MicroRNA (miRNA) regulation clearly impacts animal development, but the extent to which development—with its resulting diversity of cellular contexts—impacts miRNA regulation is unclear. Here, we ...compared cohorts of genes repressed by the same miRNAs in different cell lines and tissues and found that target repertoires were largely unaffected, with secondary effects explaining most of the differential responses detected. Outliers resulting from differential direct targeting were often attributable to alternative 3′ UTR isoform usage that modulated the presence of miRNA sites. More inclusive examination of alternative 3′ UTR isoforms revealed that they influence ∼10% of predicted targets when comparing any two cell types. Indeed, considering alternative 3′ UTR isoform usage improved prediction of targeting efficacy significantly beyond the improvements observed when considering constitutive isoform usage. Thus, although miRNA targeting is remarkably consistent in different cell types, considering the 3′ UTR landscape helps predict targeting efficacy and explain differential regulation that is observed.
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•Cellular context does not detectably affect the majority of miRNA targets•Differential 3′ UTR isoforms explain cell-type-specific targeting that is observed•Considering the 3′ UTR landscape improves prediction of targeting efficacy•miRNA-mediated repression shapes the 3′ UTR landscape
MicroRNAs function in many biological contexts, but the extent to which these different contexts modulate the cohort of genes regulated by a miRNA was unclear. Nam et al. show that miRNA targeting is remarkably consistent between different cell types and that most differential targeting that is observed is explained by differences in 3′ UTR isoforms.
Measuring similarities between objects based on their attributes has been an important problem in many disciplines. Object-attribute associations can be depicted as links on a bipartite graph. A ...similarity measure can be thought as a unipartite projection of this bipartite graph. The most widely used bipartite projection techniques make assumptions that are not often fulfilled in real life systems, or have the focus on the bipartite connections more than on the unipartite connections. Here, we define a new similarity measure that utilizes a practical procedure to extract unipartite graphs without making a priori assumptions about underlying distributions. Our similarity measure captures the relatedness between two objects via the likelihood of a random walker passing through these nodes sequentially on the bipartite graph. An important aspect of the method is that it is robust to heterogeneous bipartite structures and it controls for the transitivity similarity, avoiding the creation of unrealistic homogeneous degree distributions in the resulting unipartite graphs. We test this method using real world examples and compare the obtained results with alternative similarity measures, by validating the actual and orthogonal relations between the entities.
The prevalent affirmative action policy in school choice limits the number of admitted majority students to give minority students higher chances to attend their desired schools. There have been ...numerous efforts to reconcile affirmative action policies with celebrated matching mechanisms such as the deferred acceptance and top trading cycles algorithms. Nevertheless, it is theoretically shown that under these algorithms, the policy based on majority quotas may be detrimental to minorities. Using simulations we find that this is a more common phenomenon rather than a peculiarity-up to 25% of minorities and 55% of majorities can be worse off. To circumvent the inefficiency caused by majority quotas, we offer a different interpretation of the affirmative action policies based on minority reserves. With minority reserves, schools give higher priority to minority students up to the point that the minorities fill the reserves. We compare the welfare effects of these policies. The deferred acceptance algorithm with minority reserves Pareto dominates the one with majority quotas. Our simulations, which allows for correlations between student preferences and school priorities, indicate that minorities are on average better off with minority reserves while adverse effects on majorities are mitigated.
Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as ‘nodes’ and ...‘edges’, respectively. Better understanding of genotype‐to‐phenotype relationships in human disease will require modeling of how disease‐causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products (‘node removal’) and interaction‐specific or edge‐specific (‘edgetic’) alterations. Global computational analyses of ∼50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies.
Synopsis
Genotype‐to‐phenotype relationships in human genetic disease are often modeled as: ‘mutation in gene X leads to loss of gene product X, which leads to disease A’. However, single ‘gene‐loss’ models cannot explain the increasingly appreciated prevalence of complex genotype‐to‐phenotype relationships, particularly with instances of allelic or locus hetrogeneity (Goh et al, 2007).
Genes and gene products function not in isolation but as components of complex networks of macromolecules (DNA, RNA, or proteins) and metabolites linked through biochemical or physical interactions, often represented in ‘interactome’ network models as ‘nodes’ and ‘edges’, respectively. Here we use network perturbation models to explain molecular dysfunctions underlying human disease in addition to the gene‐loss model.
We hypothesize that different mutations leading to different molecular defects to proteins may cause distinct perturbations of cellular networks, giving rise to distinct phenotypic outcomes (Figure 1). For example, truncations close to the start of an open‐reading frame, or mutations that grossly destabilize a protein structure, can be modeled as removing a protein node from the network (‘node removal’). Alternatively, single amino‐acid substitutions that affect specific binding sites, or truncations that preserve certain domains of a protein, may give rise to partially functional gene products with specific changes in distinct molecular interaction(s) (edge‐specific or ‘edgetic’ perturbations) (Figure 1B).
