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Biomedical subjects

Michael P H Stumpf

Publications and source records attributed to Michael P H Stumpf.

At least 19 recordsLinked to original sources
PubMed2006

The effects of incomplete protein interaction data on structural and evolutionary inferences.

BACKGROUND: Present protein interaction network data sets include only interactions among subsets of the proteins in an organism. Previously this has been ignored, but in principle any global network analysis that only looks at partial data may be biased. Here we demonstrate the need to consider network sampling properties explicitly and from the outset in any analysis. RESULTS: Here we study how properties of the yeast protein interaction network are affected by random and non-random sampling schemes using a range of different network statistics. Effects are shown to be independent of the inherent noise in protein interaction data. The effects of the incomplete nature of network data become very noticeable, especially for so-called network motifs. We also consider the effect of incomplete network data on functional and evolutionary inferences. CONCLUSION: Crucially, when only small, partial network data sets are considered, bias is virtually inevitable. Given the scope of effects considered here, previous analyses may have to be carefully reassessed: ignoring the fact that present network data are incomplete will severely affect our ability to understand biological systems.

Evolution, Molecular↗
PubMed2006

Evidence for an apartheid-like social structure in early Anglo-Saxon England.

The role of migration in the Anglo-Saxon transition in England remains controversial. Archaeological and historical evidence is inconclusive, but current estimates of the contribution of migrants to the English population range from less than 10000 to as many as 200000. In contrast, recent studies based on Y-chromosome variation posit a considerably higher contribution to the modern English gene pool (50-100%). Historical evidence suggests that following the Anglo-Saxon transition, people of indigenous ethnicity were at an economic and legal disadvantage compared to those having Anglo-Saxon ethnicity. It is likely that such a disadvantage would lead to differential reproductive success. We examine the effect of differential reproductive success, coupled with limited intermarriage between distinct ethnic groups, on the spread of genetic variants. Computer simulations indicate that a social structure limiting intermarriage between indigenous Britons and an initially small Anglo-Saxon immigrant population provide a plausible explanation of the high degree of Continental male-line ancestry in England.

Computer Simulation↗
PubMed2006

Induction and function of the phage shock protein extracytoplasmic stress response in Escherichia coli.

The phage shock protein (Psp) F regulon response in Escherichia coli is thought to be induced by impaired inner membrane integrity and an associated decrease in proton motive force (pmf). Mechanisms by which the Psp system detects the stress signal and responds have so far remained undetermined. Here we demonstrate that PspA and PspG directly confront a variety of inducing stimuli by switching the cell to anaerobic respiration and fermentation and by down-regulating motility, thereby subtly adjusting and maintaining energy usage and pmf. Additionally, PspG controls iron usage. We show that the Psp-inducing protein IV secretin stress, in the absence of Psp proteins, decreases the pmf in an ArcB-dependent manner and that ArcB is required for amplifying and transducing the stress signal to the PspF regulon. The requirement of the ArcB signal transduction protein for induction of psp provides clear evidence for a direct link between the physiological redox state of the cell, the electron transport chain, and induction of the Psp response. Under normal growth conditions PspA and PspD control the level of activity of ArcB/ArcA system that senses the redox/metabolic state of the cell, whereas under stress conditions PspA, PspD, and PspG deliver their effector functions at least in part by activating ArcB/ArcA through positive feedback.

Bacterial Outer Membrane Proteins↗
PubMed2006

A likelihood approach to analysis of network data.

Biological, sociological, and technological network data are often analyzed by using simple summary statistics, such as the observed degree distribution, and nonparametric bootstrap procedures to provide an adequate null distribution for testing hypotheses about the network. In this article we present a full-likelihood approach that allows us to estimate parameters for general models of network growth that can be expressed in terms of recursion relations. To handle larger networks we have developed an importance sampling scheme that allows us to approximate the likelihood and draw inference about the network and how it has been generated, estimate the parameters in the model, and perform parametric bootstrap analysis of network data. We illustrate the power of this approach by estimating growth parameters for the Caenorhabditis elegans protein interaction network.

