Analysing biological pathways in genome-wide association studies

Genome-wide association (GWA) studies have typically focused on the analysis of single markers, which often lacks the power to uncover the relatively small effect sizes conferred by most genetic variants. Recently, pathway-based approaches have been developed, which use prior biological knowledge on gene function to facilitate more powerful analysis of GWA study data sets. These approaches typically examine whether a group of related genes in the same functional pathway are jointly associated with a trait of interest. Here we review the development of pathway-based approaches for GWA studies, discuss their practical use and caveats, and suggest that pathway-based approaches may also be useful for future GWA studies with sequencing data.     

Linking alpha-synuclein properties with oxidation: a hypothesis on a mechanism underling cellular aggregation

α-Synuclein is a small, natively unstructured protein with propensity to aggregate. α-Synuclein fibrils are major components of Lewy bodies that are hallmarks of many neurodegenerative diseases. The solution properties and aggregation behavior of α-synuclein has been well characterized, but despite numerous studies that address the role of α-synuclein in cells, a clear physiological function of this protein remains a mystery. Over a hundred review articles of α-synuclein have been written in the last decade, making it difficult to list all of the important studies that have added to our insight of α-synuclein physiology. Instead, we briefly review the status of α-synuclein research and propose a model based on the idea that α-synuclein may not have an intrinsic activity in cells but rather, it modifies the function of a group of protein partners that in turn affect cell processes. We propose that it is the loss of its cellular partners under oxidative conditions that promotes α-synuclein aggregation accelerating neuronal death.     

Dominance orders in animal societies: The self-organization hypothesis revisited

In previous papers (Theraulaz et al., 1995; Bonabeau et al., 1996) we suggested, following Hogeweg and Hesper (1983, 1985), that the formation of dominance orders in animal societies could result from a self-organizing process involving a double reinforcement mechanism: winners reinforce their probability of winning and losers reinforce their probability of losing. This assumption, and subsequent models relying on it, were based on empirical data on primitively eusocial wasps (Polistes dominulus). By reanalysing some of the experimental data that was previously thought to be irrelevant, we show that it is impossible to distinguish this assumption from a competing assumption based on preexisting differences among individuals. We propose experiments to help discriminate between the two assumptions and their corresponding models—the self-organization model and the correlational model. We urge other researchers to be cautious when interpreting their dominance data with the ’self-organization mindset’; in particular, ‘winner and loser effects’, which are often considered to give support to the self-organization assumption, are equally consistent with the correlational assumption.     

Incorporating biological pathways via a Markov random field model in genome-wide association studies

Genome-wide association studies (GWAS) examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may interact with each other to affect disease risk. Much knowledge has been accumulated in the literature on biological pathways and interactions. It is conceivable that appropriate incorporation of such prior knowledge may improve the likelihood of making genuine discoveries. Although a number of methods have been developed recently to prioritize genes using prior biological knowledge, such as pathways, most methods treat genes in a specific pathway as an exchangeable set without considering the topological structure of a pathway. However, how genes are related with each other in a pathway may be very informative to identify association signals. To make use of the connectivity information among genes in a pathway in GWAS analysis, we propose a Markov Random Field (MRF) model to incorporate pathway topology for association analysis. We show that the conditional distribution of our MRF model takes on a simple logistic regression form, and we propose an iterated conditional modes algorithm as well as a decision theoretic approach for statistical inference of each gene's association with disease. Simulation studies show that our proposed framework is more effective to identify genes associated with disease than a single gene-based method. We also illustrate the usefulness of our approach through its applications to a real data example.     

The uniqueness of biological self-organization: challenging the Darwinian paradigm

Here we discuss the challenge posed by self-organization to the Darwinian conception of evolution. As we point out, natural selection can only be the major creative agency in evolution if all or most of the adaptive complexity manifest in living organisms is built up over many generations by the cumulative selection of naturally occurring small, random mutations or variants, i.e., additive, incremental steps over an extended period of time. Biological self-organization—witnessed classically in the folding of a protein, or in the formation of the cell membrane—is a fundamentally different means of generating complexity. We agree that self-organizing systems may be fine-tuned by selection and that self-organization may be therefore considered a complementary mechanism to natural selection as a causal agency in the evolution of life. But we argue that if self-organization proves to be a common mechanism for the generation of adaptive order from the molecular to the organismic level, then this will greatly undermine the Darwinian claim that natural selection is the major creative agency in evolution. We also point out that although complex self-organizing systems are easy to create in the electronic realm of cellular automata, to date translating in silico simulations into real material structures that self-organize into complex forms from local interactions between their constituents has not proved easy. This suggests that self-organizing systems analogous to those utilized by biological systems are at least rare and may indeed represent, as pre-Darwinists believed, a unique ascending hierarchy of natural forms. Such a unique adaptive hierarchy would pose another major challenge to the current Darwinian view of evolution, as it would mean the basic forms of life are necessary features of the order of nature and that the major pathways of evolution are determined by physical law, or more specifically by the self-organizing properties of biomatter, rather than natural selection.     

