Prioritizing functional modules mediating genetic perturbations and their phenotypic effects: a global strategy

We have developed a global strategy based on the Bayesian network framework to prioritize the functional modules mediating genetic perturbations and their phenotypic effects among a set of overlapping candidate modules. We take lethality in Saccharomyces cerevisiae and human cancer as two examples to show the effectiveness of this approach. We discovered that lethality is more conserved at the module level than at the gene level and we identified several potentially 'new' cancer-related biological processes.     

Seed selection strategy in global network alignment without destroying the entire structures of functional modules

Background

Network alignment is one of the most common biological network comparison methods. Aligning protein-protein interaction (PPI) networks of different species is of great important to detect evolutionary conserved pathways or protein complexes across species through the identification of conserved interactions, and to improve our insight into biological systems. Global network alignment (GNA) problem is NP-complete, for which only heuristic methods have been proposed so far. Generally, the current GNA methods fall into global heuristic seed-and-extend approaches. These methods can not get the best overall consistent alignment between networks for the opinionated local seed. Furthermore These methods are lost in maximizing the number of aligned edges between two networks without considering the original structures of functional modules.

Methods

We present a novel seed selection strategy for global network alignment by constructing the pairs of hub nodes of networks to be aligned into multiple seeds. Beginning from every hub seed and using the membership similarity of nodes to quantify to what extent the nodes can participate in functional modules associated with current seed topologically we align the networks by modules. By this way we can maintain the functional modules are not damaged during the heuristic alignment process. And our method is efficient in resolving the fatal problem of most conventional algorithms that the initialization selected seeds have a direct influence on the alignment result. The similarity measures between network nodes (e.g., proteins) include sequence similarity, centrality similarity, and dynamic membership similarity and our algorithm can be called Multiple Hubs-based Alignment (MHA).

Results

When applying our seed selection strategy to several pairs of real PPI networks, it is observed that our method is working to strike a balance, extending the conserved interactions while maintaining the functional modules unchanged. In the case study, we assess the effectiveness of MHA on the alignment of the yeast and fly PPI networks. Our method outperforms state-of-the-art algorithms at detecting conserved functional modules and retrieves in particular 86% more conserved interactions than IsoRank.

Conclusions

We believe that our seed selection strategy will lead us to obtain more topologically and biologically similar alignment result. And it can be used as the reference and complement of other heuristic methods to seek more meaningful alignment results.

     

Four characters in a trade-off: dissecting their phenotypic and genetic relations

Phenotypic characters may covary negatively because they are in a trade-off or positively because they contribute to a single function. Genetic correlations can be used to test the validity and generality of these functional relationships by indicating the level of genetic integration and checking the conditions under which they are expressed. Phenotypic correlations indicate that there is a widespread trade-off between flight capability and early fecundity in insects. Different wing morphs (long and short wing) are thought to have a suite of reproductive and flight capability traits. In a half-sib mating experiment, we estimated phenotypic relationships between two flight-capability-related characters (flight muscle condition, wing morph) and two components of early fecundity (number of eggs in the ovaries, number of eggs laid), as well as genetic correlations relating wing morph and both components of fecundity in the wing-dimorphic cricket, Gryllus firmus. The number of eggs in the ovaries and the number of eggs laid were negatively correlated phenotypically and genetically with wing length morph (i.e., long wings associated with low fecundity). Both fecundity characters differed between wing morphs, but only if flight muscle was present and not histolyzed. The phenotypic and genetic correlations between fecundity characters were not significant. This suggests that the phenotypic relationship between ovary development and eggs laid is complex, they are not genetically integrated, and they may evolve independently. However, both early fecundity characters are functionally and genetically integrated within the trade-off to a similar degree. Finally, the trade-off affects early fecundity of both wing morphs suggesting that the functional relationship depends on flight muscle size. Received: 1 December 1998 / Accepted: 20 May 1999     

Identification of functional modules that correlate with phenotypic difference: the influence of network topology

One of the important challenges to post-genomic biology is relating observed phenotypic alterations to the underlying collective alterations in genes. Current inferential methods, however, invariably omit large bodies of information on the relationships between genes. We present a method that takes account of such information - expressed in terms of the topology of a correlation network - and we apply the method in the context of current procedures for gene set enrichment analysis.     

