Accurate inference of relationships in sib-pair linkage studies.

Relative-pair designs are routinely employed in linkage studies of complex genetic diseases and quantitative traits. Valid application of these methods requires correct specification of the relationships of the pairs. For example, within a sibship, presumed full sibs actually might be MZ twins, half sibs, or unrelated. Misclassification of half-sib pairs or unrelated individuals as full sibs can result in reduced power to detect linkage. When other family members, such as parents or additional siblings, are available, incorrectly specified relationships usually will be detected through apparent incompatibilities with Mendelian inheritance. Without other family members, sibling relationships cannot be determined absolutely, but they still can be inferred probabilistically if sufficient genetic marker data are available. In this paper, we describe a simple likelihood ratio method to infer the true relationship of a putative sibling pair. We explore the number of markers required to accurately infer relationships typically encountered in a sib-pair study, as a function of marker allele frequencies, marker spacing, and genotyping error rate, and we conclude that very accurate inference of relationships can be achieved, given the marker data from even part of a genome scan. We compare our method to related methods of relationship inference that have been suggested. Finally, we demonstrate the value of excluding non-full sibs in a genetic linkage study of non-insulin-dependent diabetes mellitus.     

RAxML-III: a fast program for maximum likelihood-based inference of large phylogenetic trees

MOTIVATION: The computation of large phylogenetic trees with statistical models such as maximum likelihood or bayesian inference is computationally extremely intensive. It has repeatedly been demonstrated that these models are able to recover the true tree or a tree which is topologically closer to the true tree more frequently than less elaborate methods such as parsimony or neighbor joining. Due to the combinatorial and computational complexity the size of trees which can be computed on a Biologist's PC workstation within reasonable time is limited to trees containing approximately 100 taxa. RESULTS: In this paper we present the latest release of our program RAxML-III for rapid maximum likelihood-based inference of large evolutionary trees which allows for computation of 1.000-taxon trees in less than 24 hours on a single PC processor. We compare RAxML-III to the currently fastest implementations for maximum likelihood and bayesian inference: PHYML and MrBayes. Whereas RAxML-III performs worse than PHYML and MrBayes on synthetic data it clearly outperforms both programs on all real data alignments used in terms of speed and final likelihood values. Availability SUPPLEMENTARY INFORMATION: RAxML-III including all alignments and final trees mentioned in this paper is freely available as open source code at http://wwwbode.cs.tum/~stamatak CONTACT: stamatak@cs.tum.edu.     

Efficient estimation of SNP heritability using Gaussian predictive process in large scale cohort studies

With the advent of high throughput genetic data, there have been attempts to estimate heritability from genome-wide SNP data on a cohort of distantly related individuals using linear mixed model (LMM). Fitting such an LMM in a large scale cohort study, however, is tremendously challenging due to its high dimensional linear algebraic operations. In this paper, we propose a new method named PredLMM approximating the aforementioned LMM motivated by the concepts of genetic coalescence and Gaussian predictive process. PredLMM has substantially better computational complexity than most of the existing LMM based methods and thus, provides a fast alternative for estimating heritability in large scale cohort studies. Theoretically, we show that under a model of genetic coalescence, the limiting form of our approximation is the celebrated predictive process approximation of large Gaussian process likelihoods that has well-established accuracy standards. We illustrate our approach with extensive simulation studies and use it to estimate the heritability of multiple quantitative traits from the UK Biobank cohort.     

BFL: a node and edge betweenness based fast layout algorithm for large scale networks

Background  

Network visualization would serve as a useful first step for analysis. However, current graph layout algorithms for biological pathways are insensitive to biologically important information, e.g. subcellular localization, biological node and graph attributes, or/and not available for large scale networks, e.g. more than 10000 elements.     

On relationship inference using gamete identity by descent data.

Related individuals are identical by descent (IBD) at a genetic locus if they share the same DNA material from a common ancestor. Continuous gamete IBD data consist of the lengths of (in order) IBD and non-IBD regions along the genomes for gametes segregating from two related individuals and can be used to distinguish different relationships. Under the assumption that the crossovers follow a Poisson process, we show that the exact calculation of the likelihood of a particular relationship for a given gamete IBD datum is tractable. Greatgrandparent--greatgrandchild and cousin relationships are used as examples to illustrate our methods.     

MM3工程菌的大规模发酵培养工艺研究

首先在50L发酵罐上研究了MM3工程菌的发酵培养工艺。确定了接种量、搅拌转速、pH和补料速率等参数,活菌数可达每毫升211亿。以溶氧为放大准则可成功地将该工艺在200L国产发酵罐上再现。说明该工艺具有可放大性,可在全国各药厂推广应用。     

Model choice for phylogeographic inference using a large set of models

Model‐based analyses are common in phylogeographic inference because they parameterize processes such as population division, gene flow and expansion that are of interest to biologists. Approximate Bayesian computation is a model‐based approach that can be customized to any empirical system and used to calculate the relative posterior probability of several models, provided that suitable models can be identified for comparison. The question of how to identify suitable models is explored using data from Plethodon idahoensis, a salamander that inhabits the North American inland northwest temperate rainforest. First, we conduct an ABC analysis using five models suggested by previous research, calculate the relative posterior probabilities and find that a simple model of population isolation has the best fit to the data (PP = 0.70). In contrast to this subjective choice of models to include in the analysis, we also specify models in a more objective manner by simulating prior distributions for 143 models that included panmixia, population isolation, change in effective population size, migration and range expansion. We then identify a smaller subset of models for comparison by generating an expectation of the highest posterior probability that a false model is likely to achieve due to chance and calculate the relative posterior probabilities of only those models that exceed this expected level. A model that parameterized divergence with population expansion and gene flow in one direction offered the best fit to the P. idahoensis data (in contrast to an isolation‐only model from the first analysis). Our investigation demonstrates that the determination of which models to include in ABC model choice experiments is a vital component of model‐based phylogeographic analysis.     