Animals↗
PubMed2006

Network motifs: structure does not determine function.

BACKGROUND: A number of publications have recently examined the occurrence and properties of the feed-forward motif in a variety of networks, including those that are of interest in genome biology, such as gene networks. The present work looks in some detail at the dynamics of the bi-fan motif, using systems of ordinary differential equations to model the populations of transcription factors, mRNA and protein, with the aim of extending our understanding of what appear to be important building blocks of gene network structure. RESULTS: We develop an ordinary differential equation model of the bi-fan motif and analyse variants of the motif corresponding to its behaviour under various conditions. In particular, we examine the effects of different steady and pulsed inputs to five variants of the bifan motif, based on evidence in the literature of bifan motifs found in Saccharomyces cerevisiae (commonly known as baker's yeast). Using this model, we characterize the dynamical behaviour of the bi-fan motif for a wide range of biologically plausible parameters and configurations. We find that there is no characteristic behaviour for the motif, and with the correct choice of parameters and of internal structure, very different, indeed even opposite behaviours may be obtained. CONCLUSION: Even with this relatively simple model, the bi-fan motif can exhibit a wide range of dynamical responses. This suggests that it is difficult to gain significant insights into biological function simply by considering the connection architecture of a gene network, or its decomposition into simple structural motifs. It is necessary to supplement such structural information by kinetic parameters, or dynamic time series experimental data, both of which are currently difficult to obtain.

Amino Acid Motifs↗
PubMed2005

Complex networks and simple models in biology.

The analysis of molecular networks, such as transcriptional, metabolic and protein interaction networks, has progressed substantially because of the power of models from statistical physics. Increasingly, the data are becoming so detailed--though not always complete or correct--that the simple models are reaching the limits of their usefulness. Here, we will discuss how network information can be described and to some extent quantified. In particular statistics offers a range of tools, such as model selection, which have not yet been widely applied in the analysis of biological networks. We will also outline a number of present challenges posed by biological network data in systems biology, and the extent to which these can be addressed by new developments in statistics, physics and applied mathematics.

Animals↗
PubMed2005

Sampling properties of random graphs: the degree distribution.

We discuss two sampling schemes for selecting random subnets from a network, random sampling and connectivity dependent sampling, and investigate how the degree distribution of a node in the network is affected by the two types of sampling. Here we derive a necessary and sufficient condition that guarantees that the degree distributions of the subnet and the true network belong to the same family of probability distributions. For completely random sampling of nodes we find that this condition is satisfied by classical random graphs; for the vast majority of networks this condition will, however, not be met. We furthermore discuss the case where the probability of sampling a node depends on the degree of a node and we find that even classical random graphs are no longer closed under this sampling regime. We conclude by relating the results to real Eschericia coli protein interaction network data.

Journal Article↗
PubMed2005

Recombination hotspots as a point process.

The variation of the recombination rate along chromosomal DNA is one of the important determinants of the patterns of linkage disequilibrium. A number of inferential methods have been developed which estimate the recombination rate and its variation from population genetic data. The majority of these methods are based on modelling the genealogical process underlying a sample of DNA sequences and thus explicitly include a model of the demographic process. Here we propose a different inferential procedure based on a previously introduced framework where recombination is modelled as a point process along a DNA sequence. The approach infers regions containing putative hotspots based on the inferred minimum number of recombination events; it thus depends only indirectly on the underlying population demography. A Poisson point process model with local rates is then used to infer patterns of recombination rate estimation in a fully Bayesian framework. We illustrate this new approach by applying it to several population genetic datasets, including a region with an experimentally confirmed recombination hotspot.

