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Results for “deleterious mutation”

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PubMed2005

Functional evaluation and cancer risk assessment of BRCA2 unclassified variants.

The influence of germ line BRCA2 unclassified variants (UCV), including missense mutations and in-frame deletions and insertions on BRCA2 function and on cancer risk, has not been defined although these mutations account for 43% of all identified BRCA2 sequence alterations. To investigate the effects of UCVs on BRCA2 function, we compared mutant and wild-type forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, and genome instability. We confirm that the effects of known deleterious mutations can be distinguished from neutral polymorphisms and wild-type BRCA2 in these assays, and we characterize the influence of a series of UCVs on BRCA2 function. We also describe how the results from the assays can be combined with data from analysis of cosegregation of the UCVs with cancer, co-occurrence of the UCVs with other deleterious mutations, and interspecies sequence variation in a comprehensive framework in an effort to better distinguish between disease predisposing and neutral UCVs. This combined approach represents a useful means of addressing the functional significance and cancer relevance of UCVs in BRCA2.

Animals↗

PubMedDate not supplied

Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation.

Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test.

Adult↗

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↗

PubMed1996

The novel UGT1 gene complex links bilirubin, xenobiotics, and therapeutic drug metabolism by encoding UDP-glucuronosyltransferase isozymes with a common carboxyl terminus.

The UDP-glucuronosyltransferase system (transferase) plays an important role in the pharmacokinetics of clearance of endogenous metabolites, therapeutic drugs, and xenobiotics. The human bilirubin and phenol transferases are encoded by the same gene complex which we designate UGT1. The gene arrangement indicates there are 6 exon 1s each with a promoter and each of which can predictably undergo differential splicing to the 4 common exons (2 through 5) to generate possibly 6 different mRNAs. The entire unique amino acid terminus of each isoform is encoded by an exon 1, and the common carboxyl terminus is encoded by the 4 common exons. Evidence supports the existence of other exon 1s upstream of the currently described locus. The 13-bp deletion in exon 2 represents the most common defect, to date, in the Crigler-Najjar, Type I individuals. Different point mutations in the 4 common exons and in exon 1 of UGT1A, however, also account for defective bilirubin transferase activity. The gene arrangement, in conjunction with the toxicity data from the Gunn rat, leads to the prediction that detoxification of bilirubin, xenobiotics, and therapeutic drugs is linked to the UGT1 locus. The Crigler-Najjar syndromes are uncommon, but the Gilbert individuals are commonly represented in 6% of the population. It is expected that, similar to the deleterious mutations in the common region of the UGT1 locus in Crigler-Najjar, Type I individuals, there is a range of moderate to intermediate deleterious mutations in this region of the gene of at least some Gilbert's individuals. Linkages, therefore, at this locus could signal that these individuals are at risk for certain drug toxicities and/or idiosyncratic drug reactions.

Animals↗

PubMed2002

The evolution of gene duplicates.

Gene and genome duplications have given rise to enormous variability among species in the number of genes within their genomes. Gene copies have in turn played important roles in adaptation, having been implicated in the evolution of the immune response, insecticide resistance, efficient protein synthesis, and vertebrate body plans. In this chapter, we discuss the life history of gene duplications, from their first appearance within a population, through the period during which they rise in frequency or disappear, to their long-term fate. At each phase, we discuss the evolutionary processes that have influenced the dynamics of gene duplications and shaped their ultimate roles within a population. We argue that there is no evidence that organisms have evolved strategies to promote gene duplication in order to permit adaptive evolution. In contrast, many mechanisms exist to silence or eliminate duplicated genes, suggesting that selection has acted largely to reduce the rate of gene duplication. We also argue that natural selection has functioned as an effective sieve, increasing the representation of beneficial gene duplicates among those that establish within a population and that play a long-term role in evolution. To refine our understanding of how selection acts on new gene duplications, we provide a model incorporating a single-copy gene, its gene duplicate, and selection either favoring heterozygotes or eliminating deleterious mutations. Although both forms of selection can increase the initial rate of spread of a gene duplicate, the efficacy with which they do so differs dramatically. Heterozygote advantage always increases the rate of spread and can have a large impact. In contrast, masking deleterious mutations never has a large effect on the rate of spread of the duplicate, and this minor effect can be negative as well as positive. In both cases, the degree of linkage between the two gene copies affects the rate of spread of the duplication. Finally, we discuss evolutionary processes that occur over longer periods after a gene duplication has become established within a population. These long-term processes include maintenance, inactivation, and diversification in function. Consideration of each of the short-term and long-term processes affecting duplicated genes illustrates the subtle ways in which selection has acted to shape genomic structure.