A fast method for computing high-significance disease association in large population-based studies

Because of rapid progress in genotyping techniques, many large-scale, genomewide disease-association studies are now under way. Typically, the disorders examined are multifactorial, and, therefore, researchers seeking association must consider interactions among loci and between loci and other factors. One of the challenges of large disease-association studies is obtaining accurate estimates of the significance of discovered associations. The linkage disequilibrium between SNPs makes the tests highly dependent, and dependency worsens when interactions are tested. The standard way of assigning significance (P value) is by a permutation test. Unfortunately, in large studies, it is prohibitively slow to compute low P values by this method. We present here a faster algorithm for accurately calculating low P values in case-control association studies. Unlike with several previous methods, we do not assume a specific distribution of the traits, given the genotypes. Our method is based on importance sampling and on accounting for the decay in linkage disequilibrium along the chromosome. The algorithm is dramatically faster than the standard permutation test. On data sets mimicking medium-to-large association studies, it speeds up computation by a factor of 5,000-100,000, sometimes reducing running times from years to minutes. Thus, our method significantly increases the problem-size range for which accurate, meaningful association results are attainable.     

phylosem: A fast and simple R package for phylogenetic inference and trait imputation using phylogenetic structural equation models

Phylogenetic comparative methods (PCMs) can be used to study evolutionary relationships and trade-offs among species traits. Analysts using PCM may want to (1) include latent variables, (2) estimate complex trait interdependencies, (3) predict missing trait values, (4) condition predicted traits upon phylogenetic correlations and (5) estimate relationships as slope parameters that can be compared with alternative regression methods. The Comprehensive R Archive Network (CRAN) includes well-documented software for phylogenetic linear models (phylolm), phylogenetic path analysis (phylopath), phylogenetic trait imputation (Rphylopars) and structural equation models (sem), but none of these can simultaneously accomplish all five analytical goals. We therefore introduce a new package phylosem for phylogenetic structural equation models (PSEM) and summarize features and interface. We also describe new analytical options, where users can specify any combination of Ornstein-Uhlenbeck, Pagel's-δ and Pagel's-λ transformations for species covariance. For the first time, we show that PSEM exactly reproduces estimates (and standard errors) for simplified cases that are feasible in sem, phylopath, phylolm and Rphylopars and demonstrate the approach by replicating a well-known case study involving trade-offs in plant energy budgets.     

NEKTAR,SPICE and Vortonics: using federated grids for large scale scientific applications

In response to a joint call from US’s NSF and UK’s EPSRC for applications that aim to utilize the combined computational resources of the US and UK, three computational science groups from UCL, Tufts and Brown Universities teamed up with a middleware team from NIU/Argonne to meet the challenge. Although the groups had three distinct codes and aims, the projects had the underlying common feature that they were comprised of large-scale distributed applications which required high-end networking and advanced middleware in order to be effectively deployed. For example, cross-site runs were found to be a very effective strategy to overcome the limitations of a single resource. The seamless federation of a grid-of-grids remains difficult. Even if interoperability at the middleware and software stack levels were to exist, it would not guarantee that the federated grids can be utilized for large scale distributed applications. There are important additional requirements for example, compatible and consistent usage policy, automated advanced reservations and most important of all co-scheduling. This paper outlines the scientific motivation and describes why distributed resources are critical for all three projects. It documents the challenges encountered in using a grid-of-grids and some of the solutions devised in response.     

Enuresis: familial incidence and relationship to allergic disorders

An analysis is made of the incidence of allergic diseases in 105 enuretic boys and girls, in their parents and siblings, and in matched controls. There is an increased incidence of hay fever, urticaria and food and drug allergies in enuretic boys. There is an increased incidence of enuresis in the parents of enuretic children. Enuretic children and their fathers are significantly more prone to develop urinary infections than are controls; there is also an increased incidence in urinary infections in their mothers, but numbers are insufficient to indicate that this is significant.     

Preparative scale cell-free expression systems: new tools for the large scale preparation of integral membrane proteins for functional and structural studies

Cell-free expression techniques have emerged as promising tools for the production of membrane proteins for structural and functional analysis. Elimination of toxic effects and a variety of options to stabilize the synthesized proteins enable the synthesis of otherwise difficult to obtain proteins. Modifications in the reaction design result in preparative scale production rates of cell-free reactions and yield in milligram amounts of membrane proteins per one millilitre of reaction volume. A diverse selection of detergents can be supplied into the reaction system without inhibitory effects to the translation machinery. This offers the unique opportunity to produce a membrane protein directly into micelles of a detergent of choice. We present detailed protocols for the cell-free production of membrane proteins in different modes and we summarize the current knowledge of this technique. A special emphasize will be on the production of soluble and functionally folded membrane proteins in presence of suitable detergents. In addition, we will highlight the advantages of cell-free expression for the structural analysis of membrane proteins especially by liquid state nuclear magnetic resonance spectroscopy and we will discuss new strategies for structural approaches.