Genome-wide prioritization of disease genes and identification of disease-disease associations from an integrated human functional linkage network

Background

Recent studies have shown that the regulatory effect of microRNAs can be investigated by examining expression changes of their target genes. Given this, it is useful to define an overall metric of regulatory effect for a specific microRNA and see how this changes across different conditions.

Results

Here, we define a regulatory effect score (RE-score) to measure the inhibitory effect of a microRNA in a sample, essentially the average difference in expression of its targets versus non-targets. Then we compare the RE-scores of various microRNAs between two breast cancer subtypes: estrogen receptor positive (ER⁺) and negative (ER^-). We applied this approach to five microarray breast cancer datasets and found that the expression of target genes of most microRNAs was more repressed in ER^- than ER⁺; that is, microRNAs appear to have higher RE-scores in ER^- breast cancer. These results are robust to the microRNA target prediction method. To interpret these findings, we analyzed the level of microRNA expression in previous studies and found that higher microRNA expression was not always accompanied by higher inhibitory effects. However, several key microRNA processing genes, especially Ago2 and Dicer, were differentially expressed between ER^- and ER⁺ breast cancer, which may explain the different regulatory effects of microRNAs in these two breast cancer subtypes.

Conclusions

The RE-score is a promising indicator to measure microRNAs' inhibitory effects. Most microRNAs exhibit higher RE-scores in ER^- than in ER⁺ samples, suggesting that they have stronger inhibitory effects in ER^- breast cancers.     

Host associations and evolutionary relationships of avian blood parasites from West Africa

The host specificity of blood parasites recovered from a survey of 527 birds in Cameroon and Gabon was examined at several levels within an evolutionary framework. Unique mitochondrial lineages of Haemoproteus were recovered from an average of 1.3 host species (maximum = 3) and 1.2 host families (maximum = 3) while lineages of Plasmodium were recovered from an average of 2.5 species (maximum = 27) and 1.6 families (maximum = 9). Averaged within genera, lineages of both Plasmodium and Haemoproteus were constrained in their host distribution relative to random expectations. However, while several individual lineages within both genera exhibited significant host constraint, host breadth varied widely among related lineages, particularly within the genus Plasmodium. Several lineages of Plasmodium exhibited extreme generalist host-parasitism strategies while other lineages appeared to have been constrained to certain host families over recent evolutionary history. Sequence data from two nuclear genes recovered from a limited sample of Plasmodium parasites indicated that, at the resolution of this study, inferences regarding host breadth were unlikely to be grossly affected by the use of parasite mitochondrial lineages as a proxy for biological species. The use of divergent host-parasitism strategies among closely related parasite lineages suggests that host range is a relatively labile character. Since host specificity may also influence parasite virulence, these results argue for considering the impact of haematozoa on avian hosts on a lineage-specific basis.     

Inference of higher-order relationships in the cycads from a large chloroplast data set

Theria includes Eutheria and its sister taxon Metatheria. Placentalia includes extant eutherians plus their most recent common ancestor. The oldest eutherian is from 125mya (million years ago). Molecular studies place this origin at about 130-185mya. Older dates cannot be refuted based on fossil evidence as earliest eutherian remains are scarce. Earliest superordinal clades (hence Placentalia) range from 64-104mya (median 84mya) based on molecules, similar to 85-90mya based on fossils. Superordinal clades Archonta, Ferungulata, Glires, and Paenungulata based on fossils are similar to molecularly based clades, except Afrotheria was not predicted by fossils. Both fossils and molecules recognize 16 of 18 extant placental orders. Fossils place the origins of orders around 65mya as do some molecular studies, but others suggest ordinal diversification as old as 100mya. Fossil evidence supports a Laurasian origin for Eutheria (and Metatheria) and Placentalia, although some molecular studies suggest a Gondwanan origin for both taxa.     

