Showing papers on "Mutation (genetic algorithm) published in 1987"

Loss of Genetic Diversity from Managed Populations: Interacting Effects of Drift, Mutation, Immigration, Selection, and Population Subdivision

Abstract: A computer simulation program was used to examine interacting effects of genetic drift, mutation, immigration from outside populations, directional and balancing selection, and population subdivision on the loss of genetic variability from small, managed populations. Stochastic ewnts were simulated with a pseudo-random number generator, and the genetic variation (expected heterozygosity) witbin and between populations was monitored in 25 populations for 100 generations. Genetic drift was the overriding factor controling the loss of genetic variation Mutation has no noticeable effect on populations of the size typically managed in zoos and nature preserves Immigration from a large source population can strikingly slow, halt, or even reverse the loss of genetic variation, even with only one or a few migrants per generation. Unless selection is stronger than commonly observed in natural populations, it is inefficient in countering drift when population sizes are on the order of 100 or fewer. Subdivided populations rapidly lose variability from within each sub-population but retain variation across the subpopulations better than does a panmictic population. These results suggest that population managers should be concerned with the variation-depleting effects of genetic drift, perhaps almost to the exclusion of consideration of selection and mutation Drift can be countered by the introduction of vety occasional immigrants or, less effectively, by division of the managed population into smaller breeding groups that interchange enough migrants to prevent unacceptably deleterious inbreeding within each subpopulation

Mutation drift and repertoire shift in the maturation of the immune response.

Abstract: The halltnark of the immune response is its specificity and the specificity is directly correlated with the affinity of the antigen-antibody interaction. The requirement for high affinity antibodies may be more important than specificity alone, since antibodies are designed to detect soluble antigens which are sometimes capable of inflicting great harm at very low concentrations (e.g. toxins). This may not be required by. or may even be a disadvantage to T-cell responses where the affinity for the ligand involves interactions of the T-cell receptor not only with antigen, but also with other molecules, e.g. those involved in MHC restriction (Yague et al. 1985. Dembic et al. 1986). T cells therefore may not have developed the equivalent of the elaborate mechanism which is the object of this paper. During the course of an antigen-specific immune response, the affinity of the serum increases with time, a phenomenon commonly referred to as maturation of the response (Jerne 1951, Siskind & Benaceraff 1969). Such a maturation results from specific alterations of the structure of the antibody molecules (Steiner & Eisen 1967). What is the precise nature of these alterations, which are the root of the production of high affinity antibodies? There is no doubt that somatic mutation contributes to antibody diversity (Weigert et al. 1970. Bernard et al. 1978, Griffiths et al. 1984). There are many reasons to believe that a mechanism of hypermutation operates within restricted stretches of the DNA to further diversify the genes encoding the antibody molecules (Kim et al. 1981, Gearhart & Bogenhagen 1983). This mutational drift is, however, not the full extent of the change. Major changes in the antibody structures involved result from a shift in the antigen-specific B-cell repertoire over the course of the immune response. In the primary response the most frequent B-cell clones already expressing antibody molecules with a relatively

Deletion of genes on chromosome 1 in endocrine neoplasia.

Abstract: Recent studies have identified normal cellular DNA sequences which are lost in the development of embryonal1–6 and adult7,8 tumours. These tumours are thought to arise after a primary mutation in one allele of such a sequence is followed by loss of its normal homologue. In familial cases, the primary mutation is transmitted in the germ line. The secondary mutation may involve a substantial loss of chromosomal material and thus lead to identification of the site of the inherited mutation. We have examined constitutional and tumour genotypes of medullary thyroid carcinomas and phaeochromocytomas which develop in the dominantly inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2) 9 to locate the predisposing gene in this syndrome. We observed deletion of a hypervariable region of DNA on the short arm of chromosome 1 in seven out of fourteen tumours. Analysis of the parental origin of the deleted allele in two families showed that it was derived from the affected parent in one case, which suggests that the deletion does not reflect the site of the inherited mutation in MEN2. The deleted region is distal to the breakpoint commonly detected in neuroblastomas, which share with the tumours of MEN2 embryological origin from neuroectoderm.

Evolution of genetic variability in a spatially heterogeneous environment: effects of genotype-environment interaction.

