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Biomedical subjects

S A Frank

Publications and source records attributed to S A Frank.

At least 19 recordsLinked to original sources
PubMed2003

Genetic variation of polygenic characters and the evolution of genetic degeneracy.

The classical model of mutation-selection balance for quantitative characters sums the effects of individual sites to determine overall character value. I develop an alternative version of this classical model in which character value depends on the averaging of the effects of the individual sites. In this new averaging model, the equilibrium patterns of variance in allelic effects and character values change with the number of sites that affect a character in a different way from the classical model of summing effects. Besides changing the patterns of variance, the averaging model favours the addition of loci to the control of character values, perhaps explaining in part the recent observation of widespread genetic degeneracy.

Biological Evolution↗
PubMed2001

Gene discovery and gene function assignment in filamentous fungi.

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.

Alleles↗
PubMed2001

The probability of severe disease in zoonotic and commensal infections.

Cross-species transfers of pathogens (zoonoses) cause some of the most virulent diseases, including anthrax, hantavirus and Q fever. Zoonotic infections occur when a pathogen moves from its reservoir host species into a secondary host species. Similarly, commensal infections often have a primary reservoir location within their hosts' bodies from which they rarely cause disease symptoms, but commensals such as Neisseria meningitidis cause severe disease when they cross into a different body compartment from their normal location. Both zoonotic and commensal infections cause either mild symptoms or severe disease, but rarely intermediate symptoms. We develop a mathematical model for studying three factors that affect the probability of severe disease: the size of the inoculum, the route of inoculation and the frequency of naturally occurring infections that do not cause symptoms but do induce protective immunity (vaccinating inoculations). With a single route of infection, increasing pathogen density causes inoculations to develop more often into disease rather than asymptomatic vaccinations that provide protective immunity. With two routes of infection, it may happen that a lower density of a pathogen or of a particular antigenic variant leads to a relatively higher frequency of disease-inducing versus vaccinating inoculations. This reversal occurs when one route of infection tends to vaccinate against relatively common pathogens but less often vaccinates against relatively rare pathogens, whereas the other route of infection is susceptible to disease-inducing inoculation even at relatively low pathogen density.

Animals↗
PubMed2001

Recent advances in large-scale transposon mutagenesis.

Transposons were identified as mobile genetic elements over fifty years ago and subsequently became powerful tools for molecular-genetic studies. Recently, transposon-mutagenesis strategies have been developed to identify essential and pathogenicity-related genes in pathogenic microorganisms. Also, a number of in vitro transposition systems have been used to facilitate genome sequence analysis. Finally, transposon mutagenesis of yeast and complex eukaryotes has provided valuable functional genomic information to complement genome-sequencing projects.

Animals↗
PubMed2001

Multiplicity of infection and the evolution of hybrid incompatibility in segmented viruses.

Some viral genomes are divided into segments. When multiple viruses infect a single cell, progeny form by reassorted mixtures of genomic segments. Hybrid incompatibilities arise when a progeny virus has incompatible segments from different parental viruses. Hybrid incompatibility has been observed in influenza and in the multiparticle plant virus Dianthovirus. Hybrid incompatibility provides an opportunity to study rates of viral evolution, divergence and speciation, and the extent of epistatic interactions among components of the viral genome. This paper presents mathematical and computer simulation models to study hybrid incompatibility between diverging strains. The models identify multiplicity of infection as a key factor. When many viral particles infect each host cell, the effective ploidy of the genetic system is high. High ploidy dilutes the contribution of each locus to the phenotype, weakening the selective intensity on each locus. Weaker selection on variant alleles allows the population to maintain greater genetic diversity and to be more easily perturbed by stochastic fluctuations. Greater diversity and stochastic fluctuations explore more widely the space of epistatic interactions, causing more frequent shifts among favoured combinations of alleles. Variable ploidy of viral genetics differs from standard Mendelian genetics.

Computer Simulation↗
PubMed2000

Within-host spatial dynamics of viruses and defective interfering particles.