Inference of relationships in population data using identity-by-descent and identity-by-state

It is an assumption of large, population-based datasets that samples are annotated accurately whether they correspond to known relationships or unrelated individuals. These annotations are key for a broad range of genetics applications. While many methods are available to assess relatedness that involve estimates of identity-by-descent (IBD) and/or identity-by-state (IBS) allele-sharing proportions, we developed a novel approach that estimates IBD0, 1, and 2 based on observed IBS within windows. When combined with genome-wide IBS information, it provides an intuitive and practical graphical approach with the capacity to analyze datasets with thousands of samples without prior information about relatedness between individuals or haplotypes. We applied the method to a commonly used Human Variation Panel consisting of 400 nominally unrelated individuals. Surprisingly, we identified identical, parent-child, and full-sibling relationships and reconstructed pedigrees. In two instances non-sibling pairs of individuals in these pedigrees had unexpected IBD2 levels, as well as multiple regions of homozygosity, implying inbreeding. This combined method allowed us to distinguish related individuals from those having atypical heterozygosity rates and determine which individuals were outliers with respect to their designated population. Additionally, it becomes increasingly difficult to identify distant relatedness using genome-wide IBS methods alone. However, our IBD method further identified distant relatedness between individuals within populations, supported by the presence of megabase-scale regions lacking IBS0 across individual chromosomes. We benchmarked our approach against the hidden Markov model of a leading software package (PLINK), showing improved calling of distantly related individuals, and we validated it using a known pedigree from a clinical study. The application of this approach could improve genome-wide association, linkage, heterozygosity, and other population genomics studies that rely on SNP genotype data.     

Histidine domain-protein tyrosine phosphatase interacts with Grb2 and GrpL

Background

Histidine domain-protein tyrosine phosphatase (HD-PTP) plays a key role in vesicle trafficking and biogenesis. Although it is a large protein with at least five distinct structural domains, only a few of its interactors are presently known, and the significance of these interactions is largely obscure.

Methodology and Results

In this study we performed a yeast two-hybrid screening using a human colon cDNA library and found that Grb2 and GrpL are binding partners of HD-PTP. Co-immunoprecipitation, pull-down and immunocytochemistry experiments confirmed the interactions. We also discovered that the central proline-rich and histidine-rich domain of HD-PTP is responsible for these interactions.

Significance

The interaction of HD-PTP with two adapters of the Grb2 family, essential for numerous signaling pathways, suggests that HD-PTP might be important for signaling through a plethora of receptors.     

Gill monogeneans of neotropical cichlid fish: diversity,phylogenetic relationships,and host-parasite cophylogenetic associations

Host-parasite coevolution is one of the main topics of the evolutionary biology of host-parasite associations. The majority of monogeneans parasitizing fish exhibit a high degree of host specificity. As a result, their evolutionary history might be intertwined with that of their fish hosts. The Cichlidae represent a diverse group of secondary freshwater fish with disjunctive distribution. Host-specific dactylogyrid monogeneans commonly parasitize cichlid fish. Their high diversity is associated with the main areas of cichlid distribution, i.e., Neotropical America and Africa. Nevertheless, the parasite fauna of cichlids from Neotropical America is still underexplored. A total of 31 cichlid species were examined for the presence of monogeneans, with 20 of them being parasitized. On these cichlids, 30 monogeneans belonging to the genera Gussevia, Trinidactylus, and Scadicleithrum were identified, 17 of them potentially representing new species for science. Phylogenetic analyses revealed three monophyletic groups of Neotropic cichlid monogeneans. Genus Gussevia was monophyletic, while Sciadicleithrum resulted polyphyletic. Sciedicleithrum from South America and Sciadicleithrum from Mexico represented two divergent lineages. The plesiomorphic Neotropical cichlid host group for dactylogyrid monogeneans was Cichlini, from which the representatives of other Neotropical cichlid tribes were colonised. Cophylogenetic analyses revealed a statistically significant cophylogenetic signal in the investigated host-parasite system, with host switch and duplication representing the main coevolutionary events for monogeneans parasitizing Neotropical cichlids. This scenario is in accordance with previous studies focussed on dactylogyridean monogeneans parasitizing freshwater fish in Europe and Africa.     

