence or absence of the specific mutation with a statistically significant difference between the sample optical density (OD) and the background OD, with a sensitivity and specificity of 100%. This assay is straightforward, accurate, inexpensive, and allows for rapid, high-throughput analysis of samples, making it ideal for genomic mutation or polymorphism screening studies in both clinical and research settings.

Biological Assay↗
PubMed2001

Genetic fidelity under harsh conditions: analysis of spontaneous mutation in the thermoacidophilic archaeon Sulfolobus acidocaldarius.

Microbes whose genomes are encoded by DNA and for which adequate information is available display similar genomic mutation rates (average 0.0034 mutations per chromosome replication, range 0.0025 to 0.0046). However, this value currently is based on only a few well characterized microbes reproducing within a narrow range of environmental conditions. In particular, no genomic mutation rate has been determined either for a microbe whose natural growth conditions may extensively damage DNA or for any member of the archaea, a prokaryotic lineage deeply diverged from both bacteria and eukaryotes. Both of these conditions are met by the extreme thermoacidophile Sulfolobus acidocaldarius. We determined the genomic mutation rate for this species when growing at pH 3.5 and 75 degrees C based on the rate of forward mutation at the pyrE gene and the nucleotide changes identified in 101 independent mutants. The observed value of about 0.0018 extends the range of DNA-based microbes with rates close to the standard rate simultaneously to an archaeon and to an extremophile whose cytoplasmic pH and normal growth temperature greatly accelerate the spontaneous decomposition of DNA. The mutations include base pair substitutions (BPSs) and additions and deletions of various sizes, but the S. acidocaldarius spectrum differs from those of other DNA-based organisms in being relatively poor in BPSs. The paucity of BPSs cannot yet be explained by known properties of DNA replication or repair enzymes of Sulfolobus spp. It suggests, however, that molecular evolution per genome replication may proceed more slowly in S. acidocaldarius than in other DNA-based organisms examined to date.

Base Sequence↗
PubMed2006

[The significance of mutations in genomic evolution].

One of the fundamental questions in biological sciences and key problem to be solved in evolutionary biology is that how intra-and interspecific genomic diversity formed, accumulated and preserved in the long history of evolution. It is well known that mutation is the major driving force that has shaped genomes. Moreover mutation research forms the basis for the study of genome evolution. So a full understanding of mutation is necessary to unravel the mechanisms of genome evolution. In the review, we summarize the progress of mutation research and latest development in this field with an emphasis on the property of mutation and its profound significance toward genomic evolution.

Animals↗
PubMed1994

Alteration of the p53 locus in benign hyperplastic prostatic epithelium associated with high-grade prostatic adenocarcinoma.

Recent evidence suggests that the tumor suppressor protein, p53, protects somatic cells against the accumulation of genomic mutations. The genomes of cells lacking normal p53 function may become hypermutable, a condition that might result in the accumulation of multiple genetic alterations as the affected cells proliferate. Such cells may then become more susceptible to malignant transformation. We hypothesized that some high-grade prostate cancers might arise from foci of morphologically benign cells that had previously sustained p53 lesions. As an initial test of this hypothesis, we employed a microdissection technique to isolate morphologically benign cells within hyperplastic glands located near foci of high-grade adenocarcinoma. Genomic DNA from these cells was subjected to polymerase chain reaction amplification and single-stranded conformational polymorphism analysis for detecting alterations in the p53 locus. With use of this approach, gross alterations in the p53 locus were demonstrated in benign cells in 1 of 20 (5%) specimens harboring high-grade malignancy (Gleason grade 7 or higher). Thus, in some cases, hyperplastic prostatic epithelium harbors preneoplastic genetic alterations that could possibly give rise to high-grade malignancies.

Adenocarcinoma↗