Defective-interfering (DI) viruses arise spontaneously by deletion mutations. The shortened genomes of the DI particles cannot replicate unless they coinfect a cell with a wild-type virus. Upon coinfection, the DI genome replicates more quickly and outcompetes the wild type. The coinfected cell produces mostly DI viruses. At the population level, the abundances of DI and wild-type viruses fluctuate dramatically under some conditions. In other cases, the DI viruses appear to mediate persistent infections with relatively low levels of host cell death. This moderation of viral damage has led some to suggest DI particles as therapeutic agents. Previous mathematical models have shown that either fluctuation or persistence can occur for plausible parameter values. I develop new mathematical models for the population dynamics of DI and wild-type viruses. My work extends the theory by developing specific predictions that can be tested in the laboratory. These predictions, if borne out by experiment, will explain the key processes that control the diversity of observed outcomes. The most interesting prediction concerns the rate at which killed host cells are replaced. A low rate of replacement causes powerful epidemics followed by a crash in viral abundance. As the rate of replacement increases, the frequency of oscillations increases in DI and wild-type viral abundances, but the severity (amplitude) of the fluctuations declines. At higher replacement rates for host cells, nearly all cells become infected by DI particles and a low level of fluctuating, wild-type viremia persists.

Defective Viruses↗
PubMed2000

Use of thallium(I) ethoxide in Suzuki cross coupling reactions.

[reaction: see text]Thallium(I) ethoxide promotes Suzuki cross couplings for a range of vinyl- and arylboronic acids with vinyl and aryl halide partners in good to excellent yields. This reagent offers distinct advantages over thallium(I) hydroxide in terms of commercial availability, stability, and ease of use.

Boronic Acids↗
PubMed2000

Specific and non-specific defense against parasitic attack.

Specific defense protects against some parasite genotypes but not others, whereas non-specific defense is effective against all genotypes of a parasite. Some empirical studies observe hosts with variability only in non-specific defense, other studies find only specific defense. I analyse a model with combined specific and non-specific defense to determine the conditions that favor detectable variation in each form of defense. High variation in non-specific defense is often maintained when resistance increases in an accelerating way with investment, whereas low variation tends to occur when resistance increases at a decelerating rate with investment. Variation in specific defense rises as the parasite pays a higher cost to attack a broad host range (high cost of virulence), as the number of alternative specificities declines, and as the average level of non-specific defense increases. The last condition occurs because greater non-specific protection tends to stabilize the gene frequency dynamics of specific defense. Selection favors a negative association between costly components of specific and non-specific defense-hosts defended by one component are favored if they have reduced allocation to other costly components. A negative association confounds the measurement of costs of resistance. Individuals with specific defense may have reduced investment in costly non-specific defense. This leads to an apparent advantage of specifically defended hosts in the absence of parasites and a measured cost of resistance that is negative.

Animals↗
PubMed1999

A model for the sequential dominance of antigenic variants in African trypanosome infections.

Trypanosoma brucei infects various domestic and wild mammals in equatorial Africa. The parasite's genome contains several hundred alternative and highly diverged surface antigens, of which only a single one is expressed in any cell. Individual cells occasionally change expression of their surface antigen, allowing them to escape immune surveillance. These switches appear to occur in a partly random way, creating a diverse set of antigenic variants. In spite of this diversity, the parasitaemia develops as a series of outbreaks, each outbreak dominated by relatively few antigenic types. Host-specific immunity eventually clears the dominant antigenic types and a new outbreak follows from antigenic types that have apparently been present all along at low frequency. This pattern of sequential dominance by different antigenic types remains unexplained. I use a mathematical model of parasitaemia and host immunity to show that small variations in the rate at which each type switches to other types can explain the observations. My model shows that randomly chosen switch rates do not provide sufficiently ordered parasitaemias to match the observations. Instead, minor modifications of switch rates by natural selection are required to develop a sequence of ordered parasitaemias.

Animals↗
PubMed1999

Population and quantitative genetics of regulatory networks.