Inference of phylogenetic relationships within Fabriciidae (Sabellida,Annelida) using molecular and morphological data

Cladistic relationships among fabriciids have to date been explored in the context of adult morphology, but resolution has been declining as more species are described. In this study, we incorporated data on the reproductive system, including features related to the male sperm and sperm storage by females, to supplement existing data on adult morphology (for a total of 50 characters). Three nuclear DNA markers (18S rDNA approximately 1800 bp, the D1 region of 28S rDNA approximately 320 bp, and histone H3 approximately 330 bp) were sequenced from 21 species of fabriciids. We assessed the phylogeny of Fabriciidae based on an integrative analysis of these morphological and molecular characters. Our results show that, in addition to three previously recovered apomorphies for Fabriciidae (absence of ventral lips, modification of abdominal uncini to an elongate manubrium, and presence of branchial hearts), six more apomorphies associated with the reproductive system can be used to support this clade—spermiogenesis only in the thorax, spermiogenesis in large clusters with a central cytophore, single dorsal sperm duct, sperm nuclear projection, thickening of the sperm nuclear membrane and the sperm extra‐axonemal sheath. The results require the erection of two new genera and two new species, which are described. © The Willi Hennig Society 2010.     

Novel perennial ryegrass-Neotyphodium endophyte associations: relationships between seed weight,seedling vigour and endophyte presence

Two forage cultivars of perennial ryegrass (Lolium perenne) colonised by the mutualistic fungal endophyte Neotyphodium lolii, strain AR37, were used to investigate relationships between seed weight, seed vigour and endophyte presence. Seed was separated into six fractions according to weight, with each fraction divided into two further groups with the first being subject to accelerated ageing. Seed germination rates and proportions of viable and total endophyte frequencies were assessed for each fraction. Heavier fractions of seed produced a higher number of endophyte infected seedlings sooner than the lighter fractions for both cultivars. The highest proportion of viable endophyte was found in the fastest germinating perennial ryegrass seed for all weight fractions, from both cultivars, indicating a strong relationship between endophyte presence and seed germination rate. For one of the cultivars, after accelerated ageing, as seed weight increased the proportion of viable endophyte increased and the discrepancy between the proportion of endophyte in fresh and accelerated aged seed was reduced. This implies that for this cultivar heavier ryegrass seed provides a more favourable habitat to the dormant endophyte than lighter seed during storage and/or allowed for a greater biomass of endophyte hyphae to proliferate in the seed tissues prior to seed dormancy, thus allowing the fungus to develop more propagules and greater nutritional reserves.     

Phytoplankton associations in two pools and their relationships with associated benthic flora

Summary The theory underlying the delineation of phytoplankton association is examined, and the associations of Abbot's pond and Priddy pool are characterised according to the conclusions derived from this examination. The importance of extended investigations is stressed. Abbot's pond has a eu-planktonic flora with abundant Asterionella formosa, Pandorina morum and Chrysococcus diaphanus. The euphytoplankton of Priddy pool consists of a very few species, of which Dinobryon sertularia is most abundant, but owing to the action of wind on the pool, many species are introduced into the open water by disturbance of benthic habitats.     

Host plant associations, diversity and species—area relationships of mesophyll-feeding leafhoppers of trees and shrubs in Britain

Abstract. 1. Sixty-two British species of Typhlocybine leafhoppers are known to feed on the leaf-mesophyll tissue of trees and shrubs. British host records for fifty-five of these are given.
2. The leafhopper faunas of thirty-six species of native and introduced trees and shrubs are described.
3. The Shannon-Wiener equation was used to calculate species diversity for adult samples collected from twenty different species at sixteen different localities in Wales, southern England and northern Scotland.
4. Sørensen's coefficients were calculated for rearing data from Britain generally, and subjected to cluster analysis. Most trees have low similarities with respect to leafhopper faunas and are quite distinct. Taxonomic relationships of trees appear to be relatively unimportant in determining the similarities of their leaf-hopper faunas.
5. Using the same data, species—area relationships were calculated for thirty-four different tree and shrub species and their associated leaf-hoppers. A significant regression was obtained, but it explained only 16% of the variation. It is thus suggested that host plant range is relatively unimportant in determining the numbers of these species associated with different trees in Britain.
6. Some introduced species of trees, particularly the recently planted Nothofagus , have acquired large leafhopper faunas.     

