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Results for “deleterious mutation”

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PubMed2000

A test for epistasis among induced mutations in Caenorhabditis elegans.

Synergistic epistasis, in which deleterious mutations tend to magnify each other's effects, is a necessary component of the mutational deterministic hypothesis for the maintenance of sexual production. We tested for epistasis for life-history traits in the soil nematode Caenorhabditis elegans by inducing mutations in two genetic backgrounds: a wild-type strain and a set of genetically loaded lines that contain large numbers of independent mildly detrimental mutations. There was no significant difference between the effect of new mutations on the wild-type background and the genetically loaded background for four out of five fitness correlates. In these four cases, the maximum level of epistasis compatible with the data was very low. The fifth trait, late productivity, is not likely to be an important component of fitness. This suggests either that specific environmental conditions are required to cause epistasis or that synergistic epistasis is not a general phenomenon. We also suggest a new mechanism by which deleterious mutations may provide an advantage to sexual reproduction under low selection coefficients.

Analysis of Variance↗

PubMed1995

Evolutionary consequences of mutation and selection within an individual.

Whether in sexual or asexual organisms, selection among cell lineages during development is an effective way of eliminating deleterious mutations. Using a mathematical analysis, we find that relatively small differences in cell replication rates during development can translate into large differences in the proportion of mutant cells within the adult, especially when development involves a large number of cell divisions. Consequently, intraorganismal selection can substantially reduce the deleterious mutation rate observed among offspring as well as the mutation load within a population, because cells rather than individuals provide the selective "deaths" necessary to stem the tide of deleterious mutations. The reduction in mutation rate among offspring is more pronounced in organisms with plastic development than in those with structured development. It is also more pronounced in asexual organisms that produce multicellular rather than unicellular offspring. By effecting the mutation rate, intraorganismal selection may have broad evolutionary implications; as an example, we consider its influence on the evolution of ploidy levels, finding that cell-lineage selection is more effective in haploids and tends to favor their evolution.

Biological Evolution↗

PubMed2026

The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals.

The distribution of fitness effects (DFE) describes the selection coefficients of newly arising mutations and fundamentally influences population genetic processes. However, the extent and mechanisms of differences in the DFE for non-synonymous mutations have not been systematically investigated across species with divergent phylogenetic histories and ecologies. Here, we inferred the DFE in natural populations of 11 animal (sub)species, including humans, mice, fin whales, vaquitas, wolves, collared flycatchers, pied flycatchers, halictid bees, Drosophila, and mosquitoes. We found that mammals have a higher proportion of strongly deleterious mutations (defined as s≤-0.01; 22% to 47% in mammals; 0.0% to 5.4% in insects and birds) and a lower proportion of weakly deleterious mutations than insects and birds. Further, the DFE co-varies with phylogeny, such that the mean mutation effects are more similar in closely related species (Pagel's λ = 0.84, P = 0.01). Next, we investigated whether various summary statistics of the DFE were related to variation in life-history traits across these organisms. We found some support for genome size, body mass, and long-term effective population size being correlated with the DFE. Overall, our findings are consistent with predictions derived independently from the Fisher's Geometric Model (FGM), which defines organismal complexity as the number of phenotypes under selection. FGM predicts that mutations are more deleterious in complex organisms, while strongly deleterious mutations occur more frequently in smaller populations. Our study demonstrates strong phylogenetic signal in the evolution of a fundamental population genetics parameter, and proposes that, through mechanisms of epistasis, long-term population size and organismal complexity could be underlying variation in the DFE across animals.

Journal Article↗

PubMed1995

Muller's ratchet, epistasis and mutation effects.