Taking advantage of the large number of known disease‐causing allelic variations in human Mendelian disorders, we investigated how disease‐associated mutations may cause complete loss of gene products or, alternatively, may cause specific loss or gain of individual molecular interaction(s). We examined ∼50 000 Mendelian disease‐causing alleles, affecting over 1900 protein‐coding genes, altogether associated with more than 2000 human disorders available in the Human Gene Mutation Database (HGMD) (Stenson et al, 2003), that can be subdivided into two subsets: truncating’ alleles (truncations or frameshifts caused by stop codons, out‐of‐frame insertions or deletions, or defective splicing) versus ‘in‐frame’ alleles (missense mutations and in‐frame insertions or deletions). Over 50% (27 919/52 491) of Mendelian alleles in HGMD correspond to ‘in‐frame’ mutations. Our hypothesis is that, ‘in‐frame’ alleles may affect specific interactions of a given gene product while leaving most other interactions unperturbed.
Although exceptions may apply, our hypothesis has several predictions. First, ‘truncating’ versus ‘in‐frame’ alleles may distribute differently among autosomal dominant and autosomal recessive disease, given that dominant mutations are more likely to be edgetic than recessive ones. Indeed, autosomal dominant and autosomal recessive traits annotated in the Online Mendelian Inheritance in Man (OMIM) database (Hamosh et al, 2005) show a clear separation with respect to the associated ‘in‐frame’ versus ‘truncating’ mutations. Among genes affected solely by ‘in‐frame’ mutations, the proportion of dominant diseases is ∼10‐fold higher than that of recessive ones, supporting ‘in‐frame’ mutations causing distinct molecular defects as opposed to ‘truncating’ mutations.
A proof‐of‐principle characterization of binary protein interaction defects of mutant alleles associated with five genetic disorders supports our hypothesis that ‘in‐frame’ alleles indeed produce mostly functional proteins, preserving many specific protein interactions. As grossly disruptive mutations versus mutations leading to loss or gain of specific interaction(s) probably distribute differently on protein structures, we examined available three‐dimensional structures of all disease proteins. Mutated residues in autosomal dominant disease are significantly more exposed to the surface of the structure than those in autosomal recessive disease, consistent with the idea that disease with distinct modes of inheritance probably involves distinct network perturbations.
A second testable prediction of our edgetic perturbation model is that edgetic perturbation versus gene loss for a given gene product might in some cases cause different diseases. We examined 142 genes associated with two or more distinct diseases in which at least five distinct alleles have been reported for each disease. We found ∼30% of the cases for which distribution of ‘in‐frame’ versus ‘truncating’ mutations is significantly different between the two diseases linked to the same gene (P<0.05). Hence, when affecting the same gene, node removal versus edgetic perturbation can confer strikingly different phenotypes.
A third testable prediction is that different edgetic perturbations for a given gene product might cause phenotypically distinguishable diseases (Figure 6). We used predicted Pfam domains (Finn et al, 2006) as surrogates for functional interaction domains, assuming that ‘in‐frame’ mutations located in distinct Pfam domain‐encoding sequences probably alter distinct interactions. Among 169 genes associated with two or more diseases and encoding proteins containing at least two Pfam domains, nine proteins have at least two Pfam domains significantly enriched with ‘in‐frame’ mutations (P<0.05). For each of the nine proteins, we found a striking pattern of near mutual exclusivity, whereby different Pfam domains seem to be specifically affected in distinct disorders (Figure 6B).
We conclude that edgetic alleles probably underlie many complex genotype‐to‐phenotype relationships in human disease, such as incomplete penetrance or variable expressivity, as well as allele‐specific phenotypic variations among patients. Edgetic perturbation of human inherited disorders might help explain how seemingly devastating alleles have appeared and persevered in human populations.
We present alternative models to explain molecular dysfunctions underlying human inherited disorders based on interaction‐specific or “edgetic” perturbations rather than complete loss of gene products.
We find that a substantial fraction of known genetic variants in human Mendelian disorders likely cause edgetic perturbations.
We find frequent situations where edgetic perturbation models can explain how different mutations in a single gene can cause distinct disorders.
Edgetic perturbation models should provide alternative explanations to complex genotype‐to‐phenotype relationships
The homeostatic balance of hepatic glucose utilization, storage, and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver ...senses extracellular glucose to cue glucose utilization versus production is not fully understood. We show that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by Bcl-2-associated agonist of cell death (BAD), a protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism toward diminished glycolysis, excess fatty acid oxidation, and exaggerated glucose production that escapes suppression by insulin. Genetic and biochemical evidence suggests that BAD’s suppression of gluconeogenesis is actuated by phosphorylation of its BCL-2 homology (BH)-3 domain and subsequent activation of glucokinase. The physiologic relevance of these findings is evident from the ability of a BAD phosphomimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin-resistant and high-fat diet models of diabetes and insulin resistance.
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•BAD modulates hepatic glucose output by coordinating glycolysis and gluconeogenesis•BAD is required for the suppression of hepatic glucose production by insulin•The effect of BAD on glucose utilization and production is mediated by glucokinase•Hepatic expression of BAD improves glycemia in models of diabetes and obesity
Besides apoptosis, the BCL-2 family protein BAD has specific functions in glucose metabolism. Giménez-Cassina et al. show that hepatic BAD downregulates gluconeogenesis by activating glucokinase through a phosphorylation-dependent mechanism downstream of insulin. Expression of a BAD phosphomimic variant improves glycemia in mouse models of diabetes and insulin resistance.