Animals↗

PubMed2005

Epistatic interactions among herbicide resistances in Arabidopsis thaliana: the fitness cost of multiresistance.

The type of interactions among deleterious mutations is considered to be crucial in numerous areas of evolutionary biology, including the evolution of sex and recombination, the evolution of ploidy, the evolution of selfing, and the conservation of small populations. Because the herbicide resistance genes could be viewed as slightly deleterious mutations in the absence of the pesticide selection pressure, the epistatic interactions among three herbicide resistance genes (acetolactate synthase CSR, cellulose synthase IXR1, and auxin-induced AXR1 target genes) were estimated in both the homozygous and the heterozygous states, giving 27 genotype combinations in the model plant Arabidopsis thaliana. By analyzing eight quantitative traits in a segregating population for the three herbicide resistances in the absence of herbicide, we found that most interactions in both the homozygous and the heterozygous states were best explained by multiplicative effects (each additional resistance gene causes a comparable reduction in fitness) rather than by synergistic effects (each additional resistance gene causes a disproportionate fitness reduction). Dominance coefficients of the herbicide resistance cost ranged from partial dominance to underdominance, with a mean dominance coefficient of 0.07. It was suggested that the csr1-1, ixr1-2, and axr1-3 resistance alleles are nearly fully recessive for the fitness cost. More interestingly, the dominance of a specific resistance gene in the absence of herbicide varied according to, first, the presence of the other resistance genes and, second, the quantitative trait analyzed. These results and their implications for multiresistance evolution are discussed in relation to the maintenance of polymorphism at resistance loci in a heterogeneous environment.

Arabidopsis↗

PubMed1998

Mutation and selection at silent and replacement sites in the evolution of animal mitochondrial DNA.

Two patterns are presented that illustrate the interaction of mutation and selection in the evolution of animal mtDNA: 1) variation among taxa in the ratio of polymorphism to divergence (rpd) at silent and replacement sites in protein-coding genes, and 2) strand-differences in polymorphism and divergence at 'silent' sites that suggest a mutation-selection balance in the evolution of codon usage. Cytochrome b data from GenBank show that about half of the species pairs tested have a significant excess of amino acid polymorphism, relative to divergence. The remaining half of species pairs do not depart from neutrality, but generally do show an excess of amino acid polymorphism. Sequences from Drosophila pseudoobscura displaying a signature of an expanding population show a slight, but non-significant, deficiency of amino acid polymorphism suggestive of recently intensified selection on mildly deleterious mutations. Genes whose reading frames lie on the major coding strand of Drosophila mtDNA show a preponderance of T- > C substitutions, while genes encoded on the minor strand experience more A- > G than T- > C substitutions between species at both silent and replacement sites. However, silent mutations at third codon positions are introduced into the population in proportions opposite to those observed as fixed differences between species (e.g., an excess of T- > C polymorphisms are found at the ND5 gene on the minor coding strand). The high A + T content of insect mtDNAs imposes strong codon usage bias favoring A-ending and T-ending codons resulting in a distinct mutation-selection balance for genes encoded on opposites strands. Thus, at both replacement and silent sites, mutations that appear to be constrained in terms of divergence between species are in excess within species. The data suggest that mildly deleterious mutations are common in mitochondrial genes. A test of this, and a competing, hypothesis is proposed that requires additional sequence surveys of polymorphism and divergence. An important challenge is to tease apart the impact of mutation and selection on levels of polymorphism versus divergence in a genome that does not generally recombine.

Animals↗

PubMed2003

Ecological and evolutionary opportunities of apomixis: insights from Taraxacum and Chondrilla.