Abstract: Classical population genetic models show that disruptive selection in a spatially variable environment can maintain genetic variation. We present quantitative genetic models for the effects of disruptive selection between environments on the genetic covariance structure of a polygenic trait. Our models suggest that disruptive selection usually does not alter the equilibrium genetic variance, although transient changes are predicted. We view a quantitative character as a set of character states, each expressed in one environment. The genetic correlation between character states expressed in different environments strongly affects the evolution of the genetic variability. (1) If the genetic correlation between character states is not ± 1, then the mean phenotype expressed in each environment will eventually attain the optimum value for that environment; this is the evolution of phenotypic plasticity (Via & Lande, 1985). At the joint phenotypic optimum, there is no disruptive selection between environments and thus no increase in the equilibrium genetic variability over that maintained by a balance between mutation and stabilizing selection within each environment. (2) If, however, the genetic correlation between character states is ± 1, the mean phenotype will not evolve to the joint phenotypic optimum and a persistent force of disruptive selection between environments will increase the equilibrium genetic variance. (3) Numerical analyses of the dynamic equations indicate that the mean phenotype can usually be perturbed several phenotypic standard deviations from the optimum without producing transient changes of more than a few per cent in the genetic variances or correlations. It may thus be reasonable to assume a roughly constant covariance structure during phenotypic evolution unless genetic correlations among character states are extremely high or populations are frequently perturbed. (4) Transient changes in the genetic correlations between character states resulting from disruptive selection act to constrain the evolution of the mean phenotype rather than to facilitate it.

Adaptive landscapes, genetic distance and the evolution of quantitative characters.

Abstract: Summary The maintenance of polygenic variability by a balance between mutation and stabilizing selection has been analysed using two approximations: the 'Gaussian' and the 'house of cards'. These lead to qualitatively different relationships between the equilibrium genetic variance and the parameters describing selection and mutation. Here we generalize these approximations to describe the dynamics of genetic means and variances under arbitrary patterns of selection and mutation. We incorporate genetic drift into the same mathematical framework. The effects of frequency-independent selection and genetic drift can be determined from the gradient of log mean fitness and a covariance matrix that depends on genotype frequencies. These equations describe an 'adaptive landscape', with a natural metric of genetic distance set by the covariance matrix. From this representation we can change coordinates to derive equations describing the dynamics of an additive polygenic character in terms of the moments (means, variances, ...) of allelic effects at individual loci. Only under certain simplifying conditions, such as those derived from the Gaussian and house-of-cards approximations, do these general recursions lead to tractable equations for the first few phenotypic moments. The alternative approximations differ in the constraints they impose on the distributions of allelic effects at individual loci. The Gaussian-based prediction that evolution of the phenotypic mean does not change the genetic variance is shown to be a consequence of the assumption that the allelic distributions are never skewed. We present both analytical and numerical results delimiting the parameter values consistent with our approximations.

Molecular evolutionary clock and the neutral theory

Abstract: From the standpoint of the neutral theory of molecular evolution, it is expected that a universally valid and exact molecular evolutionary clock would exist if, for a given molecule, the mutation rate for neutral alleles per year were exactly equal among all organisms at all times. Any deviation from the equality of neutral mutation rate per year makes the molecular clock less exact. Such deviation may be due to two causes: one is the change of the mutation rate per year (such as due to change of generation span), and the other is the alteration of the selective constraint of each molecule (due to change of internal molecular environment). A statistical method was developed to investigate the equality of evolutionary rates among lineages. This was used to analyze protein data to demonstrate that these two causes are actually at work in molecular evolution. It was emphasized that departures from exact clockwise progression of molecular evolution by no means invalidates the neutral theory. It was pointed out that experimental studies should be done to settle the issue of whether the mutation rate for nucleotide change is more constant per year or per generation among organisms whose generation spans are very different.

Using the genetic algorithm to generate LISP source code to solve the prisoner's dilemma

Abstract: The genetic algorithm is adapted to manipulate Lisp S-expressions. The traditional genetic operators of crossover, inversion, and mutation are modified for the Lisp domain. The process is tested using the Prisoner's Dilemma. The genetic algorithm produces solutions to the Prisoner's Dilemma as Lisp S-expressions and these results are compared to other published solutions.

Selection, Generalized Transmission and the Evolution of Modifier Genes. I. The Reduction Principle