I evolved boolean regulatory networks in a computer simulation. I varied mutation, recombination, the size of the network, and the number of connections per node. I measured the performance of networks and the heritability and epistasis of genetic effects. Networks of intermediate connectivity performed best. The distinction between metabolic and quantitative genetic additivity explained some of the variation in performance. Metabolic additivity describes the interaction between changes in a single network, whereas quantitative genetic additivity measures the consistency of phenotypic effect caused by gene substitution in randomly chosen members of the population. I analysed metabolic additivity by the distribution of epistatic effects of pairs of mutations in individual networks. I measured quantitative genetic additivity by heritability. Highly connected networks had greater metabolic additivity for perturbations to individual networks, but had lower additivity when measured by the average effect of a gene substitution (heritability). The lower heritability of highly connected nets appeared to reduce the effectiveness of recombination in searching evolutionary space.

Animals↗
PubMed1998

Inducible defence and the social evolution of herd immunity.

Many organisms vary their level of investment in defensive characters. Protective traits may be induced upon exposure to predators or parasites. In a similar way, humans vaccinate in response to threatening epidemics. When most group members defend themselves, epidemics die out quickly because parasites cannot spread. A high level of group (herd) immunity is therefore beneficial to the group. There is, however, a well-known divergence between the optimum degree of induction for selfish individuals and the level of induction that maximizes group benefit. I develop two optimality models for the frequency of induction. The first model shows that higher relatedness favours more induction and a smaller difference between selfish and cooperative optima. The second model assumes variation in the vigour of individuals and therefore differences in the relative cost for induction. The model predicts that strong individuals induce more easily than weak individuals. Small differences in vigour cause a large divergence in the optimal levels of induction for strong and weak individuals. The concept of genetic relatedness in an evolutionary model is analogous to correlated interests and correlated strategies in an economic model of human behaviour. The evolutionary models presented here therefore provide a basis for further study of human vaccination.

Animals↗
PubMed1997

Multivariate analysis of correlated selection and kin selection, with an ESS maximization method.

Kin selection coefficients are used in two distinct ways. First, these coefficients measure phenotypic correlations that affect the marginal costs and benefits of behaviors. For example, the phenotypic correlation in sex ratio produced by two females in an isolated patch influences the favoured sex ratio. Second, kin selection coefficients describe genotypic correlations that measure fidelity of transmission. For example, a female values daughters vs. nieces according to genotypic correlations. It is widely known that kin selection coefficients may be interpreted as phenotypic or genotypic correlations in different contexts. However, these different interpretations have never been fully separated, and their different role have not been clearly explained. I provide proofs of a generic analytical approach. The technique automatically separates phenotypic correlations among social partners from genotypic components of transmission. The result is a general method that can be derived from first principles and applied to multivariate problems in social evolution. I emphasize a simple, practical maximization method that can be used to calculate equilibrium conditions for complex social interactions.

Animals↗
PubMed1997

The design of adaptive systems: optimal parameters for variation and selection in learning and development.

Some aspects of learning and development are based on evolutionary change within the organism. In trial and error learning, variant ideas or behaviors are generated and selective filters (learning rules) choose among the population of variants. Development may, in some cases, proceed by selection within a population of variant cellular lineages. This paper analyses abstract properties of selective systems to understand the evolutionary dynamics that occur within organisms. The Price Equation and Fisher's fundamental theorem of natural selection, two of the most powerful concepts in evolutionary genetics, are applied in a general way to internal selective systems in learning and development. This analysis emphasizes generative mechanisms and selective filters as genetically controlled phenotypes of individual organisms. Generative mechanisms create the variation on which selection acts. Selective filters determine the extent to which selection within the organism optimizes organismal performance. The methods of Price and Fisher provide a general way in which to partition evolutionary change into improvements caused by selection and the tendency of high performance variants to deteriorate because of competition or environmental change. This balance between selective improvement, at a rate equal to the variance in fitness, and a matching deterioration in performance, provides general insight into the common properties of adaptive systems in genetics, learning and development. These ideas are applied to a model of honey bee foraging. This example clarifies the relation between genes and phenotypes controlled by internal selective systems.