Bayes Theorem↗
PubMed2005

Gene expression profiles of Blumeria graminis indicate dynamic changes to primary metabolism during development of an obligate biotrophic pathogen.

cDNA microarrays of Blumeria graminis f sp hordei transcript profiles during the asexual development cycle reveal the dynamics of global gene expression as the fungus germinates, penetrates, feeds on its host, and produces masses of conidia for dispersal. The expression profiles of genes encoding enzymes involved in primary metabolism show that there is a striking degree of coordinate regulation of some of the genes in the same pathway. In one example, genes encoding several glycolytic enzymes are significantly upregulated as mature appressoria form and also in infected epidermis, which contain fungal haustoria. In another example, mRNAs for lipid degrading enzymes are initially expressed at high levels in the conidia and the early germination stages and decrease significantly later. We discuss these results and draw inferences on the metabolic status of this obligate biotrophic fungus as it infects its host and completes its life cycle.

Ascomycota↗
PubMed2005

Comparative analysis of the Saccharomyces cerevisiae and Caenorhabditis elegans protein interaction networks.

BACKGROUND: Protein interaction networks aim to summarize the complex interplay of proteins in an organism. Early studies suggested that the position of a protein in the network determines its evolutionary rate but there has been considerable disagreement as to what extent other factors, such as protein abundance, modify this reported dependence. RESULTS: We compare the genomes of Saccharomyces cerevisiae and Caenorhabditis elegans with those of closely related species to elucidate the recent evolutionary history of their respective protein interaction networks. Interaction and expression data are studied in the light of a detailed phylogenetic analysis. The underlying network structure is incorporated explicitly into the statistical analysis. The increased phylogenetic resolution, paired with high-quality interaction data, allows us to resolve the way in which protein interaction network structure and abundance of proteins affect the evolutionary rate. We find that expression levels are better predictors of the evolutionary rate than a protein's connectivity. Detailed analysis of the two organisms also shows that the evolutionary rates of interacting proteins are not sufficiently similar to be mutually predictive. CONCLUSION: It appears that meaningful inferences about the evolution of protein interaction networks require comparative analysis of reasonably closely related species. The signature of protein evolution is shaped by a protein's abundance in the organism and its function and the biological process it is involved in. Its position in the interaction networks and its connectivity may modulate this but they appear to have only minor influence on a protein's evolutionary rate.

Animals↗
PubMed2005

Subnets of scale-free networks are not scale-free: sampling properties of networks.

Most studies of networks have only looked at small subsets of the true network. Here, we discuss the sampling properties of a network's degree distribution under the most parsimonious sampling scheme. Only if the degree distributions of the network and randomly sampled subnets belong to the same family of probability distributions is it possible to extrapolate from subnet data to properties of the global network. We show that this condition is indeed satisfied for some important classes of networks, notably classical random graphs and exponential random graphs. For scale-free degree distributions, however, this is not the case. Thus, inferences about the scale-free nature of a network may have to be treated with some caution. The work presented here has important implications for the analysis of molecular networks as well as for graph theory and the theory of networks in general.

Journal Article↗
PubMed2005

Localized breakdown in linkage disequilibrium does not always predict sperm crossover hot spots in the human MHC class II region.

To investigate the relationship between meiotic crossover hot spots and block-like linkage disequilibrium (LD), we have extended our high-resolution studies of the human MHC class II region to a 90-kb segment upstream of the HLA-DOA gene. LD blocks in this region are not as well defined as in the neighboring 210-kb DNA segment but do show two regions of LD breakdown in which coalescent analysis indicates substantial historical recombination. Sperm crossover analysis of one region revealed a novel localized hot spot similar in intensity and morphology to most other MHC hot spots. Crossovers at this hot spot are not obviously affected by a large insertion/deletion polymorphism near the hot spot. The second region of LD breakdown, within the DPB1 gene, shows an extremely low level of sperm crossover activity and does not contain a sperm crossover hot spot. These results highlight the complexity of LD patterns and the importance of experimentally verifying crossover hot spots.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

HIV and the CCR5-Delta32 resistance allele.

The combination of molecular biology, epidemiology, virology, evolutionary and population genetics has enabled us to understand the delicate interplay between HIV and the CCR5-Delta32 HIV resistance allele. We here review and collect from the different approaches to show how they can be combined to elucidate the interaction between host and pathogen genetics in this system. We will present an overview of the normal role of CCR5, its involvement in HIV, the molecular biology of the CCR5-Delta32 allele and its probable origins. By focusing on this well-documented and important system we hope to demonstrate the power that such a "holistic" approach might offer in the study of infectious diseases.