The ecological and evolutionary opportunities of apomixis in the short and the long term are considered, based on two closely related apomictic genera: Taraxacum (dandelion) and Chondrilla (skeleton weed). In both genera apomicts have a wider geographical distribution than sexuals, illustrating the short-term ecological success of apomixis. Allozymes and DNA markers indicate that apomictic populations are highly polyclonal. In Taraxacum, clonal diversity can be generated by rare hybridization between sexuals and apomicts, the latter acting as pollen donors. Less extensive clonal diversity is generated by mutations within clonal lineages. Clonal diversity may be maintained by frequency-dependent selection, caused by biological interactions (e.g. competitors and pathogens). Some clones are geographically widespread and probably represent phenotypically plastic 'general-purpose genotypes'. The long-term evolutionary success of apomictic clones may be limited by lack of adaptive potential and the accumulation of deleterious mutations. Although apomictic clones may be considered as 'evolutionary dead ends', the genes controlling apomixis can escape from degeneration and extinction via pollen in crosses between sexuals and apomicts. In this way, apomixis genes are transferred to a new genetic background, potentially adaptive and cleansed from linked deleterious mutations. Consequently, apomixis genes can be much older than the clones they are currently contained in. The close phylogenetic relationship between Taraxacum and Chondrilla and the similarity of their apomixis mechanisms suggest that apomixis in these two genera could be of common ancestry.

Asteraceae↗

PubMed2005

UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families.

In human, rat, and mice, a UGT1 complex locus provides for developmental-, inducer-, and cell-specific synthesis of a family of chemical-detoxifying isozymes, UDP-glucuronosyltransferases, which prevent toxicities, mutagenesis, and/or carcinogenesis. Between 10 and 14 first exons with individual promoter elements are tandemly arrayed upstream of 4 shared exons so as to synthesize independently as many overlapping primary transcripts. RNA splice sites allow a lead exon to join the common exons to generate mRNAs with unique 5' ends, but common 3' ends. Intra- and interspecies comparisons of amino acid sequences encoded by first exons show an evolutionary continuum; also, recognizable bilirubin- and phenol-specific catalytic units are differentially regulated by model compounds, phenobarbital, and/or aromatic hydrocarbons. Whereas UGT1 loci allow minimal changes to achieve new isozymes, a single deleterious mutation in a common exon negatively impacts the arrangement by inactivating the entire family of isozymes compared to an event at independent loci as seen in the UGT2 family. In humans, lethal hyperbilirubinemic Crigler-Najjar type 1 and milder diseases/syndromes are due to deleterious to mildly deleterious mutations in the bilirubin-specific UGT1A1 or a common exon. In addition, the number of TA repeats (N(5-8)) in the UGT1A1 proximal TATA box affects transcriptional rate and, thus, activity. Evidence also shows that polymorphisms in nonbilirubin-specific first exons also impact chemical detoxifications and other diseases.

Animals↗

PubMed2006

Heterosis in an isolated, effectively small, and self-fertilizing population of the flowering plant Leavenworthia alabamica.

Mildly deleterious mutations are thought to play a major role in the extinction of natural populations, especially those that are small, isolated, or inbred. Self-fertilization should reduce the effective size of populations and simultaneously reduce migration between populations. A history of self-fertilization should therefore cause a population to harbor a substantial "local drift load" caused by the fixation of mildly deleterious mutations. This hypothesis was tested in Leavenworthia alabamica, which contains large, self-incompatible populations and smaller self-compatible populations with adaptations for self-fertilization. The fitness of offspring from within- and between-population crosses was compared to quantify heterosis caused by the masking of deleterious alleles in the heterozygous state. Little heterosis was observed in crosses between five large, self-incompatible populations and two of the three small, self-fertilizing populations of L. alabamica. However, the most geographically isolated and genetically divergent self-fertilizing population (Tuscumbia) exhibited a 110.2% increase in germination and a 73.6% increase in fitness, which is consistent with a sizeable local drift load. The finding of substantial heterosis for fitness supports the idea that small effective size, reproductive isolation, and self-fertilization can make populations particularly vulnerable to mutation accumulation.

Biological Evolution↗

PubMed1988

Inactivation of human keratin genes: the spectrum of mutations in the sequence of an acidic keratin pseudogene.