Adaptation, Physiological↗
PubMed1997

Developmental selection and self-organization.

Developmental selection is the differential survival and proliferation of developmental units, such as cellular lineages. This type of internal selection has been proposed as an explanation for diverse examples of self-organization, from the wiring of brains to the formation of pores on leaf surfaces. A general understanding of developmental selection has been slowed by failure to understand its relationship to familiar forms of genetical selection and evolution. I show the formal analogies between models of developmental selection and genetical selection. The general method I outline for the analysis of selective systems partitions self-organizing selective systems into generative rules that create variation and selective filters that move the population toward a target design. The method also emphasizes aggregate statistical measures of evolving systems, such as the covariance between particular traits and fitness. The identification of useful aggregate measures is a crucial step in the analysis of selective systems. I apply these concepts to a model of self-organization in ant colonies.

Biological Evolution↗
PubMed1997

Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms.

To determine the roles of intensity and duration of nocturnal physical activity in causing rapid phase shifts of human circadian rhythms, eight healthy men were studied three times under constant conditions with no exercise, a 3-h bout of moderate-intensity exercise, or a 1-h bout of high-intensity exercise. Exercise stimulus was centered at 0100. Circadian phase was estimated from the onsets of the nocturnal elevation of plasma thyrotropin (TSH) and melatonin. Mean phase shifts of TSH onsets were -18 +/- 8 (baseline), -78 +/- 10 (low-intensity exercise, P < 0.01), and -95 +/- 19 min (high-intensity exercise, P < 0.01). Mean phase delays of melatonin onsets were -23 +/- 10 (baseline), -63 +/- 8 (low-intensity exercise, P < 0.04), and -55 +/- 15 min (high-intensity exercise, P < 0.12). Taken together with our previous findings, this study indicates that nocturnal physical activity may phase delay human circadian rhythms and demonstrates that phase-shifting effects may be determined with exercise durations and intensities compatible with the demands of a real-life setting.

Adult↗
PubMed1996

How to make a kin selection model.

Kin selection arguments, based on Hamilton's (1964) concept of inclusive fitness, provide a powerful heuristic and can therefore give us valuable insights into the different pathways through which natural selection acts. But their formulation can be quite tricky, requiring as they do, a close accounting of all the fitness effects of a particular item of behaviour. Here we propose a "direct fitness" formulation of inclusive fitness which often has a more straightforward derivation. Our method finds ESS trait values by the standard optimization techniques of simple differentiation plus two additional steps. First, slopes of group phenotype on individual genotype arise naturally during differentiation, and these slopes are replaced by coefficients of relatedness. Second, when behaviours influence different classes such as age, sex of recipient, or other life history components of fitness, the fitness effects on each component are weighted by reproductive value. We illustrate this technique first in a homogeneous population, with examples of group competition and partial dispersal behaviour, and then in a class-structured population, with examples of sex allocation and altruism between age classes.

Age Factors↗
PubMed1996

Host-symbiont conflict over the mixing of symbiotic lineages.

Host and symbiont often conflict over patterns of symbiont transmission. Symbionts favour dispersal out of the host to avoid competition with close relatives. Migration leads to competition among different symbiotic lineages, with potentially virulent side-effects on the host. The hosts are favoured to restrict symbiont migration and reduce the virulent tendencies of the symbionts. Reduced mixing of symbionts would, in many cases, lower symbiont virulence and increase the mean fitness of the host population. But a host modifier allele that reduced symbiont mixing increases only when directly associated with reduced virulence. The association between modifiers and reduced virulence depends on the particular details of symbiont biology. The importance of this direct association between modifier and virulence was first noted by Hoekstra (1987) when studying the evolution of uniparental inheritance of cytoplasmic elements. I apply Hoekstra's insight to a wide range of host-symbiont life histories, expanding the scope beyond cytoplasmic inheritance and genomic conflict. My comparison of differing symbiont life histories leads to a careful analysis of the conditions under which hosts are favoured to control mixing of their symbionts.

Alleles↗