Alleles↗
PubMed2004

Allelic histories: positive selection on a HIV-resistance allele.

The CCR5-Delta32 allele crucially determines the course of HIV infection and appears to be highly protective against the disease. Population genetic studies suggest that the allele has been under positive selection in Europe in the past. In a recent paper, Alison Galvani and Montgomery Slatkin collate the available evidence and use a mathematical model to strongly suggest that smallpox could have exerted sufficient selection pressure to explain the distribution of the allele across Europe. This is a beautiful example of the power of mathematical models in evolutionary genetics.

Journal Article↗
PubMed2004

Haplotype diversity and SNP frequency dependence in the description of genetic variation.

Haplotype diversity is controlled by a variety of processes, including mutation, recombination, marker ascertainment and demography. Understanding the extent to which genetic variation at physically linked loci is co-inherited is crucial for the design of the HapMap project and the correct interpretation of the resulting data. In the absence of an analytical theory extensive coalescent simulations are used to disentangle the influence of all of these factors on haplotype diversity. In addition to these qualitative insights, this study also demonstrates (i) that marker spacing and frequency profoundly influence observed levels of haplotype diversity; (ii) that the spectrum of haplotypes contains information about how exhaustively genetic variation in a region is described by a given marker set; and (iii) that so-called haplotype blocks can be generated due by the stochasticity inherent in the recombination process without having to assume variation in the recombination rate.

Computer Simulation↗
PubMed2004

The extent and importance of intragenic recombination.

We have studied the recombination rate behaviour of a set of 140 genes which were investigated for their potential importance in inflammatory disease. Each gene was extensively sequenced in 24 individuals of African descent and 23 individuals of European descent, and the recombination process was studied separately in the two population samples. The results obtained from the two populations were highly correlated, suggesting that demographic bias does not affect our population genetic estimation procedure. We found evidence that levels of recombination correlate with levels of nucleotide diversity. High marker density allowed us to study recombination rate variation on a very fine spatial scale. We found that about 40 per cent of genes showed evidence of uniform recombination, while approximately 12 per cent of genes carried distinct signatures of recombination hotspots. On studying the locations of these hotspots, we found that they are not always confined to introns but can also stretch across exons. An investigation of the protein products of these genes suggested that recombination hotspots can sometimes separate exons belonging to different protein domains; however, this occurs much less frequently than might be expected based on evolutionary studies into the origins of recombination. This suggests that evolutionary analysis of the recombination process is greatly aided by considering nucleotide sequences and protein products jointly.

Africa↗
PubMed2003

A Y chromosome census of the British Isles.

The degree of population replacement in the British Isles associated with cultural changes has been extensively debated. Recent work has demonstrated that comparisons of genetic variation in the British Isles and on the European Continent can illuminate specific demographic processes in the history of the British Isles. For example, Wilson et al. used the similarity of Basque and Celtic Y chromosomes to argue for genetic continuity from the Upper Palaeolithic to the present in the paternal history of these populations (see also ). Differences in the Y chromosome composition of these groups also suggested genetic signatures of Norwegian influence in the Orkney Islands north of the Scottish mainland, an important center of Viking activities between 800 and 1300 A.D. More recently, Weale et al. argued for substantial Anglo-Saxon male migration into central England based on the analysis of eight British sample sets collected on an east-west transect across England and Wales. To provide a more complete assessment of the paternal genetic history of the British Isles, we have compared the Y chromosome composition of multiple geographically distant British sample sets with collections from Norway (two sites), Denmark, and Germany and with collections from central Ireland, representing, respectively, the putative invading and the indigenous populations. By analyzing 1772 Y chromosomes from 25 predominantly small urban locations, we found that different parts of the British Isles have sharply different paternal histories; the degree of population replacement and genetic continuity shows systematic variation across the sampled areas.

Chromosomes, Human, Y↗