In this study, computer simulation is used to show that despite synergistic epistasis for fitness, Muller's ratchet can lead to lethal fitness loss in a population of asexuals through the accumulation of deleterious mutations. This result contradicts previous work that indicated that epistasis will halt the ratchet. The present results show that epistasis will not halt the ratchet provided that rather than a single deleterious mutation effect, there is a distribution of deleterious mutation effects with sufficient density near zero. In addition to epistasis and mutation distribution, the ability of Muller's ratchet to lead to the extinction of an asexual population under epistasis for fitness depends strongly on the expected number of offspring that survive to reproductive age. This strong dependence is not present in the nonepistatic model and suggests that interpreting the population growth parameter as fecundity is inadequate. Because a continuous distribution of mutation effects is used in this model, an emphasis is placed on the dynamics of the mutation effect distribution rather than on the dynamics of the number of least mutation loaded individuals. This perspective suggests that current models of gene interaction are too simple to apply directly to long-term prediction for populations undergoing the ratchet.

Computer Simulation↗

PubMed1997

Evolution of sex and the molecular clock in RNA viruses.

Although there exist many hypotheses for the advantage of sexual reproduction, Muller's ratchet is one that has received recent attention as an explanation for the evolution of sex in RNA viruses. Muller's ratchet provides for an advantage of sex when the rate of deleterious mutations is high and population size is small. A small population size intensifies genetic drift, which can lead to the random loss of genomes that are free of deleterious mutations. Sex becomes advantageous because it can re-create, through genetic exchange, genomes with fewer or no mutations. RNA viruses may be subject to Muller's ratchet because they have very high mutation rates and they may experience genetic drift if their populations are forced through small bottlenecks during infection. This review discusses the results of laboratory studies examining the possibility of an advantage of sex through Muller's ratchet in RNA viruses. Data from studies of wild populations of RNA viruses are also considered, and a model is presented for how an observed pattern of molecular evolution (or the molecular clock) in wild populations may be explained by Muller's ratchet (or a similar process) and the addition of compensatory mutations to Ohta's model of evolution by slightly deleterious mutations.

Evolution, Molecular↗

PubMed2005

Estimation of the rate and effects of deleterious genomic mutations in finite populations with linkage disequilibrium.

Under several assumptions such as infinite population size with unlinked loci at linkage equilibrium (LD) under mutation-selection (M-S) balance, the rate (U), and the average effects (dominance and selection coefficients h and s) of deleterious genomic mutations (DGM) can be estimated by the Deng-Lynch method in some natural populations. However, all natural populations are finite in size and many of them are not large enough to be considered as approximately infinite. In the absence of an analytical estimation approach to characterize DGM in finite populations, we test the robustness and applicability of the Deng-Lynch method in finite populations with computer simulations. The results indicate that the estimation obtained by the Deng-Lynch method in finite populations with LD is generally robust when population size is greater than 400. With constant mutation effects, in outcrossing populations, the estimates U and ĥ are unbiased or only slightly upwardly biased, and ŝ is unbiased for most cases. In highly selfing populations, U and ĥ are upwardly biased, U is no more than 1.5U and ĥ is less than 1.1 h, and ŝ is either unbiased or slightly downwardly biased. With variable mutation effects, U ranges from 0.56 to 0.72U, and s ranges from 1.4 to 1.8s. Generally speaking, with the same finite population size, the estimation in outcrossing populations is better than in highly selfing populations. Given that even the order of the magnitude of the parameters of DMG (U in particular) is controversial, our investigation here may provide a basis for using the Deng-Lynch method to characterize DGM in finite populations of size greater than 400 in the presence of LD.

Genetics, Population↗

PubMed2006

High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-León (central Spain).