Abstract: Modifier gene models are used to explore the evolution of features of organisms, such as the genetic system, that are not directly involved in the determination of fitness. Recent work has shown that a general "reduction principle" holds in models of selectively neutral modifiers of recombination, mutation, and migration. Here we present a framework for models of modifier genes that shows these reduction results to be part of a more general theory, for which recombination and mutation are special cases. The deterministic forces that affect the genetic composition of a population can be partitioned into two categories: selection and transmission. Selection includes differential viabilities, fertilities, and mating success. Imperfect transmission occurs as a result of such phenomena as recombination, mutation and migration, meiosis, gene conversion, and meiotic drive. Selectively neutral modifier genes affect transmission, and a neutral modifier gene can evolve only by generating association with selected genes whose transmission it affects. We show that, in randomly mating populations at equilibrium, imperfect transmission of selected genes allows a variance in their marginal fitnesses to be maintained. This variance in the marginal fitnesses of selected genes is what drives the evolution of neutral modifier genes. Populations with a variance in marginal fitnesses at equilibrium are always subject to invasion by modifier genes that bring about perfect transmission of the selected genes. It is also found, within certain constraints, that for modifier genes producing what we call "linear variation" in the transmission processes, a new modifier allele can invade a population at equilibrium if it reduces the level of imperfect transmission acting on the selected genes, and will be expelled if it increases the level of imperfect transmission. Moreover, the strength of the induced selection on the modifier gene is shown to range up to the order of the departure of the genetic system from perfect transmission.

Mating-type switching in filamentous ascomycetes.

Abstract: Little is known concerning the mating-type genes of filamentous ascomycetes, compared to those of the yeasts Saccharomyces cerevisiae (reviewed by HERSKOWITZ and OSHIMA 1981; KLAR, STRATHERN and HICKS 1984) and Schizosaccharomyces pombe (see BEACH 1983, EGEL 1984). The two mating-type alleles that are typically present in genetically well-studied filamentous species, such as Neurospora crassa, Sordaria brevicollis and Ascobolus immersus, appear to be extremely stable. Mutations to loss of mating-type function have been obtained in Neurospora (GRIFFITHS and DELANCE 1978; GRIFFITHS 1982). Some of these mutations are revertible, but no changes or reversals of mating specificity have been found. In N . crassa, the mating-type genes specify functions not only in the sexual phase of the life cycle but also in the vegetative phase, where strains of opposite mating type show vegetative (heterokaryon) incompatibility with one another. Efforts to separate these different functions of the Neurospora mating-type gene by recombination have failed (PITTENCER 1957; NEWMEYER, HOWE and GALEAZZI 1973), but the two have been resolved by mutation. GRIFFITHS and DELANCE (1978) obtained a single, unique mutant in which the vegetative incompatibility function was inactivated while the mating function was retained. In all other mating-type mutations which they obtained, both the vegetative and sexual functions were inactivated. Recent developments with Neurospora may have opened the way for a better understanding. The mating-type locus has been cloned molecularly (VOLLMER and YANOFSKY 1986). A biological assay has been developed for the pheromone involved in attracting trichogynes to cells of opposite mating type, and the pheromone is being characterized (BISTIS 198 1, 1983). Complementing self-sterile mutants have been obtained and have been used for genetic manipulations in the homothallic (normally self-fertile) species Neurospora africana (SANDS 1982; ARNOLD 1983). In contrast to the stability of mating type in species such as N . crassa, what appears to be a regularly occurring unidirectional reversal of mating type has been described in the filamentous ascomycetes Chromocrea spinulosa (MATHIESON 1952), Sclerotinia trgoliorum (UHM and FUJII 1983a,b), and Glomerella cingulata (WHEELER 1950).'

Inequality in mutation rates of the two strands of DNA.

Abstract: As the mechanisms for replicating the two strands of duplex DNA differ1 it is, in principle, possible for the mutation rates to differ depending on which strand is being copied. In the absence of selection this would lead to a difference in the measured rate of a particular base substitution, such as T to C, depending on which DNA strand was analysed to determine the rate. Thus a change such as T to C on one DNA strand results from either a direct T-to-C mutation on that strand or an A-to-G mutation on the complementary strand; for the other strand the situation is reversed, and it can be seen that different processes are responsible for the two cases, allowing for asymmetry in substitution rate. We have tested whether such asymmetry indeed occurs by studying equivalent sequences from the β-globin complexes of six species of primate. Our results reveal an asymmetry in substitution rates consistent with predictions based on strand-inequalities in mutation rates. Our sequence comparisons also allow us to make predictions about the positions of replication origins and the replication error rates of one strand relative to the other.