Keratins are cytoskeletal proteins encoded by a multigene family. We have identified the first human keratin pseudogene and determined its complete nucleotide sequence. Sequence comparisons indicate that the pseudogene arose from a very recent duplication of the 50-kd keratin (K14) gene. The coding and the intron sequences of the two genes are 95% and 93% identical, respectively. Although the sequence of the regulatory region in the pseudogene is virtually identical to that in the 50-kd functional gene, several deleterious mutations have been identified in the pseudogene. There are three frameshifts in the coding regions, one of which is a perfect 8-bp duplication. A single-base-pair deletion in the first exon and a single-base-pair insertion in the penultimate exon also result in frameshifts. The three remaining deleterious mutations interfere with the mRNA processing signals: two alter the intron/exon boundaries, and the third disrupts the polyadenylation signal. These mutations clearly identify the sequence as a human keratin pseudogene.

Base Sequence↗

PubMed2006

No Evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families.

The discovery of deleterious mutations in the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, has facilitated the identification of individuals at particularly high risk of these diseases. There is a wide variation between populations in the prevalence and related risks of various types of BRCA1/2 mutations, so estimates cannot be extrapolated to Canadians, especially not founder populations such as French- Canadians. Polymerase chain reaction (PCR)-based methods were used to detect the majority of these mutations. These approaches usually failed to detect large DNA rearrangements, which have been claimed to be involved in other populations in 5% to up to 36% of BRCA1-positive families. There is very little information about the contribution of this type of mutation in BRCA2-positive families. To investigate if our available mutation spectrum of BRCA1 and BRCA2 in high-risk French-Canadian breast/ovarian cancer families has been biased by PCR-based direct sequencing methods, we first used Southern blot analysis to test DNA samples from 61 affected/obligate carrier individuals from 58 families in which no BRCA1/2 deleterious mutation was found. Finally, 154 individuals from 135 BRCA1/2 nonconclusive families, including all those tested previously by Southern blot analysis, were tested with the new multiplex ligation probe amplification (MLPA) technique. These approaches failed to detect any rearrangement. Moreover, if the frequency of MLPA-detectable rearrangements in our cohort of 135 BRCA1/2 nonconclusive families was 2.2% or higher, we would have had a 95% or greater chance of observing at least one such rearrangement. As no rearrangements were identified, such large rearrangements must be quite rare in our population.

Blotting, Southern↗

PubMed1999

Further genetic studies on the Katsunuma population of Drosophila melanogaster.

Changes in the genetic structure of the Katsunuma natural population of Drosophila melanogaster have been examined during the past 35 years. The frequency of recessive lethal genes on the second chromosome once increased from 15% to 30% in the early 1970s, then decreased to about 24% in the late 1970s, and thereafter showed no significant changes. Sterility genes, the frequency of which is always less than the lethals, showed a similar tendency. The SD (segregation distorter) mutant gene disappeared but some others such as rbl (reduced bristle) and bw (brown) persisted in the population. The frequency of inversion-carrying chromosomes gradually decreased in the period, such that the standard chromosome frequency in the second and third chromosomes increased from about 40% to more than 80%. Coincident with these frequency changes is the invasion of a transposable element P into the Katsunuma population. The P element should have invaded into Katsunuma in the late 1960s. It spread over the population apparently inducing deleterious mutations, causing the decrease in the allelism rate, and hence increasing the effective population size. Soon, however, most flies became resistant to the P element-mediated transposition as they began to harbor defective P elements. During the course of spreading, the P element must also have induced deleterious mutations on the polymorphic inversions, breaking up the heterotic gene complexes along the chromosomes, which probably caused the reduction in the frequency of inversion chromosomes. Temporal invasion of D. simulans, a sibling species of D. melanogaster, into Katsunuma occurred several times after 1978, and the species seems to have been settled since 1990. This, however, did not have any effect on the genetic structure of D. melanogaster population.

Animals↗

PubMed1992

A comprehensive scanning method for rapid detection of beta-globin gene mutations and polymorphisms.

