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PubMed2006

Upper limit of the rate and per generation effects of deleterious genomic mutations.

Unbiased or upper limit estimates of the rate (U) of genomic mutations to mildly deleterious alleles are crucial in genetic and conservation studies and in human health care. However, only a few estimates of the lower bounds of U are available. We present a fairly robust estimation that yields an upper limit of U and a nearly unbiased estimate of the per generation fitness decline due to new deleterious mutations. We applied the approach to three species of the freshwater microcrustacean Daphnia and revealed that the upper limit of U for egg survivorship is 0.73 (SD = 0.30) in 14 D. pulicaria populations. For the first four clutches, per generation decline in fecundity due to deleterious mutations ranged from 2.2% to 7.8% in 20 D. pulex populations and from 1.1% to 5.1% in 8 D. obtusa populations. These results indicate the mutation pressure is high in natural Daphnia populations. The approach investigated here provides a potential way to quickly and conveniently characterize U and per generation effects of deleterious genomic mutations on fitness or its important components such as fecundity.

Animals↗

PubMed1996

Estimate of the genomic mutation rate deleterious to overall fitness in E. coli.

Mutations are a double-edged sword: they are the ultimate source of genetic variation upon which evolution depends, yet most mutations affecting fitness (viability and reproductive success) appear to be harmful. Deleterious mutations of small effect can escape natural selection, and should accumulate in small population. Reduced fitness from deleterious-mutation accumulation may be important in the evolution of sex, mate choice, and diploid life-cycles, and in the extinction of small populations. Few empirical data exist, however. Minimum estimates of the genomic deleterious-mutation rate for viability in Drosophila melanogaster are surprisingly high, leading to the conjecture that the rate for total fitness could exceed 1.0 mutation per individual per generation. Here we use Escherichia coli to provide an estimate of the genomic deleterious-mutation rate for total fitness in a microbe. We estimate that the per-microbe rate of deleterious mutations is in excess of 0.0002.

Animals↗

PubMed2003

High deleterious genomic mutation rate in stationary phase of Escherichia coli.

In natural habitats, bacteria spend most of their time in some form of growth arrest. Little is known about deleterious mutations in such stages, and consequently there is limited understanding of what evolutionary events occur. In a deleterious mutation accumulation experiment in prolonged stationary phase of Escherichia coli, about 0.03 slightly deleterious mutations were observed per genome per day. This is over an order of magnitude higher than extrapolations from fast-growing cells, but in line with inferences from observations in adaptive stationary phase mutation experiments. These findings may affect understanding of bacterial evolution and the emergence of bacterial pathogenicity.

Biological Evolution↗

PubMed2005

Deleterious genomic mutation rate for viability in Drosophila melanogaster using concomitant sibling controls.

New deleterious mutations may reduce health and fitness and are involved in the evolution and maintenance of numerous biological processes. Hence, it is important to estimate the deleterious genomic mutation rate (U) in representative higher organisms. However, these estimated rates vary widely, mainly because of inadequate experimental controls. Here we describe an experimental design (the Binscy assay) with concomitant sibling controls and estimate U for viability in Drosophila melanogaster to be 0.31. This estimate, like most published studies, focuses on viability mutations and the overall deleterious genomic mutation rate would therefore be higher.

Animals↗

PubMed2005

Epistasis and the adaptability of an RNA virus.

We have explored the patterns of fitness recovery in the vesicular stomatitis RNA virus. We show that, in our experimental setting, reversions to the wild-type genotype were rare and fitness recovery was at least partially driven by compensatory mutations. We compared compensatory adaptation for genotypes carrying (1) mutations with varying deleterious fitness effects, (2) one or two deleterious mutations, and (3) pairs of mutations showing differences in the strength and sign of epistasis. In all cases, we found that the rate of fitness recovery and the proportion of reversions were positively affected by population size. Additionally, we observed that mutations with large fitness effect were always compensated faster than mutations with small fitness effect. Similarly, compensatory evolution was faster for genotypes carrying a single deleterious mutation than for those carrying pairs of mutations. Finally, for genotypes carrying two deleterious mutations, we found evidence of a negative correlation between the epistastic effect and the rate of compensatory evolution.

Adaptation, Biological↗

PubMed2003

Dominance and overdominance of mildly deleterious induced mutations for fitness traits in Caenorhabditis elegans.

