Robust Prediction of Expression Differences among Human Individuals Using Only Genotype Information

Many genetic variants that are significantly correlated to gene expression changes across human individuals have been identified, but the ability of these variants to predict expression of unseen individuals has rarely been evaluated. Here, we devise an algorithm that, given training expression and genotype data for a set of individuals, predicts the expression of genes of unseen test individuals given only their genotype in the local genomic vicinity of the predicted gene. Notably, the resulting predictions are remarkably robust in that they agree well between the training and test sets, even when the training and test sets consist of individuals from distinct populations. Thus, although the overall number of genes that can be predicted is relatively small, as expected from our choice to ignore effects such as environmental factors and trans sequence variation, the robust nature of the predictions means that the identity and quantitative degree to which genes can be predicted is known in advance. We also present an extension that incorporates heterogeneous types of genomic annotations to differentially weigh the importance of the various genetic variants, and we show that assigning higher weights to variants with particular annotations such as proximity to genes and high regional G/C content can further improve the predictions. Finally, genes that are successfully predicted have, on average, higher expression and more variability across individuals, providing insight into the characteristics of the types of genes that can be predicted from their cis genetic variation.     

A case study of a shared/buy-in computing ecosystem

Many research institutions are deploying computing clusters based on a shared/buy-in paradigm. Such clusters combine shared computers, which are free to be used by all users, and buy-in computers, which are computers purchased by users for semi-exclusive use. The purpose of this paper is to characterize the typical behavior and performance of a shared/buy-in computing cluster, using data traces from the Shared Computing Cluster (SCC) at Boston University that runs under this paradigm as a case study. Among our main findings, we show that the semi-exclusive policy, which allows any SCC user to use idle buy-in resources for a limited time, increases the utilization of buy-in resources by 17.4%, thus significantly improving the performance of the system as a whole. We find that jobs allowed to run on idle buy-in resources arrive more frequently and run for a shorter time than other jobs. Finally, we identify the run time limit (i.e., the maximum time during which a job is allowed to use resources) and the type of parallel environment as two factors that have a significant impact on the different performance experienced by shared and buy-in jobs.     

When TRBP leaves Dicer at the alt‐’ER

The principle underlying miRNA silencing seems rather simple: Dicer is required for the biogenesis of endogenous miRNAs, and mature miRNAs at the RNA‐induced silencing complex, RISC, bind to targets by sequence complementary, inhibiting protein expression. However, research shows that there are many degrees of complexity to miRNA regulation. A new study by Antoniou et al 1 that is published in this issue of EMBO Reports explores an interesting neuron‐specific facet of miRNA biogenesis. We learn that in neuronal dendrites, the endoplasmic reticulum (ER) acts as a regulatory domain for the dynamic encounter of TRBP and Dicer, two proteins required for the biogenesis of miRNAs, thus affecting neuron morphogenesis.     

HAPLOFREQ--estimating haplotype frequencies efficiently.

A commonly used tool in disease association studies is the search for discrepancies between the haplotype distribution in the case and control populations. In order to find this discrepancy, the haplotypes frequency in each of the populations is estimated from the genotypes. We present a new method HAPLOFREQ to estimate haplotype frequencies over a short genomic region given the genotypes or haplotypes with missing data or sequencing errors. Our approach incorporates a maximum likelihood model based on a simple random generative model which assumes that the genotypes are independently sampled from the population. We first show that if the phased haplotypes are given, possibly with missing data, we can estimate the frequency of the haplotypes in the population by finding the global optimum of the likelihood function in polynomial time. If the haplotypes are not phased, finding the maximum value of the likelihood function is NP-hard. In this case, we define an alternative likelihood function which can be thought of as a relaxed likelihood function. We show that the maximum relaxed likelihood can be found in polynomial time and that the optimal solution of the relaxed likelihood approaches asymptotically to the haplotype frequencies in the population. In contrast to previous approaches, our algorithms are guaranteed to converge in polynomial time to a global maximum of the different likelihood functions. We compared the performance of our algorithm to the widely used program PHASE, and we found that our estimates are at least 10% more accurate than PHASE and about ten times faster than PHASE. Our techniques involve new algorithms in convex optimization. These algorithms may be of independent interest. Particularly, they may be helpful in other maximum likelihood problems arising from survey sampling.     

Probabilistic discovery of overlapping cellular processes and their regulation.

In this paper, we explore modeling overlapping biological processes. We discuss a probabilistic model of overlapping biological processes, gene membership in those processes, and an addition to that model that identifies regulatory mechanisms controlling process activation. A key feature of our approach is that we allow genes to participate in multiple processes, thus providing a more biologically plausible model for the process of gene regulation. We present algorithms to learn each model automatically from data, using only genomewide measurements of gene expression as input. We compare our results to those obtained by other approaches and show that significant benefits can be gained by modeling both the organization of genes into overlapping cellular processes and the regulatory programs of these processes. Moreover, our method successfully grouped genes known to function together, recovered many regulatory relationships that are known in the literature, and suggested novel hypotheses regarding the regulatory role of previously uncharacterized proteins.     