Linkage relationships and allelic associations of the cystic fibrosis locus and four marker loci

Summary The linkage relationships between the cystic fibrosis (CF) locus and four marker loci (MET-H, MET-D, D7S8 and D7S16), allelic associations between these loci and the extent of informativity at these marker loci were investigated in a sample of 206 families with at least one child affected by CF. The data were contributed by 11 laboratories from Europe and Israel. The maximum lod scores and recombination frequency estimates ( ) (and confidence limits of ) were: 18.3 at =0.007(0.001–0.038) for CF vs. MET, 11.0 at (0.001–0.068) for CF vs. D7S8, and 5.7 at =0.0(0.0–0.064) for CF vs. D7S16. A gene order of CF-MET-D7S8 was best supported by the data, but its preference to the order D7S8-CF-MET is mainly based on one single family. There are significant allelic associations between CF, MET, D7S8 and D7S16; these allelic associations affect the risk of random individuals to be carriers of CF.     

弄岗北热带喀斯特季节性雨林群丛数量 分类及与环境的关系

以弄岗15 ha北热带喀斯特季节性雨林监测样地各样方的相对海拔、坡度、坡向、凹凸度和物种重要值数据为变量, 采用多元回归树方法将喀斯特季节性雨林森林群落分为8个群丛。同时, 按乔木层、亚乔木层优势种为主, 灌木层指示种为辅的方法分别把8类群丛命名为: (A)南方紫金牛(Ardisia thyrsiflora)–苹婆(Sterculia monosperma)–中国无忧花(Saraca dives)群丛, 该群丛类型主要分布于土壤和空气的湿度都较大的谷底边缘; (B)对叶榕(Ficus hispida)–苹婆–董棕(Caryota obtusa)群丛, 该群丛类型主要分布于伴有季节性水淹、土壤和空气湿度都很大的谷底; (C)山石榴(Catunaregam spinosa)–广西牡荆–蚬木(Excentrodendron tonkinense)群丛, 该群丛类型主要分布于受太阳直射时间较长、水分条件中等偏旱的中下坡阳坡地带; (D)垂茉莉(Clerodendrum wallichii)–苹婆–广西棋子豆(Cychidendron guangxiensis)群丛, 该群丛类型主要分布于受太阳直射时间稍短、水分条件适中的中下坡阴坡地带; (E)米仔兰(Aglaia odorata)–闭花木(Cleistanthus sumatranus)–蚬木群丛, 该群丛类型主要分布于土壤湿度中等偏旱的中上坡半阴坡地带; (F)割舌树(Walsura robusta)–闭花木–蚬木群丛, 该群丛类型主要分布于土壤湿度中等偏旱、比较陡峭的半阳坡地带; (G)枝花流苏树(Chionanthus ramiflorus)–广西牡荆–蚬木群丛, 该群丛类型主要分布于坡度缓和、太阳直射的时间较短、水分条件适中的垭口部位; (H)齿叶黄皮(Clausena dunniana)–黄梨木(Boniodendron minius)–蚬木群丛, 该群丛类型主要分布于受到太阳直射时间最长、岩石裸露度最大、气温干燥、土壤水分严重不足的山顶及其周围。群丛划分说明该区域植被差异主要源于相对海拔和坡向变化, 各群丛物种组成并不存在明显界限, 而是随环境梯度逐渐变化, 反映了植被分布具有连续性, 间断只是相对的。     

Inference of Structure Ensembles of Flexible Biomolecules from Sparse,Averaged Data

We present the theoretical foundations of a general principle to infer structure ensembles of flexible biomolecules from spatially and temporally averaged data obtained in biophysical experiments. The central idea is to compute the Kullback-Leibler optimal modification of a given prior distribution with respect to the experimental data and its uncertainty. This principle generalizes the successful inferential structure determination method and recently proposed maximum entropy methods. Tractability of the protocol is demonstrated through the analysis of simulated nuclear magnetic resonance spectroscopy data of a small peptide.     

Inference from Stratified Samples: Study Design,Bias and Graphical Model Representations

Stratification is a widely used strategy in empirical research to improve efficiency of the sampling design. One concern of stratification is that ignoring it on analysis may bias the relationship between variables. A weighted analysis can only be carried out when sampling weights are known. When these are unknown, valid inference on the relationship between variables then depends on the ignorability of the design, which may be difficult to establish. Here, graphical representations of multivariate dependencies and independencies are used to find necessary conditions for ignorability of stratified sampling designs for inference on conditional and marginal relationships between variables.     