Somatic Mutation in Anti‐Phosphorylcholine Antibodies

Abstract: A detailed analysis of the genes and proteins that participate in the murine immune response to PC has provided key insights at the structural level into the phenomenon of somatic mutation in B cells. Most anti-PC antibodies are encoded by 1 VH gene of the S107 subfamily, and 3 VK genes, VKT15 of the VK22 subfamily, VKM3 from the VK8 subfamily, and VK167 from the VK24 subfamily. No mutation was detected in these genes until the 2nd wk after immunization, indicating that mutation is under developmental control. The protein sequences of 73 heavy and light chains derived from the secondary response support the concept of developmental activation of mutation after antigen stimulation. No mutation was found in the IgM antibodies, whereas half of the IgG and IgA antibodies had mutation. Most of the mutated antibodies had higher affinity for antigen than their germline counterparts, which suggests that the major role of somatic mutation is to increase affinity rather than to create new specificities. Nucleotide sequencing established two hallmarks of mutation in immunoglobulin genes: mutations are targeted to a 1 kilobase region surrounding and including the rearranged variable gene, and they occur at an extraordinary frequency of 10(-2) nucleotide substitutions. Mutation is probably caused by DNA repair, and may occur during error-prone repair of nicked DNA around the variable gene or during mismatch repair of misaligned structural intermediates. The elucidation of this remarkable mechanism clearly requires studies of a more dynamic character. Two major questions that need to be answered are: what targets mutation to the variable gene, and what enzymes are involved?

The parD- mutant of Escherichia coli also carries a gyrAam mutation. The complete sequence of gyrA.

Abstract: Summary The phenotype of a recently-described mutant (OVG), conditionally defective in chromosome partitioning and septal positioning, was originally thought to be due to a new gene (parD) mapping at 88.4 min. We have now shown that, in addition to the parD mutation, OV6 carries a gyrAam mutation and that this mutation is probably responsible for the gross phenotype of the mutant. We have cloned the gyrA gene, identified the GyrA protein, sequenced the gyrA gene and flanking genes, cloned and sequenced the gyrAam, mutation, and identified its truncated product, in addition, we have identified the transcriptional start point of the gyrA gene. The E. coli GyrA protein has extensive homologies with Gyrase proteins of other organisms and weak sequence homologies with some eukaryotic cytoskeletal proteins.

Computer-aided pipeline operation using genetic algorithms and rule learning. PART I: Genetic algorithms in pipeline optimization

Abstract: In this two-paper series, techniques connected with artificial intelligence and genetics are applied to achieve computer-based control of gas pipeline systems. In this, the first paper, genetic algorithms are developed and applied to the solution of two classical pipeline optimization problems, the steady serial line problem, and the single transient line problem. Simply stated, genetic algorithms are canonical search procedures based on the mechanics of natural genetics. They combine a Darwinian survival of the fittest with a structured, yet randomized, information exchange between artificial chromosomes (strings). Despite their reliance on stochastic processes, genetic algorithms are no simple random walk; they carefully and efficiently exploit historic information to guide future trials. In the two pipeline problems, a simple three-operator genetic algorithm consisting of reproduction, crossover, and mutation finds near-optimal performance quickly. In, the steady serial problem, near-optimal performance is found after searching less than 1100 of 1.1(1012) alternatives. Similarly, efficient performance is demonstrated in the transient problem. Genetic algorithms are ready for application to more complex engineering optimization problems. They also can serve as a searning mechanism in a larger rule learning procedure. This application is discussed in the sequal.

The infinitely-many-alleles model with selection as a measure-valued diffusion

Abstract: In [4], a diffusion model is constructed for a genetic system in which all alleles are selectively neutral and all mutants are new. The state of this model is the vector of order statistics of the gene frequencies. This reordering of the frequencies is necessary because of the assumption on mutation. Fixing the order of the alleles results in a model in which the sum of the gene frequencies is less than one for all positive time. Unfortunately, reordering makes it virtually impossible to study models with selection using this approach.

The same beta-globin gene mutation is present on nine different beta-thalassemia chromosomes in a Sardinian population.

Abstract: The predominant beta-thalassemia in Sardinia is the beta 0 type in which no beta-globin chains are synthesized in the homozygous state. We determined the beta-thalassemia mutations in this population by the oligonucleotide-probe method and defined the chromosome haplotypes on which the mutation resides. The same beta 39(CAG----TAG) nonsense mutation was found on nine different chromosome haplotypes. Although this mutation may have arisen more than once, the multiple haplotypes could also be generated by crossing over and gene conversion events. These findings underscore the frequency of mutational events in the beta-globin gene region.

Measurements of mutation rates in B lymphocytes.