Living in the city: can anyone become an ‘urban exploiter'?

Aim As urban landscapes expand, shifts in biodiversity are occurring. This is leading biogeographers and ecologists to consider human‐dominated landscapes in their current work. One question that arises is: what characterizes those species that are widespread in the most highly urban environments compared with those restricted to less urbanized areas in the city? Here, we aim to identify the traits that enable species to become urban exploiters, i.e. to dominate highly urbanized surroundings. Identifying these traits may help us better predict and possibly mitigate the biotic homogenization occurring in these areas. Location Israel in general, with special focus on the city of Jerusalem. Methods Combining literature and field‐based data for birds in Israel we compared phenotypic, behavioural and life‐history traits between urban exploiters and urban adapters. The latter occur in urban landscapes, but are characteristic of the less urbanized parts of the city. We then examined the trends along a finer field‐sampled gradient of increasing urbanization from sub‐natural to downtown areas within the city of Jerusalem. Results Urban exploiters and adapters differed primarily in social structure and migratory status: exploiters were significantly more social and sedentary than urban adapters. Clear trends were also seen for dietary preferences along a gradient of increasing urbanization in Jerusalem, such that, with increasing urbanization, the proportion of granivorous species increased whereas the proportion of species feeding on invertebrates declined. In contrast, neither relative brain size nor behavioural flexibility, as measured by feeding innovations, differed significantly among urban exploiters and adapters in Israel or along the urbanization gradient in Jerusalem specifically. Main conclusions The results of our study suggest that being successful in more vs. less urbanized environments in the city is not necessarily a factor of brain size nor of how flexible and behaviourally innovative the species is; rather, it depends on a combination of traits, including diet, degree of sociality, sedentariness and preferred nesting sites.     

Modulation of the K(v)4.3 channel by syntaxin 1A

The SNARE protein syntaxin 1A (Syn1A) is known to inhibit delayed rectifier K(+) channels of the K(v)1 and K(v)2 families with heterogeneous effects on their gating properties. In this study, we explored whether Syn1A could directly modulate K(v)4.3, a rapidly inactivating K(v) channel with important roles in neuroendocrine cells and cardiac myocytes. Immunoprecipitation studies in HEK293 cells coexpressing Syn1A and K(v)4.3 revealed a direct interaction with increased trafficking to the plasma membrane without a change in channel synthesis. Paradoxically, Syn1A inhibited K(v)4.3 current density. In particular, Syn1A produced a left-shift in steady-state inactivation of K(v)4.3 without affecting either voltage dependence of activation or gating kinetics, a pattern distinct from other K(v) channels. Combined with our previous reports, our results further verify the notion that the mechanisms involved in Syn1A-K(v) interactions vary significantly between K(v) channels, thus providing a wide scope for Syn1A modulation of exocytosis and membrane excitability.     

Multifaceted plant responses to circumvent Phe hyperaccumulation by downregulation of flux through the shikimate pathway and by vacuolar Phe sequestration

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase (PAL) isoforms that catalyze the non‐oxidative deamination of Phe to trans‐cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81–94% led to an 18‐fold expansion of the internal Phe pool. Phe accumulation had multifaceted intercompartmental effects on aromatic amino acid metabolism. It resulted in a decrease in the overall flux through the shikimate pathway, and a redirection of carbon flux toward the shikimate‐derived aromatic amino acids tyrosine and tryptophan. Accumulation of Phe did not lead to an increase in flux toward phenylacetaldehyde, for which Phe is a direct precursor. Metabolic flux analysis revealed this to be due to the presence of a distinct metabolically inactive pool of Phe, likely localized in the vacuole. We have identified a vacuolar cationic amino acid transporter (PhCAT2) that contributes to sequestering excess of Phe in the vacuole. In vitro assays confirmed PhCAT2 can transport Phe, and decreased PhCAT2 expression in PAL‐RNAi transgenic plants resulted in 1.6‐fold increase in phenylacetaldehyde emission. These results demonstrate mechanisms by which plants maintain intercompartmental aromatic amino acid homeostasis, and provide critical insight for future phenylpropanoid metabolic engineering strategies.     

The diet of native and invasive fish species along the eastern Mediterranean coast (Osteichthyes)

The opening of the Suez Canal in 1869 enabled the invasion of more than 100 alien fish species into the Mediterranean. The aim of the present study was to compare the diet of native and alien fish species and to identify possibly shared food resources. We examined the diet composition of 13 of the most abundant fish species (6 alien, 7 native) on shallow soft bottom off southern Israel. All 13 species are omnivorous/carnivorous. The native fish exhibited a wider diversity of food types than the aliens. Alien fish prey upon and are preyed by native species as well as by other alien fish. A high level of diet overlap was found among some species, the aliens Saurida lessepsianus and Scomberomorus commerson overlapped with the native Synodus saurus; and the alien Nemipterus randalli with the native species Pagrus caeruleostictus, Lithognathus mormyrus and Pagellus erythrinus. The identified diet overlap is discussed, and the possibility of competitive interactions between these species is considered.