We estimated the average dominance coefficient of mildly deleterious mutations (h, the proportion by which mutations in the heterozygous state reduce fitness components relative to those in the homozygous state) in the nematode Caenorhabditis elegans. From 56 worm lines that carry mutations induced by the point mutagen ethyl methanesulfonate (EMS), we selected 19 lines that are relatively high in fitness and estimated the viabilities, productivities, and relative fitnesses of heterozygotes and homozygotes compared to the ancestral wild type. There was very little effect of homozygous or heterozygous mutations on egg-to-adult viability. For productivity and relative fitness, we found that the average dominance coefficient, h, was approximately 0.1, suggesting that mildly deleterious mutations are on average partially recessive. These estimates were not significantly different from zero (complete recessivity) but were significantly different from 0.5 (additivity). In addition, there was a significant amount of variation in h among lines, and analysis of average dominance coefficients of individual lines suggested that several lines showed overdominance for fitness. Further investigation of two of these lines partially confirmed this finding.

Animals↗

PubMed2006

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers.

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.

Chromosome Aberrations↗

PubMed2000

The fitness effects of spontaneous mutations in Caenorhabditis elegans.

Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity.

Animals↗

PubMed2004

Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious.

Mutation rates of human immunodeficiency virus type 1 (HIV-1) genomes have been estimated using purified reverse transcriptase or single-round infection system. Since small sequences were used as templates, the overall mutation rates could only be extrapolated and the biological significance of mutations is unknown. For direct estimation of HIV-1 mutation rates and understanding of the potential biological influences of mutations, we obtained 19 complete or nearly full-length proviral genomes from single-round-infected adherent cells of lymphocytes by using a lambda phage library method and a long-range PCR technique. Analysis of 160,000 bp of sequences showed that the overall mutation rate of HIV-1 genomes was 5.4 x 10(-5) per base per replication cycle. On average, 1.1 mutations (range, 0 to 3) were generated in each viral genome during one infection cycle. Inspection of the mutations in the HIV-1 genome revealed that all site mutations within protein-coding regions were nonsynonymous mutations. Among all mutations, half were deleterious (premature stop codon and deletions) and would result in defective genomes. By applying the same system to an HIV-1 genome with a G262A mutation in the thumb region of the reverse transcriptase, a significant increase was observed in deletion and insertion mutation rates but no increase in the overall mutation rate in viral genomes was found.

Base Sequence↗

PubMed1993

Evolution of aging: testing the theory using Drosophila.

Evolutionary explanations of aging (or senescence) fall into two classes. First, organisms might have evolved the optimal life history, in which survival and fertility late in life are sacrificed for the sake of early reproduction or high pre-adult survival. Second, the life history might be depressed below this optimal compromise by the influx of deleterious mutations; since selection against late-acting mutations is weaker, deleterious mutations will impose a greater load on late life. We discuss ways in which these theories might be investigated and distinguished, with reference to experimental work with Drosophila. While genetic correlations between life history traits determine the immediate response to selection, they are hard to measure, and may not reflect the fundamental constraints on life history. Long term selection experiments are more likely to be informative. The third approach of using experimental manipulations suffers from some of the same problems as measures of genetic correlations; however, these two approaches may be fruitful when used together. The experimental results so far suggest that aging in Drosophila has evolved in part as a consequence of selection for an optimal life history, and in part as a result of accumulation of predominantly late-acting deleterious mutations. Quantification of these effects presents a major challenge for the future.

Aging↗

PubMed2000

Effect of deleterious mutation-accumulation on the fitness of RNA bacteriophage MS2.

RNA viruses show the highest mutation rate in nature. It has been extensively demonstrated that, in the absence of purifying selection, RNA viruses accumulate deleterious mutations at a high rate. However, the parameters describing this accumulation are, in general, poorly understood. The present study reports evidences for fitness declines by the accumulation of deleterious mutations in the bacteriophage MS2. We estimated the rate of fitness decline to be as high as 16% per bottleneck transfer. In addition, our results agree with an additive model of fitness effects.