Abstract: It is established that somatic mutation is an important source of antibody diversity in vivo. It is also established that Igh-V gene segments are hypermutable in vitro. This is not a completely satisfactory situation. While there is no reason to believe that Igh-V genes are not hypermutable in vivo as well, direct experimental evidence is lacking. Perhaps experiments with transgenic mice will soon fill this gap. It is not so clear how much higher than normal the rate of hypermutation is. As far as we are aware, there are no direct measurements of mutation rates per base pair per cell generation in mammals, certainly not for lymphocyte cell lines. For a variety of reasons, it is difficult to measure very low mutation rates. The general consensus is that the normal rate should be somewhere between 10(-10) and 10(-12) mutations per base pair per cell generation. Therefore, an experiment designed to directly determine a rate using the compartmentalization test would involve hundreds of cultures, each containing at least 10(9) cells. It is not a trivial problem to find one or a few mutants among so many cells. It is simple to study mutation to resistance to a drug, for example, ouabain or azaguanine, but, as we discussed, there are technical and conceptual pitfalls. The vast excess of dead cells influences the growth of a few mutant cells, particularly in lymphocyte cell lines. Even if this problem could be solved, the mutation rate so obtained would be "per gene(s)" and not "per base pair". The problems associated with cytotoxic agents can be avoided by immunofluorescence methods in conjunction with selective cloning or cell sorting. Using these techniques, we have carried out extensive experiments to determine whether the immunoglobulin mutator system acts, at least partially, on genetic elements other than those in or near the heavy chain variable region gene segment. For an opal termination codon in a heavy chain constant region gene segment, the rate of reversion was less than 10(-7) per base pair per cell generation. This upper limit was fixed by the high rate of small deletions at the heavy chain locus. For an allotype mutation at B2m, the gene encoding beta 2 microglobulin, the rate of mutation was less than 10(-8). This upper limit could be lowered by at least two orders of magnitude by using a high-speed cell sorter.

A gene location for the inheritance of the cataract Fraser (CatFr) mouse congenital cataract.

Abstract: Animal models which emulate defects similar to those in man are required for medical research. Many investigations on the cellular, developmental and molecular aspects of cataractogenesis use the cataract Fraser (Cat) mouse. This report shows that the Cat and Lop lens abnormalities are linked, and are probably allelic genes on chromosome 10. It also shows that the Cat gene is maintained on an inbred genetic background which differs from 79 other strains; it is proposed that this strain be named CAT.

Delayed mutation in Chinese hamster cells.

Abstract: The possibility was examined that mutational events can be delayed for more than one or two cell divisions following treatment of Chinese hamster cells with the DNA alkylating agent ethyl methane sulfonate. If mutations in mammalian cells are delayed, the proportion of mutant cells in colonies grown from single mutagen-treated cells will reflect the cell division at which the mutation is genetically fixed, i.e., a first division mutation yields a 1/2 mutant colony, a fifth division mutation produces a 1/32 mutant colony, etc. In the present study, replating of cells from single colonies grown for six to seven days after mutagen treatment resulted in the discrete ratios of glucose-6-phosphate dehydrogenase (G6PD)-deficient mutant to wild-type colonies expected for a delayed mutational process which produces mutations over at least 8–10 cell generations. Further, when cells from 7- to 10-day colonies, grown from ethyl methane sulfonate (EMS)-treated cells were replated into selective medium containing 6-thioguanine (6TG), the number of 6TG-resistant colonies obtained per flask was distributed over a very wide range, consistent with a mutational delay process. These results could not be explained by differences in the number of cells per colony or plating efficiency in selective medium. Assuming that the relative number of 6TG-resistant colonies per flask reflects the time of mutation, EMS treatment produced two groups of mutational events: one which occurred within the first five cell generations and another uniformly distributed over at least the next eight to nine divisions. These results support the conclusion that EMS induces mutants for at least 10–14 cell generations after treatment and raise the possibility that current methods to assess the mutagenic potential of an agent might lead to significant underestimation. The role of delayed mutation in the phenomenon of “mutation expression time” is also discussed.

Adaptation of Drosophila melanogaster populations to high mutation pressure: evolutionary adjustment of mutation rates

Abstract: Evolutionary aspects of high mutation pressure were studied in laboratory populations of Drosophila melanogaster that have irradiation histories up to 600 generations. Dose-response regressions for the x-ray induction of various types of mutation were obtained from six of these populations. The sensitivity of these irradiated populations relative to an unirradiated control population was characterized by dose reduction factors. Sensitivity decreased stepwise with the stepwise increase in irradiation levels to which the populations had been exposed every generation (0 R, 2 kR, 4 kR, 8 kR; 1 R = 0.258 mC/kg) but remained the same over hundreds of generations when the irradiation levels were constant. Resistance is controlled by single genetic factors. Additional factors evolved in subpopulations exposed to increased irradiation levels, and different factors evolved in populations that were kept separate from the beginning of their irradiation histories. Two of three factors persisted in subpopulations no longer irradiated, but one factor disappeared; this last one behaved like a transposon. Factors of relative radio-resistance are stage specific (immature oocytes) and some of them are assumed to modify or control mutation-rate genes. The resistance factors enable populations to achieve an equilibrium between the amounts of environmental mutagens and intrinsic mutation rates.