A total of 264 unrelated breast/ovarian cancer patients and 45 healthy individuals with familial antecedents referred for genetic testing were scanned for germ-line mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis (CSGE) and heteroduplex analysis by capillary array electrophoresis (HA-CAE). We detected 101 distinct mutations (41 in BRCA1 and 60 in BRCA2); ten of them have not been previously reported. These mutations were c.2411_2429dup19, c.2802_2805delCAAA and c.5294A>G (p.E1725E) of BRCA1; and c.667C>T (p.Q147X), c.2683C>T (p.Q819X), c.5344_5347delAATA, c.5578_5579delAA;insT, c.8260_8261insGA, c.744+14C>T and c.8099A>G (p.Y2624C) of BRCA2. Twenty-four different mutations, including seven of the new mutations (five frameshift and two nonsense), were classified as pathogenic. These 24 alterations were found in 39 families (12.6% of all families). A remarkable proportion of deleterious mutations were found in BRCA2: 25 families carried a mutation in BRCA2 (BRCA2+; 64.1%) compared with 14 families BRCA1+ (35.9%). The highest incidences of deleterious mutations were found in families with three or more cases of site-specific breast cancer (BC) (27.4%) and families with BC and ovarian cancer (22.2%). Finally, four recurrent mutations, 3036_3039delACAA, c.5374_5377delTATG of BRCA2, as well as c.5272-1G>A and c.5242C>A (p.A1708E) of BRCA1, accounted for 44% of all of the deleterious mutations.

Breast Neoplasms↗

PubMed2000

The evolution of haplodiploidy under inbreeding.

Although haplodiploid organisms tend to be inbred, previous models of the evolution of haplodiploidy have assumed outbred populations. Here a model for the evolution of haplodiploidy is developed which incorporates sib mating, deleterious mutations generated by mutation, and fitness differences between haploids and diploids. Simulations of the model allow an assessment of the effect of inbreeding on the deleterious mutation and maternal transmission theories for the evolution of haplodiploidy. As expected from intuitive arguments, inbreeding favours haplodiploidy under the deleterious mutation hypothesis but disfavours haplodiploidy under the maternal transmission hypothesis. It appears that the effect of inbreeding is greater on the maternal transmission theory, and thus inbreeding may restrict the evolution of haplodiploidy.

Animals↗

PubMed2006

Muller's ratchet in symbiont populations.

Muller's ratchet, the inevitable accumulation of deleterious mutations in asexual populations, has been proposed as a major factor in genome degradation of obligate symbiont organisms. Essentially, if left unchecked the ratchet will with certainty cause extinction due to the ever increasing mutational load. This paper examines the evolutionary fate of insect symbionts, using mathematical modelling to simulate the accumulation of deleterious mutations. We investigate the effects of a hierarchical two level population structure. Since each host contains its own subpopulation of symbionts, there will be a large number of small symbiont populations linked indirectly via selection on the host level. We show that although the separate subpopulations will accumulate deleterious mutations quickly, the symbiont population as a whole will be protected from extinction by selection acting on the hosts. As a consequence, the extent of genome degradation observed in present day symbionts is more likely to represent loss of functions that were (near-) neutral to the host, rather than a snap shot of a decline towards complete genetic collapse.

Animals↗

PubMed2003

The effects of parasitism and inbreeding on the competitive ability in Daphnia magna: evidence for synergistic epistasis.

Synergistic epistasis for fitness is often assumed in models of how selection acts on the frequency and distribution of deleterious mutations. Evidence for synergistic epistasis would exist if the logarithm of fitness declines more quickly with number of deleterious mutations, than predicted by a linear decline. This can be studied indirectly by quantifying the effect of different levels of inbreeding on fitness. Here, six sets (different genetic backgrounds) of three increasingly inbred Daphnia magna clones were used to assess their relative fitness according to changes in frequency in a competition experiment against a tester clone. A novelty of the mating procedure was that the inbreeding coefficients (F) of the three clones belonging to each set increased in steps of 0.25 independent of the (unknown) inbreeding coefficient of the common ancestor. The equal increase of the inbreeding coefficients is important, because deviations influence the quantification of inbreeding depression, its variance and the detection of epistasis. In a simple mathematical model we show that when working with a partially inbred population inbreeding depression is underestimated, the variance of fitness is increased, and the detection of epistasis more difficult. Further, to examine whether an interaction between inbreeding and parasitism exists, each inbred clone was tested with and without a microsporidium infection (Octosporea bayeri). We found a nonlinear decrease of the logarithm of fitness across the three levels of inbreeding, indicating synergistic epistasis. The interaction term between parasitism and inbreeding was not significant. Our results suggest that deleterious mutations may be purged effectively once the level of inbreeding is high, but that parasitism seems not to influence this effect.