The biological sense of cancer: a hypothesis

Background  

Most theories about cancer proposed during the last century share a common denominator: cancer is believed to be a biological nonsense for the organism in which it originates, since cancer cells are believed to be ones evading the rules that control normal cell proliferation and differentiation. In this essay, we have challenged this interpretation on the basis that, throughout the animal kingdom, cancer seems to arise only in injured organs and tissues that display lost or diminished regenerative ability.     

Integration of biological networks and pathways with genetic association studies

Millions of genetic variants have been assessed for their effects on the trait of interest in genome-wide association studies (GWAS). The complex traits are affected by a set of inter-related genes. However, the typical GWAS only examine the association of a single genetic variant at a time. The individual effects of a complex trait are usually small, and the simple sum of these individual effects may not reflect the holistic effect of the genetic system. High-throughput methods enable genomic studies to produce a large amount of data to expand the knowledge base of the biological systems. Biological networks and pathways are built to represent the functional or physical connectivity among genes. Integrated with GWAS data, the network- and pathway-based methods complement the approach of single genetic variant analysis, and may improve the power to identify trait-associated genes. Taking advantage of the biological knowledge, these approaches are valuable to interpret the functional role of the genetic variants, and to further understand the molecular mechanism influencing the traits. The network- and pathway-based methods have demonstrated their utilities, and will be increasingly important to address a number of challenges facing the mainstream GWAS.     

alpha-synuclein degradation by autophagic pathways: a potential key to Parkinson's disease pathogenesis

The neuronal protein alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Excessive wild type alpha-synuclein levels can lead to PD in select familial cases and alpha-synuclein protein accumulation occurs in sporadic PD. Therefore, elucidation of the mechanisms that control alpha-synuclein levels is critical for PD pathogenesis and potential therapeutics. The subject of alpha-synuclein degradation has been controversial. Previous work shows that, in an assay with isolated liver lysosomes, purified wild type alpha-synuclein is degraded by the process of chaperone-mediated autophagy (CMA). Whether this actually occurs in a cellular context has been unclear. In our most recent work, we find that wild type alpha-synuclein, but not the closely related protein beta-synuclein, is indeed degraded by CMA in neuronal cells, including primary postnatal ventral midbrain neurons. Macroautophagy, but not the proteasome, also contributes to alpha-synuclein degradation. Therefore, two separate lysosomal pathways, CMA and macroautophagy, degrade wild type alpha-synuclein in neuronal cells. It is hypothesized that impairment of either of these two pathways, or of more general lysosomal function, may be an initiating factor in alpha-synuclein accumulation and sporadic PD pathogenesis.     

Oxalate patinas on ancient monuments: the biological hypothesis

Summary Whewellite and weddellite, calcium oxalate monohydrate and dihydrate respectively, have been found in the form of thin surface layers on limestone and marble monuments and artifacts of various historical periods at different sites. Experimental results indicate that the formation of both minerals must be attributed essentially to the action of oxalic acid secreted by microorganisms (lichens) which live and proliferate on the stone. Oxalic acid attacks the calcium carbonate of the stone surface giving rise to the precipitation of calcium oxalate.     

Principles of a new biological theory: A summary

This is a review of the present state of the author's efforts, extending over many years, to construct a formal biological theory that is entirely compatible with quantum mechanics. We point out that the correspondence between detailed realizations on the molecular level and the characteristics of a class or organisms is exceedingly multivalued with respect to the former. Biological theory deals with the process of selection of actual biological states among the very large manifold of possible ones. This may also be expressed by saying that biological theory deals with (biologically) necessary conditions but not with sufficient ones. Conditions that are both necessary and sufficient pertain to physical science (molecular biology). In conformity with a well-known theorem of von Neumann, the selective process (being partly non-mechanistic) is not assumed controlled by simple mathematical rules. The selection from a very large reservoir of possible states is here described as creativity of the organism. The ordinary process of hereditary reproduction may then be represented as creativity with constraints, where the constraints (partly non-mechanistic but compatible with quantum mechanics) are such that the progeny tends to resemble the progenitors. This scheme differs from the usual view of heredity as purely mechanistic molecular replication with possible small errors. In the new scheme a gene appears as an operative symbol which functions as the releaser of a creative process.     

An investigation of a nonlocal hyperbolic model for self-organization of biological groups

In this article, we introduce and study a new nonlocal hyperbolic model for the formation and movement of animal aggregations. We assume that the nonlocal attractive, repulsive, and alignment interactions between individuals can influence both the speed and the turning rates of group members. We use analytical and numerical techniques to investigate the effect of these nonlocal interactions on the long-time behavior of the patterns exhibited by the model. We establish the local existence and uniqueness and show that the nonlinear hyperbolic system does not develop shock solutions (gradient blow-up). Depending on the relative magnitudes of attraction and repulsion, we show that the solutions of the model either exist globally in time or may exhibit finite-time amplitude blow-up. We illustrate numerically the various patterns displayed by the model: dispersive aggregations, finite-size groups and blow-up patterns, the latter corresponding to aggregations which may collapse to a point. The transition from finite-size to blow-up patterns is governed by the magnitude of the social interactions and the random turning rates. The presence of these types of patterns and the absence of shocks are consequences of the biologically relevant assumptions regarding the form of the speed and the turning rate functions, as well as of the kernels describing the social interactions.     

