Biomedical subjects

Carl T Bergstrom

Publications and source records attributed to Carl T Bergstrom.

7 recordsLinked to original sources

PubMed2003

Mathematical models of RNA silencing: unidirectional amplification limits accidental self-directed reactions.

RNA silencing, found broadly throughout the eukaryotes, posttranscriptionally suppresses the expression of "aberrant" genes including those of many viruses and transposons. Similar to the specific immune system of vertebrates, RNA silencing works by generating specific responses against foreign elements and rapidly amplifying these responses to clear or otherwise inactivate the threat. Also like the vertebrate immune system, RNA-silencing systems risk making mistakes and mounting undesirable responses against the self. We develop a set of mathematical models of RNA silencing. We show that current models of RNA silencing do little to explain what prevents mistaken reactions from silencing vital organismal genes. We extend the basic models to show that the presumed unidirectional nature of the amplification process (namely, unidirectional RNA-directed RNA polymerase-mediated synthesis of secondary double-stranded RNA as observed in Caenorhabditis elegans) serves as a "safety mechanism" that safeguards against accidental generation of damaging self-directed reactions.

DNA Transposable Elements↗

PubMed2003

Models of CD8+ responses: 1. What is the antigen-independent proliferation program.

Recent experimental results show that even brief stimulation with antigen can cause antigen-specific CD8 T-cells to undergo sustained proliferation followed by differentiation into memory cells. These results show that the dynamics of these immune responses are not governed by constant monitoring of antigen levels, but rather that following stimulation immune cells commit to a "program". At present relatively little is known about the program which governs CD8 cell proliferation and differentiation. For example, we do not know whether the program is completely specified by the initial encounter of a T cell with antigen, or whether it subsequently can be modified by the amount of antigen present. Nor do we know whether the entire program for T cell proliferation and differentiation resides within the T cell itself, or whether some component(s) of the program are determined by cells or molecules external to the CD8 cell. In this paper we construct simple mathematical models which incorporate antigen-independent proliferation and differentiation of CD8 cells during acute infections. We use these models to determine what characteristics the program must have in order to be consistent with the existing data on the dynamics of CD8 responses, and in particular to answer the questions posed above. Our results suggest that the program is not completely defined by the initial encounter of T cell with antigen but may be augmented by exposure to antigen in a brief window shortly after infection; furthermore, parts of the program may reside external to the T-cells. Finally we examine some of the consequences of the "program" for pathogen-host coevolution.

Animals↗

PubMed2003

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures.

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.

Alleles↗

PubMed2003

The Red King effect: when the slowest runner wins the coevolutionary race.

Mutualisms provide benefits to those who participate in them. As a mutualism evolves, how will these benefits come to be allocated among the participants? We approach this question by using evolutionary game theory and explore the ways in which the coevolutionary process determines the allocation of benefits in mutualistic interactions. Motivated by the Red Queen theory, which states that coevolutionary processes favor rapid rates of evolution, we pay particular attention to the role of evolutionary rates in the establishment of mutualism and the partitioning of benefits among mutualist partners. We find that, contrary to the Red Queen, in mutualism evolution the slowly evolving species is likely to gain a disproportionate share of the benefits. Moreover, population structure serves to magnify the advantage to the slower species.

Animals↗

PubMed2003

The evolution of mutator genes in bacterial populations: the roles of environmental change and timing.

Recent studies have found high frequencies of bacteria with increased genomic rates of mutation in both clinical and laboratory populations. These observations may seem surprising in light of earlier experimental and theoretical studies. Mutator genes (genes that elevate the genomic mutation rate) are likely to induce deleterious mutations and thus suffer an indirect selective disadvantage; at the same time, bacteria carrying them can increase in frequency only by generating beneficial mutations at other loci. When clones carrying mutator genes are rare, however, these beneficial mutations are far more likely to arise in members of the much larger nonmutator population. How then can mutators become prevalent? To address this question, we develop a model of the population dynamics of bacteria confronted with ever-changing environments. Using analytical and simulation procedures, we explore the process by which initially rare mutator alleles can rise in frequency. We demonstrate that subsequent to a shift in environmental conditions, there will be relatively long periods of time during which the mutator subpopulation can produce a beneficial mutation before the ancestral subpopulations are eliminated. If the beneficial mutation arises early enough, the overall frequency of mutators will climb to a point higher than when the process began. The probability of producing a subsequent beneficial mutation will then also increase. In this manner, mutators can increase in frequency over successive selective sweeps. We discuss the implications and predictions of these theoretical results in relation to antibiotic resistance and the evolution of mutation rates.

Bacteria↗

PubMed2002

Separating equilibria in continuous signalling games.

Much of the literature on costly signalling theory concentrates on separating equilibria of continuous signalling games. At such equilibria, every signaller sends a distinct signal, and signal receivers are able to exactly infer the signaller's condition from the signal sent. In this paper, we introduce a vector-field solution method that simplifies the process of solving for separating equilibria. Using this approach, we show that continuous signalling games can have low-cost separating equilibria despite conflicting interests between signaller and receiver. We find that contrary to prior arguments, honesty does not require wasteful signals. Finally, we examine signalling games in which different signallers have different minimal-cost signals, and provide a mathematical justification for the argument that even non-signalling traits will be exaggerated beyond their phenotypic optimum when they are used by other individuals to judge condition or quality.

Communication↗

PubMed2002

Within-host population dynamics and the evolution of microparasites in a heterogeneous host population.

Why do parasites harm their hosts? The general understanding is that if the transmission rate and virulence of a parasite are linked, then the parasite must harm its host to maximize its transmission. The exact nature of such trade-offs remains largely unclear, but for vertebrate hosts it probably involves interactions between a microparasite and the host immune system. Previous results have suggested that in a homogeneous host population in the absence of super- or coinfection, within-host dynamics lead to selection of the parasite with an intermediate growth rate that is just being controlled by the immune system before it kills the host (Antia et al. 1994). In this paper, we examine how this result changes when heterogeneity is introduced to the host population. We incorporate the simplest form of heterogeneity--random heterogeneity in the parameters describing the size of the initial parasite inoculum, the immune response of the host, and the lethal density at which the parasite kills the host. We find that the general conclusion of the previous model holds: parasites evolve some intermediate growth rate. However, in contrast with the generally accepted view, we find that virulence (measured by the case mortality or the rate of parasite-induced host mortality) increases with heterogeneity. Finally, we link the within-host and between-host dynamics of parasites. We show how the parameters for epidemiological spread of the disease can be estimated from the within-host dynamics, and in doing so examine the way in which trade-offs between these epidemiological parameters arise as a consequence of the interaction of the parasite and the immune response of the host.

Animals↗