Animals↗

PubMed2005

Prevalence of BRCA mutations and founder effect in high-risk Hispanic families.

UNLABELLED: Approximately 12% of the U.S. population is Hispanic, with the majority residing in urban centers such as Los Angeles. The prevalence of BRCA mutations among high-risk Hispanic families is unknown. METHODS: One hundred and ten unrelated probands of Hispanic origin, with a personal or family history of breast and/or ovarian cancer, presented for genetic cancer risk assessment, were enrolled in an Institutional Review Board-approved registry and underwent BRCA testing. Haplotype analyses were done if BRCA mutations were observed in two or more unrelated probands. RESULTS: Mean age at diagnosis was 37 years (range = 23-59) for the 89 (81%) probands with invasive breast cancer. Overall, 34 (30.9%) had deleterious mutations (25 in BRCA1, 9 in BRCA2), 25 (22.7%) had one or more unclassified variants, and 51 (46.4%) had negative results. The mean pretest mutation probability using the Couch model, Myriad model, and BRCAPro was 19.6% (range = 4-77%). The combined average mutation probability was 32.8% for carriers, 15.5% for noncarriers, and 12.9% for variant carriers (P < 0.0001). The most common deleterious mutation was 185delAG (4 of 34, 11.8%). The Hispanic 185delAG carrier families share the same haplotype from D17s1320 through BRCA1, as do two reference Ashkenazi Jewish families. Haplotype analyses of additional recurrent BRCA1 mutations [IVS5+1G>A (n=2),S955X (n = 3), R1443X (n = 3), and 2552delC (n = 2)] also suggest founder effects, with four of six mutations seen almost exclusively in families with Latin American/Caribbean or Spanish ancestry. CONCLUSION: This is the largest study to date of high-risk Hispanic families in the United States. Six recurrent mutations accounted for 47% (16 of 34) of the deleterious mutations in this cohort. The BRCA1185delAG mutation was prevalent (3.6%) in this clinic-based cohort of predominantly Mexican descent, and shared the Ashkenazi Jewish founder haplotype.

Adult↗

PubMed2002

Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.

It is estimated that familial aggregation and genetic susceptibility play a role in as many as 10% of pancreatic ductal adenocarcinomas. To investigate the role of germ-line mutations in the etiology of pancreatic cancer, we have analyzed samples from patients with pancreatic cancer enrolled in the NFPTR for mutations in four tumor suppressor candidate genes: (a) MAP2K4; (b) MADH4; (c) ACVR1B; and (d) BRCA2 by direct sequencing of constitutional DNA. These genes are mutated in clinically sporadic pancreatic cancer, but germ-line mutations are either not reported or anecdotal in familial pancreatic cancer. Pancreatic cancer patient samples were selected from kindreds in which three or more family members were affected with pancreatic cancer, at least two of which were first-degree relatives. No mutations were identified in mitogen-activated protein kinase kinase 4 (0 of 22), MADH4 (0 of 22), or ACVR1B (0 of 29), making it unlikely that germ-line mutations in these genes account for a significant number of inherited pancreatic cancers. BRCA2 gene sequencing identified five mutations (5 of 29, 17.2%) that are believed to be deleterious and one point mutation (M192T) unreported previously. Three patients harbored the common 6174delT frameshift mutation, one had the splice site mutation IVS 16-2A > G, and one had the splice site mutation IVS 15-1G > A. Two of the five BRCA2 mutation carriers reported a family history of breast cancer, and none reported a family history of ovarian cancer. These findings confirm the increased risk of pancreatic cancer in individuals with BRCA2 mutations and identify germ-line BRCA2 mutations as the most common inherited genetic alteration yet identified in familial pancreatic cancer.