Base Sequence↗

PubMed2025

U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

The mechanisms by which somatic mutations of splicing factors, such as U2AF1S34F in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified KRAS as a key target modulated by U2AF1S34F. One specific KRAS mutation, G12S, generates a cryptic U2AF1 binding site that leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. Expression of the U2AF1S34F mutant reverts this exon skipping and restores KRAS function. Analysis of cancer genomes reveals that U2AF1S34F mutations are enriched in KRASG12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRASQ61R and U2AF1I24T mutations. Experimentally, KRASQ61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations. More broadly, they demonstrate a dynamic process of cascading selection where mutational events are positively selected in cancer genomes as a consequence of earlier mutations.

Journal Article↗

PubMed2000

True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management.

PURPOSE: The purpose of this study was to classify all ipsilateral breast tumor relapses (IBTR) in patients treated with conservative surgery and radiation therapy (CS+RT) as either new primary tumors (NP) or true local recurrences (TR) and to assess the prognostic and therapeutic implications of this classification. METHODS AND MATERIALS: Of the 1152 patients who have been treated at Yale-New Haven Hospital before 1990, 136 patients have experienced IBTR as their primary site of failure. These relapses were classified as either NP or TR. Specifically, patients were classified as NP if the recurrence was distinctly different from the primary tumor with respect to the histologic subtype, the recurrence location was in a different location, or if the flow cytometry changed from aneuploid to diploid. This information was determined by a detailed review of each patient's hospital and/or radiotherapy record, mammograms, and pathologic reports. RESULTS: As of 2/99, with a mean follow-up of 14. 2 years, the overall ipsilateral breast relapse-free rate for all 1152 patients was 86% at 10 years. Using the classification scheme outlined above, 60 patient relapses were classified as TR, 70 were classified as NP and 6 were unable to be classified. NP patients had a longer mean time to breast relapse than TR patients (7.3 years vs. 3.7 years, p < 0.0001) and were significantly younger than TR patients (48.9 years vs. 54.5 years, p < 0.01). Patients developed both TR and NP at similar rates until approximately 8 years, when TR rates stabilized but NP rates continued to rise. By 15 years following original diagnosis, the TR rate was 6.8% compared to 13.1% for NP. Of the patients who had been previously tested for BRCA1/2 mutations, 17% (8/52) had deleterious mutations. It is noteworthy that all patients with deleterious mutations had new primary IBTR, while patients without deleterious mutations had both TR and NP (p = 0.06). Ploidy was evenly distributed between TR and NP but NP had a significantly lower S phase fraction (NP 13.1 vs. TR 22.0, p < 0.05). The overall survival following breast relapse was 64% at 10 years and 49% at 15 years. With a mean follow-up of 10.4 years following breast relapse, patients with NP had better 10-year overall survival (TR 55% vs. NP 75%, p < 0.0001), distant disease-free survival (TR 41% vs. NP 85%, p < 0.0001), and cause-specific survival (TR 55% vs. NP 90%, p < 0.0001). CONCLUSION: It appears that a significant portion of patients who experience ipsilateral breast tumor relapse following conservative surgery and radiation therapy have new primary tumors as opposed to true local recurrences. True recurrence and new primary tumor ipsilateral breast tumor relapses have different natural histories, different prognoses, and, in turn, different implications for therapeutic management.

Adult↗

PubMed2005

The rate of compensatory mutation in the DNA bacteriophage phiX174.

A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage phiX174. For each deleterious mutation, we evolved 8-16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was approximately 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.

Adaptation, Biological↗

PubMed2005

The coupon collector and the suppressor mutation: estimating the number of compensatory mutations by maximum likelihood.

Compensatory mutation occurs when a loss of fitness caused by a deleterious mutation is restored by its epistatic interaction with a second mutation at a different site in the genome. How many different compensatory mutations can act on a given deleterious mutation? Although this quantity is fundamentally important to understanding the evolutionary consequence of mutation and the genetic complexity of adaptation, it remains poorly understood. To determine the shape of the statistical distribution for the number of compensatory mutations per deleterious mutation, we have performed a maximum-likelihood analysis of experimental data collected from the suppressor mutation literature. Suppressor mutations are used widely to assess protein interactions and are under certain conditions equivalent to compensatory mutations. By comparing the maximum likelihood of a variety of candidate distribution functions, we established that an L-shaped gamma distribution (alpha=0.564, theta=21.01) is the most successful at explaining the collected data. This distribution predicts an average of 11.8 compensatory mutations per deleterious mutation. Furthermore, the success of the L-shaped gamma distribution is robust to variation in mutation rates among sites. We have detected significant differences among viral, prokaryotic, and eukaryotic data subsets in the number of compensatory mutations and also in the proportion of compensatory mutations that are intragenic. This is the first attempt to characterize the overall diversity of compensatory mutations, identifying a consistent and accurate prior distribution of compensatory mutation diversity for theoretical evolutionary models.