Robust Demographic Inference from Genomic and SNP Data

We introduce a flexible and robust simulation-based framework to infer demographic parameters from the site frequency spectrum (SFS) computed on large genomic datasets. We show that our composite-likelihood approach allows one to study evolutionary models of arbitrary complexity, which cannot be tackled by other current likelihood-based methods. For simple scenarios, our approach compares favorably in terms of accuracy and speed with , the current reference in the field, while showing better convergence properties for complex models. We first apply our methodology to non-coding genomic SNP data from four human populations. To infer their demographic history, we compare neutral evolutionary models of increasing complexity, including unsampled populations. We further show the versatility of our framework by extending it to the inference of demographic parameters from SNP chips with known ascertainment, such as that recently released by Affymetrix to study human origins. Whereas previous ways of handling ascertained SNPs were either restricted to a single population or only allowed the inference of divergence time between a pair of populations, our framework can correctly infer parameters of more complex models including the divergence of several populations, bottlenecks and migration. We apply this approach to the reconstruction of African demography using two distinct ascertained human SNP panels studied under two evolutionary models. The two SNP panels lead to globally very similar estimates and confidence intervals, and suggest an ancient divergence (>110 Ky) between Yoruba and San populations. Our methodology appears well suited to the study of complex scenarios from large genomic data sets.     

Idiosyncratic soil-tree species associations and their relationships with drought in a monodominant Amazon forest

Monodominant forests are characterized by the strong influence of a single species on the structure and diversity of the community. In the tropics, monodominant forests are rare exceptions within the generally highly diverse tropical forest biome. Some studies have shown that tree monodominance may be a transient state caused by successional and demographic variation among species over time. Working in a Brosimum rubescens Taub. (Moraceae) monodominant forest at the southern edge of Amazonia, we tested the hypotheses that local-scale variation in intra- and interspecific spatial patterns of dominant tree species is affected by i) demographic rates of recruitment and mortality following severe droughts, ii) local variation in edaphic properties, and iii) occupation of species in the vertical layer of the forest. We quantified intra- and interspecific spatial patterns and edaphic associations of the five most abundant species using aggregation and association distance indices, and examined changes over time. We found some support for all hypotheses. Thus, intra- and interspecific spatial patterns of most species varied over time, principally after severe drought, emphasizing species-level variability and their interactions in sensitivity to this disturbance, even as B. rubescens monodominance was maintained. While positive and negative spatial associations with edaphic properties provide evidence of habitat specialization, the absence of negative spatial associations of B. rubescens with edaphic properties indicates that this species experiences little environmental restriction, and this may be one of the factors that explain its monodominance. Spatial repulsion and attraction between species in the same and in different vertical layers, respectively, indicates niche overlap and differentiation, while changes over time indicate that the relationships between species are dynamic and affected by drought disturbance.     

Inference of selection from multiple species alignments

The selective pressure on a protein-coding gene can be measured by comparing silent (synonymous) and replacement (nonsynonymous) substitution rates. Higher replacement than silent rates provide unequivocal evidence for adaptive evolution driven by Darwinian selection. Previous employment of this criterion involved pairwise sequence comparison, averaging rates over time and sequences, resulting in virtually no power. Recent methods apply the criterion to particular lineages on a phylogeny or to individual sites in the gene and are much more powerful. Their application has led to detection of adaptive Darwinian selection in a number of genes and organisms.     

Inference of macromolecular assemblies from crystalline state

We discuss basic physical-chemical principles underlying the formation of stable macromolecular complexes, which in many cases are likely to be the biological units performing a certain physiological function. We also consider available theoretical approaches to the calculation of macromolecular affinity and entropy of complexation. The latter is shown to play an important role and make a major effect on complex size and symmetry. We develop a new method, based on chemical thermodynamics, for automatic detection of macromolecular assemblies in the Protein Data Bank (PDB) entries that are the results of X-ray diffraction experiments. As found, biological units may be recovered at 80-90% success rate, which makes X-ray crystallography an important source of experimental data on macromolecular complexes and protein-protein interactions. The method is implemented as a public WWW service.