Activin Receptors, Type I↗

PubMed1993

[Conditions and limitations of healthy carrier screening for the mutation responsible for cystic fibrosis].

Cystic Fibrosis is an autosomal, recessive and lethal disease which affects one newborn in 2500 in most of European countries. The gene has been cloned and most of the deleterious mutations have been identified. This has led to a complete change in attitude to cystic fibrosis from a public health standpoint. Prenatal diagnosis is now available for couples of carriers (each unaffected parent carrying a deleterious mutation) with a 1/4 risk of having an affected newborn. Prenatal diagnosis can be performed through three different but complementary procedures with an overall reliability of 98%. As these couples at risk are identified by a first affected newborn, prenatal diagnosis may only prevent further ones. General screening of carriers would be valuable from a public health standpoint, for it could prevent the first affected newborn and would decrease very much the incidence of the disease. Such carrier screening is theoretically feasible through the direct analysis of identified deleterious mutations of the gene in the DNA of both parents, before any pregnancy. However there are major obstacles to general screening. On the one hand unidentified mutations are still numerous, except in certain populations, so screening is not perfect. On the other hand, the larger the number of tested mutations (and thus the better the efficiency of screening), the more expensive the procedure. New and cheaper screening technologies are therefore required but as yet unavailable. Moreover, due to the genetic variability within human populations, reliable screening can only be performed within certain homogeneous ethnic sub-populations. This limitation may raise ethical and public health questions.

Cystic Fibrosis↗

PubMed1994

Male mutation rates and the cost of sex for females.

Although we do not know why sex evolved, the twofold cost of meiosis for females provides a standard against which postulated benefits of sex can be evaluated. The most reliable benefit is sex's ability to reduce the impact of deleterious mutations. But deleterious mutations may themselves generate a large and previously overlooked female-specific cost of sex. DNA sequence comparisons have confirmed Haldane's suggestion that most mutations arise in the male germ line; recent estimates of a, the ratio of male to female mutation rates, are ten, six and two in humans, primates and rodents, respectively. Consequently, male gametes may give progeny more mutations than the associated sexual recombination eliminates. Here I describe computer stimulations showing that the cost of male mutations can easily exceed the benefits of recombination, causing females to produce fitter progeny by parthenogenesis than by mating. The persistence of sexual reproduction by females thus becomes even more problematic.

Animals↗

PubMed1994

How can the low levels of DNA sequence variation in regions of the drosophila genome with low recombination rates be explained?

Different regions of the Drosophila genome have very different rates of recombination. For example, near centromeres and near the tips of chromosomes, the rates of recombination are much lower than in other regions. Several surveys of polymorphisms in Drosophila have now documented that levels of DNA polymorphism are positively correlated with rates of recombination; i.e., regions with low rates of recombination tend to have low levels of DNA polymorphism within populations of Drosophila. Three hypotheses are reviewed that might account for these observations. The first hypothesis is that regions of low recombination have low neutral mutation rates. Under this hypothesis between-species divergences should also be low in regions of low recombination. In fact, regions of low recombination have diverged at the same rate as other regions of the genome. On this basis, this strictly neutral hypothesis is rejected. The second hypothesis is that the process of fixation of favorable mutations leads to the observed correlation between polymorphism and recombination. This occurs via genetic hitchhiking, in which linked regions of the genome are swept along with the selectively favored mutant as it increases in frequency and eventually fixes in the population. This hitchhiking model with fixation of favorable mutations is compatible with major features of the data. By assuming this model is correct, one can estimate the rate of fixation of favorable mutations. The third hypothesis is that selection against continually arising deleterious mutations results in reduced levels of polymorphism at linked loci. Analysis of this background selection model shows that it can produce some reduction in levels of polymorphism but cannot explain some extreme cases that have been observed. Thus, it appears that hitchhiking of favorable mutations and background selection against deleterious mutations must be considered together to correctly account for the patterns of polymorphism that are observed in Drosophila.