Testing a biological mechanism of the insurance hypothesis in experimental aquatic communities

1.  The insurance hypothesis predicts a stabilizing effect of increasing species richness on community and ecosystem properties. Difference among species' responses to environmental fluctuations provides a general mechanism for the hypothesis. Previous experimental investigations of the insurance hypothesis have not examined this mechanism directly.
2.  First, responses to temperature of four protist species were measured in laboratory microcosms. For each species, we measured the response of intrinsic rate of increase ( r ) and carrying capacity ( K ) to temperature.
3.  Next, communities containing pairs of species were exposed to temperature fluctuations. Community biomass varied less when correlation in K between species (but not r ) was more negative, and this resulted from more negative covariances in population sizes, as predicted. Results were contingent on species identity, with findings differing between analyses including or not including communities containing one particular species.
4.  These findings provide the clearest support to date for this mechanism of the insurance hypothesis. Biodiversity, in terms of differences in species' responses to environmental fluctuations (i.e. functional response diversity) stabilizes community dynamics.     

Protozoan parasites in group-living primates: testing the biological island hypothesis

A series of articles by W.J. Freeland published in the 1970s proposed that social organization and behavioral processes were heavily influenced by parasitic infections, which led to a number of intriguing hypotheses concerning how natural selection might act on social factors because of the benefits of avoiding parasite infections. For example, Freeland [1979] showed that all individuals within a given group harbored identical gastrointestinal protozoan faunas, which led him to postulate that social groups were akin to "biological islands" and suggest how this isolation could select specific types of ranging and dispersal patterns. Here, we reexamine the biological island hypothesis by quantifying the protozoan faunas of the same primate species examined by Freeland in the same location; our results do not support this hypothesis. In contrast, we quantified two general changes in protozoan parasite community of primates in the study area of Kibale National Park, Uganda, over the nearly 35 years between sample collections: (1) the colobines found free of parasites in the early 1970s are now infected with numerous intestinal protozoan parasites and (2) groups are no longer biological islands in terms of their protozoan parasites. Whatever the ultimate explanation for these changes, our findings have implications for studies proposing selective forces shaping primate behavior and social organization.     

Rod structures of bound water: a possible role in self-organization of biological systems and nondissipative energy transmission

Cluster–rod structure were designed, which are comprised of tetrahedral atoms with a typical torsion angle of ~38° at interatomic bonds. These structures correspond to a muscle tissue and clathrin lattice by their metrics and topology and can be formed by bound water in these systems. It is shown that the considered rod structures, which are fragments of bound water structures, can also be involved in nondissipative energy transmission as elastic energy storing structures. The estimated length of the bound water rod structure required to absorb the energy of decomposition of an ATP molecule into ADP and a phosphate group is comparable with myosin head sizes and its step along an actin filament. A mechanism of cooperative transition of the rod structure to a fragment of the ice Ih structure was demonstrated. This transition is accompanied by nondissipative release of stored energy.     

Early agricultural pathways: moving outside the 'core area' hypothesis in Southwest Asia

The origins of agriculture in the Near East has been associated with a 'core area', located in south-eastern Turkey, in which all major crops were brought into domestication within the same local domestication system operated by a single cultural group. Such an origin leads to a scenario of rapid invention of agriculture by a select cultural group and typically monophyletic origins for most crops. Surprisingly, support for a core area has never been directly tested with archaeological evidence. Over the past decade a large amount of new archaeological and genetic evidence has been discovered which brings new light on the origins of agriculture. In this review, this new evidence was brought together in order to evaluate whether a core region of origin is supported. Evidence shows that origins began earlier than previously assumed, and included 'false starts' and dead ends that involved many more species than the typical eight founder crops associated with the core area. The rates at which domestication syndrome traits became fixed were generally slow, rather than rapid, and occurred over a geographically wide range that included the North and South Levant as well as the core area. Finally, a survey of the estimated ages of archaeological sites and the onset of domestication indicates that the domestication process was ongoing in parallel outside of the core area earlier than within it. Overall, evidence suggests a scenario in which crops were domesticated slowly in different locations around the Near East rather than emanating from a core area.     

Pathway Miner: extracting gene association networks from molecular pathways for predicting the biological significance of gene expression microarray data

We have developed a web-based system (Pathway Miner) for visualizing gene expression profiles in the context of biological pathways. Pathway Miner catalogs genes based on their role in metabolic, cellular and regulatory pathways. A Fisher exact test is provided as an option to rank pathways. The genes are mapped onto pathways and gene product association networks are extracted for genes that co-occur in pathways. The networks can be filtered for analysis based on user-selected options. AVAILABILITY: Pathway Miner is a freely available web accessible tool at http://www.biorag.org/pathway.html