We describe a scanning procedure for the detection of beta-globin gene mutations and the prenatal diagnosis of beta-thalassemias. The method is based on the combined use of PCR and denaturing gradient gel electrophoresis (DGGE) of six amplified fragments encompassing the whole beta-globin coding region and splice junctions, as well as the promoter and 3' untranslated regions. The whole beta-globin gene can be rapidly scanned for the presence of deleterious mutations. The proposed diagnostic strategy provides a major improvement over current approaches to beta-globin gene analysis in both research and clinical laboratories, especially those which analyse DNA samples from individuals belonging to various ethnic or population groups. The use of this procedure has enabled us to detect six novel sequence changes in the beta-globin gene, including two deleterious mutations and four polymorphisms.

Base Sequence↗

PubMed2001

The rate of mutation and the homozygous and heterozygous mutational effects for competitive viability: a long-term experiment with Drosophila melanogaster.

The effect of 250 generations of mutation accumulation (MA) on the second chromosome competitive viability of Drosophila melanogaster was analyzed both in homozygous and heterozygous conditions. We used full-sib MA lines, where selection hampers the accumulation of severely deleterious mutations but is ineffective against mildly deleterious ones. A large control population was simultaneously evaluated. Competitive viability scores, unaffected by the expression of mutations in heterozygosis, were obtained relative to a Cy/L(2) genotype. The rate of decline in mean DeltaM approximately 0.1% was small. However, that of increase in variance DeltaV approximately 0.08 x 10(-3) was similar to the values obtained in previous experiments when severely deleterious mutations were excluded. The corresponding estimates of the mutation rate lambda > or = 0.01 and the average effect of mutations E(s) < or = 0.08 are in good agreement with Bateman-Mukai and minimum distance estimates for noncompetitive viability obtained from the same MA lines after 105 generations. Thus, competitive and noncompetitive viability show similar mutational properties. The regression estimate of the degree of dominance for mild-to-moderate deleterious mutations was approximately 0.3, suggesting that the pertinent value for new unselected mutations should be somewhat smaller.

Animals↗

PubMed2000

The degeneration of asexual haploid populations and the speed of Muller's ratchet.

The accumulation of deleterious mutations due to the process known as Muller's ratchet can lead to the degeneration of nonrecombining populations. We present an analytical approximation for the rate at which this process is expected to occur in a haploid population. The approximation is based on a diffusion equation and is valid when N exp(-u/s) >> 1, where N is the population size, u is the rate at which deleterious mutations occur, and s is the effect of each mutation on fitness. Simulation results are presented to show that the approximation estimates the rate of the process better than previous approximations for values of mutation rates and selection coefficients that are compatible with the biological data. Under certain conditions, the ratchet can turn at a biologically significant rate when the deterministic equilibrium number of individuals free of mutations is substantially >100. The relevance of this process for the degeneration of Y or neo-Y chromosomes is discussed.

Computer Simulation↗

PubMed2003

Adaptation shapes patterns of genome evolution on sexual and asexual chromosomes in Drosophila.

What advantage might sexual recombination confer? Population genetics theory predicts that asexual genomes are less efficient at eliminating deleterious mutations and incorporating beneficial alleles. Here, I compare patterns of genome evolution in a 40-kb gene-rich region on homologous neo-sex chromosomes of Drosophila miranda. Genes on the non-recombining neo-Y show various signs of degeneration, including transposable-element insertions, frameshift mutations and a higher rate of amino-acid substitution. In contrast, loci on the recombining neo-X show intact open reading frames and generally low rates of amino-acid substitution. One exceptional gene on the neo-X shows evidence for adaptive protein evolution, affecting patterns of variability at neighboring regions along the chromosome. These findings illustrate the limits to natural selection in an asexual genome. Deleterious mutations, including repetitive DNA, accumulate on a non-recombining chromosome, whereas rapid protein evolution due to positive selection is confined to the recombining homolog.

Animals↗

PubMed1995

Deleterious background selection with recombination.

An analytic expression for the expected nucleotide diversity is obtained for a neutral locus in a region with deleterious mutation and recombination. Our analytic results are used to predict levels of variation for the entire third chromosome of Drosophila melanogaster. The predictions are consistent with the low levels of variation that have been observed at loci near the centromeres of the third chromosome of D. melanogaster. However, the low levels of variation observed near the tips of this chromosome are not predicted using currently available estimates of the deleterious mutation rate and of selection coefficients. If considerably smaller selection coefficients are assumed, the low observed levels of variation at the tips of the third chromosome are consistent with the background selection model.

Animals↗