Evolutionary consequences of simulated global change: genetic adaptation or adaptive phenotypic plasticity

During the next century, natural and agricultural systems might need to adjust to a rapid increase in atmospheric CO₂ concentration and global temperature. Evolution of genotypes adapted to this global change could play a central role in plants' response. The main purpose of this study was to determine the relative importance of phenotypic and genotypic responses of plants to global change. To do so, we selected two populations of the short-lived Brassica juncea, one under ambient conditions and another one under conditions simulating global change. After seven generations of selection, differences between the two populations were examined using a reciprocal transplant garden. We monitored 14 different traits and found evidence for genetic adaptation only once, for vegetative biomass early in the growth cycle. Of the 14 traits, 11 responded plastically to the environment, but only one of these plastic changes had a possible adaptive value. Overall, the long-term evolutionary consequences of global change will depend on the response of fitness-related traits. None of the five reproductive traits measured showed any evolutionary responses. The main conclusion of our study is that Brassica juncea was apparently unable to respond evolutionarily to simulated global change either by genetic adaptation or by adaptive phenotypic plasticity. The limit to selection was apparently due to inbreeding depression induced by the harsh conditions of the predicted environment.     

Plant LysM proteins: modules mediating symbiosis and immunity

Microbial glycans, such as bacterial peptidoglycans, fungal chitin or rhizobacterial Nod factors (NFs), are important signatures for plant immune activation or for the establishment of beneficial symbioses. Plant lysin motif (LysM) domain proteins serve as modules mediating recognition of these different N-acetylglucosamine (GlcNAc)-containing ligands, suggesting that this class of proteins evolved from an ancient sensor for GlcNAc. During early plant evolution, these glycans probably served as immunogenic patterns activating LysM protein receptor-mediated plant immunity and stopping microbial infection. The biochemical potential of plant LysM proteins for sensing microbial GlcNAc-containing glycans has probably since favored the evolution of receptors facilitating microbial infection and symbiosis.     

转基因植物的表型变异、分子检测与遗传分析

本讨论了转化方法、体细胞克隆和选育过程等影响转基因植物表型变异的因素,并对转基因植物不同群体的表型变异组成和效应进行了比较分析,提出了转基因植物分子检测和遗传分析的技术策略。多数情况下,分析转基因植物回交后代(BClF1)比分析T1代能获得更可靠和有价值的结论。     

Biological invasions and phenotypic evolution: a quantitative genetic perspective

Among the many different components of global environmental change, biological invasions represent the one with the most long-term ecological and evolutionary consequences, as effects are irreversible. Although the ecological impact of invasive species has been under great scrutiny, its evolutionary aspects and consequences have remained less explored. Once established, an important part of the success of an invasive species will depend on the presence of genetic variation in populations at the geographic boundaries upon which natural selection can act. This information is integrated in G, the matrix of additive genetic variances and covariances for a suite of traits. The G-matrix shows the restrictions and potentialities of adaptive evolution and, together with natural selection determine the direction and rate of phenotypic evolution. Here I propose that a geographic analysis of G in populations of the introduced and native range becomes essential to understand critical evolutionary issues associated with invasion success.     

ModuleSearch: finding functional modules in a protein-protein interaction network

Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein-protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein-protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch.     

The relative efficacy of functional and developmental cranial modules for reconstructing global human population history

This study tests the relative efficacy of human cranial modules, defined on the basis of developmental and functional criteria, for reconstructing neutral genetic population history. Specifically, two hypotheses were tested: 1) The "basicranial hypothesis" predicts that the endochondrally ossifying basicranium will be more reliable for reconstructing population history than intramembranously ossifying regions of the human cranium. This is based on the assumption that early ossification of the basicranium and its distinct functional constraints produce a cranial structure that is relatively immune to non-neutral evolutionary forces. 2) The "single function hypothesis" predicts that cranial regions associated with a single (sensory) function are less reliable indicators of neutral genetic history. Here the prediction is based on the logic that complex, multi-functional, integrated cranial regions are less likely toexhibit homoplasy and, therefore, provide a more accurate morphological proxy for genetic relationships. The congruence between craniometric affinity matrices and neutral genetic population matrices based on autosomal microsatellite and classical markers was assessed using a series of Mantel and Dow-Cheverud tests. The results did not support the predictions of the "basicranial hypothesis," as the endochondrally ossifying basicranium was not significantly more congruent with the genetic data than intramembraneously ossifying modules. Moreover, although the results provided some support for the "single function hypothesis," defining cranial modules on the basis of anatomical or functional complexity did not provide a consistent means of predicting their phylogenetic efficacy. These results have important implications for building an accurate inference model of cranial evolution in the human fossil record.     

Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms

Recent progress in molecular microbial ecology has revealed that traditional culturing methods fail to represent the scope of microbial diversity in nature, since only a small proportion of viable microorganisms in a sample are recovered by culturing techniques. To develop methods to investigate the full extent of microbial diversity, we used a bacterial artificial chromosome (BAC) vector to construct libraries of genomic DNA isolated directly from soil (termed metagenomic libraries). To date, we have constructed two such libraries, which contain more than 1 Gbp of DNA. Phylogenetic analysis of 16S rRNA gene sequences recovered from one of the libraries indicates that the BAC libraries contain DNA from a wide diversity of microbial phyla, including sequences from diverse taxa such as the low-G+C, gram-positive Acidobacterium, Cytophagales, and Proteobacteria. Initial screening of the libraries in Escherichia coli identified several clones that express heterologous genes from the inserts, confirming that the BAC vector can be used to maintain, express, and analyze environmental DNA. The phenotypes expressed by these clones include antibacterial, lipase, amylase, nuclease, and hemolytic activities. Metagenomic libraries are a powerful tool for exploring soil microbial diversity, providing access to the genetic information of uncultured soil microorganisms. Such libraries will be the basis of new initiatives to conduct genomic studies that link phylogenetic and functional information about the microbiota of environments dominated by microorganisms that are refractory to cultivation.     

Testing the phenotypic gambit: phenotypic, genetic and environmental correlations of colour

Evolutionary theory is primarily concerned with genetic processes, yet empirical testing of this theory often involves data collected on phenotypes. To make this tenable, the implicit assumption is often made that phenotypic patterns are good predictors of genetic patterns; an assumption that coined the phenotypic gambit. Although this assumption has been validated for traits with high heritability, such as morphology, its generality for traits with low heritabilities, such as life-history and behavioural traits, remains controversial. Using a large-scale cross-fostering experiment, we were able to measure genetic, common environmental and phenotypic correlations between four colour traits and two skeletal traits in a wild population of passerine birds, the blue tit (Parus caeruleus). Colour traits had little heritable variation but common environment effects were found to be important; skeletal traits showed the opposite pattern. Positive correlations because of a shared natal environment were found between all traits, obscuring negative genetic correlations between some colour and skeletal traits. Consequently, phenotypic patterns were poor surrogates for genetic patterns and we suggest that this may be common if trade-offs or substantial parental effects exist. For this group of traits, the phenotypic gambit cannot be made and we suggest caution when inferring genetic patterns from phenotypic data, especially for behavioural and life-history traits.     

Hormonally mediated maternal effects, individual strategy and global change

A challenge to ecologists and evolutionary biologists is predicting organismal responses to the anticipated changes to global ecosystems through climate change. Most evidence suggests that short-term global change may involve increasing occurrences of extreme events, therefore the immediate response of individuals will be determined by physiological capacities and life-history adaptations to cope with extreme environmental conditions. Here, we consider the role of hormones and maternal effects in determining the persistence of species in altered environments. Hormones, specifically steroids, are critical for patterning the behaviour and morphology of parents and their offspring. Hence, steroids have a pervasive influence on multiple aspects of the offspring phenotype over its lifespan. Stress hormones, e.g. glucocorticoids, modulate and perturb phenotypes both early in development and later into adulthood. Females exposed to abiotic stressors during reproduction may alter the phenotypes by manipulation of hormones to the embryos. Thus, hormone-mediated maternal effects, which generate phenotypic plasticity, may be one avenue for coping with global change. Variation in exposure to hormones during development influences both the propensity to disperse, which alters metapopulation dynamics, and population dynamics, by affecting either recruitment to the population or subsequent life-history characteristics of the offspring. We suggest that hormones may be an informative index to the potential for populations to adapt to changing environments.     

Estimating genetic correlations based on phenotypic data: a simulation-based method

Knowledge of genetic correlations is essential to understand the joint evolution of traits through correlated responses to selection, a difficult and seldom, very precise task even with easy-to-breed species. Here, a simulation-based method to estimate genetic correlations and genetic covariances that relies only on phenotypic measurements is proposed. The method does not require any degree of relatedness in the sampled individuals. Extensive numerical results suggest that the propose method may provide relatively efficient estimates regardless of sample sizes and contributions from common environmental effects.