Epistasis, Genetic↗

PubMed2000

Pervasive compensatory adaptation in Escherichia coli.

To investigate compensatory adaptation (CA), we used genotypes of Escherichia coli which were identical except for one or two deleterious mutations. We compared CA for (i) deleterious mutations with large versus small effects, (ii) genotypes carrying one versus two mutations, and (iii) pairs of deleterious mutations which interact in a multiplicative versus synergistic fashion. In all, we studied 14 different genotypes, plus a control strain which was not mutated. Most genotypes showed CA during 200 generations of experimental evolution, where we define CA as a fitness increase which is disproportionately large relative to that in evolving control lines, coupled with retention of the original deleterious mutation(s). We observed greater CA for mutations of large effect than for those of small effect, which can be explained by the greater benefit to recovery in severely handicapped genotypes given the dynamics of selection. The rates of CA were similar for double and single mutants whose initial fitnesses were approximately equal. CA was faster for synergistic than for multiplicative pairs, presumably because the marginal gain which results from CA for one of the component mutations is greater in that case. The most surprising result in our view, is that compensation should be so readily achieved in an organism which is haploid and has little genetic redundancy This finding suggests a degree of versatility in the E. coil genome which demands further study from both genetic and physiological perspectives.

Adaptation, Physiological↗

PubMed2006

Functional origins of fitness effect-sizes of compensatory mutations in the DNA bacteriophage phiX174.

Epistasis is an important and poorly understood aspect of mutations and strongly influences the evolutionary impact of genetic variation on adaptation and fitness. Although recent studies have begun to characterize the distribution of epistatic effects between mutations affecting fitness, there is currently a lack of empirical information on the underlying biological causes of these epistatic interactions. What are the functional constraints that determine the effectiveness of a compensatory mutation at restoring fitness? We have measured the effect-sizes of 52 compensatory mutations affecting nine different deleterious mutations in the major capsid and spike proteins of the DNA bacteriophage phiX174. On average, an experimentally detectable compensatory mutation recovers about two-thirds of the fitness cost of the preceding deleterious mutation. Variation in fitness effect-sizes is only weakly associated with measures of the distance separating the deleterious and compensatory mutations in the amino acid sequence or the folded protein structure. However, there is a strong association of fitness effect-size with the correlation in the effects of the mutations on the biochemical properties of amino acids. A compensatory mutation has the largest effect-size, on average, when both the compensatory and deleterious mutations have radical effects on the overall biochemical make-up of the amino acids. By examining the relative contributions of specific biochemical properties to variation in fitness effect-size, we find that the area and charge of amino acids have a major influence, which suggests that the complexity of the amino acid phenotype is simplified by selection into a reduced number of phenotypic components.

Bacteriophage phi X 174↗

PubMed1999

Inbreeding load, average dominance and the mutation rate for mildly deleterious alleles in Mimulus guttatus.

The goal of this study is to provide information on the genetics of inbreeding depression in a primarily outcrossing population of Mimulus guttatus. Previous studies of this population indicate that there is tremendous inbreeding depression for nearly every fitness component and that almost all of this inbreeding depression is due to mildly deleterious alleles rather than recessive lethals or steriles. In this article I assayed the homozygous and heterozygous fitnesses of 184 highly inbred lines extracted from a natural population. Natural selection during the five generations of selfing involved in line formation essentially eliminated major deleterious alleles but was ineffective in purging alleles with minor fitness effects and did not appreciably diminish overall levels of inbreeding depression. Estimates of the average degree of dominance of these mildly deleterious alleles, obtained from the regression of heterozygous fitness on the sum of parental homozygous fitness, indicate that the detrimental alleles are partially recessive for most fitness traits, with h approximately 0.15 for cumulative measures of fitness. The inbreeding load, B, for total fitness is approximately 1.0 in this experiment. These results are consistent with the hypothesis that spontaneous mildly deleterious mutations occur at a rate >0.1 mutation per genome per generation.

Alleles↗