Animals↗

PubMed2005

Evolutionary constraints in conserved nongenic sequences of mammals.

Mammalian genomes contain many highly conserved nongenic sequences (CNGs) whose functional significance is poorly understood. Sets of CNGs have previously been identified by selecting the most conserved elements from a chromosome or genome, but in these highly selected samples, conservation may be unrelated to purifying selection. Furthermore, conservation of CNGs may be caused by mutation rate variation rather than selective constraints. To account for the effect of selective sampling, we have examined conservation of CNGs in taxa whose evolution is largely independent of the taxa from which the CNGs were initially identified, and we have controlled for mutation rate variation in the genome. We show that selective constraints in CNGs and their flanks are about one-half as strong in hominids as in murids, implying that hominids have accumulated many slightly deleterious mutations in functionally important nongenic regions. This is likely to be a consequence of the low effective population size of hominids leading to a reduced effectiveness of selection. We estimate that there are one and two times as many conserved nucleotides in CNGs as in known protein-coding genes of hominids and murids, respectively. Polymorphism frequencies in CNGs indicate that purifying selection operates in these sequences. During hominid evolution, we estimate that a total of about three deleterious mutations in CNGs and protein-coding genes have been selectively eliminated per diploid genome each generation, implying that deleterious mutations are eliminated from populations non-independently and that sex is necessary for long-term population persistence.

Animals↗

PubMedDate not supplied

Classification of hypotheses on the advantage of amphimixis.

A classification of hypotheses on the advantage of amphimixis over apomixis is presented. According to "Immediate Benefit" hypotheses, amphimixis is advantageous regardless of reciprocal gene exchange, because either it directly increases fitness of the progeny, reduces the deleterious mutation rate, or makes selection more efficient. In contrast, "Variation and Selection" hypotheses attribute the advantage of amphimixis to the reciprocal gene exchange that alters genetic variability and response to selection among the progeny. Most such hypotheses assume that amphimixis increases variability and efficiency of selection, but some claim that amphimixis decreases response to selection. Variation and Selection hypotheses require that some factor, either random drift or epistatic selection, makes distributions of different alleles nonindependent, while another factor, either changes of the genotype fitnesses or deleterious mutations, makes overrepresented genotypes non-optimal. Numerous Variation and Selection hypotheses, dealing with either unstructured or spatially structured populations, are reviewed. Two of them seem most plausible: better responsiveness of the amphimictic population to widely fluctuating selection, and lower mutation load in the amphimictic population under synergistic selection against deleterious mutations. In both cases the large advantage of amphimixis requires rather stringent conditions, which could be falsified by careful experiment. Further progress in understanding the evolution of amphimixis will depend mostly on such experimental work.

Environment↗

PubMed2005

High divergence among Drosophila simulans mitochondrial haplogroups arose in midst of long term purifying selection.

We characterize the type of selection acting within and among mitochondrial lineages in five closely related Drosophila species. We focus on D. simulans, where three genetically distinct mitochondrial haplogroups show high interhaplogroup divergence and low intrahaplogroup polymorphism. Using maximum likelihood models we find that the branches leading to these three distinct mitochondrial groups show a significantly reduced rate of nonsynonymous relative to synonymous substitution. This interhaplogroup rate is significantly reduced compared to the intrahaplogroup rate, and closely resembles the rate observed between distinct species. The data suggest that slightly deleterious mutations segregating within D. simulans haplogroups are removed by selection prior to their fixation among haplogroups. We explore several hypotheses to explain how lineages within a single species can be compatible with this model of slightly deleterious mutation. The most likely hypothesis is that D. simulans haplogroups have persisted in isolation, perhaps due to association with the bacterial symbiont Wolbachia and/or demographic history, introducing a bias against the fixation of slightly deleterious mutations.

Animals↗