•Develops the Production Ability measure for locations and Sophistication measures for industries.•Product Sophistication reveals how specific industry requirements are, and how sensitive industries ...are to the absence of these requirements.•Production Ability is strongly associated with income levels and economic growth of countries and cities.•An industry’s Sophistication value is strongly linked to its skill-level.•Together, these indices predict the likelihood of birth or death of industries across locations.•These new indices perform well compared to previous economic complexity measures.
Cities and countries undergo constant structural transformation. Industries need many inputs, such as regulations, infrastructure or productive knowledge, which we call capabilities. And locations are successful in hosting industries insofar as the capabilities that they can provide. We propose a capabilities-based production model and an empirical strategy to measure the Sophistication of a product and the Production Ability of a location. We apply our framework to international trade data and employment data in the United States, recovering measures of Production Ability for countries and cities, and the Sophistication of products and industries. We show that both country- and city-level measures have a strong correlation with income and economic growth at different time horizons. Product Sophistication is positively correlated with indicators of human capital and wages. Our model-based estimations predict product appearances and disappearances through the extensive margin.
Abstract We build on Baqaee and Farhi (2019, 2021) and derive a theoretically grounded criterion that allows targeting bans on exports to a sanctioned country at the level of ∼5,000 six-digit HS ...products. The criterion implies that the costs to the sanctioned country are highly convex in the market share of the sanctioning parties. Hence, there are large benefits from coordinating export bans among a broad coalition of countries. Applying our results to Russia reveals that sanctions imposed by the European Union and the United States in response to Russia’s invasion of Ukraine are not systematically related to our arguments once we condition on Russia’s total imports of a product from participating countries. We discuss drivers of these differences and then provide a quantitative evaluation of the export bans to show that (i) they are very effective with the welfare loss typically ∼100 times larger for Russia than for the sanctioners; (ii) improved coordination of the sanctions and targeting sanctions based on our criterion allows to increase the costs to Russia by about 80% with little to no extra cost to the sanctioners; and (iii) there is scope for increasing the cost to Russia further by expanding the set of sanctioned products.
Controlled choice over public schools attempts giving parents selection options while maintaining diversity of different student types. In practice, diversity constraints are often enforced by ...setting hard upper bounds and hard lower bounds for each student type. We demonstrate that, with hard bounds, there might not exist assignments that satisfy standard fairness and non-wastefulness properties; and only constrained non-wasteful assignments that are fair for same type students can be guaranteed to exist. We introduce the student exchange algorithm that finds a constrained efficient assignment among such assignments. To achieve fair (across all types) and non-wasteful assignments, we propose control constraints to be interpreted as soft bounds–flexible limits that regulate school priorities dynamically. In this setting, (i) the student-proposing deferred acceptance algorithm produces an assignment that Pareto dominates all other fair assignments while eliciting true preferences and (ii) the school-proposing deferred acceptance algorithm finds an assignment that minimizes violations of controlled choice constraints among fair assignments.
Implied comparative advantage Hausmann, Ricardo; Stock, Daniel P.; Yıldırım, Muhammed A.
Research policy,
10/2022, Letnik:
51, Številka:
8
Journal Article
Recenzirano
Odprti dostop
•We build a Ricardian-inspired model with relatedness in comparative advantage (CA).•Hidden information on endowments and requirements is recovered with correlations.•With this information, we ...calculate implied comparative advantage.•Implied CA predicts observed CA at international and subnational level.•Gap between implied and observed CA is associated with long-term evolution of production.•Implied CA is predictive of product appearances and disappearances in long term.
The comparative advantage of a location shapes its industrial structure. Current theoretical models based on this principle do not take a stance on how comparative advantages in different industries or locations are related with each other, or what such patterns of relatedness might imply about the evolution of comparative advantage. We build a simple Ricardian-inspired model and show that hidden information on inter-industry and inter-location relatedness can be captured by simple correlations between the observed structure of industries across locations, or the structure of locations across industries. We then use this recovered information to calculate a measure of implied comparative advantage, and show that it explains much of the location’s current industrial structure. We give evidence that these patterns are present in a wide variety of contexts, namely the export of goods (internationally) and the employment, payroll and number of establishments across the industries of subnational regions (in the US, Chile and India). In each of these cases, the deviations between the observed and implied comparative advantage in the past tend to be highly predictive of future industry growth, especially at horizons of a decade or more; this explanatory power holds at both the intensive as well as the extensive margin. These results suggest that a component of the long-term evolution of comparative advantage is already implied in today’s patterns of production.
Drug-target network Barabási, Albert-László; Vidal, Marc; Y ld r m, Muhammed A ...
Nature biotechnology,
10/2007, Letnik:
25, Številka:
10
Journal Article
Recenzirano
The global set of relationships between protein targets of all drugs and all disease-gene products in the human protein-protein interaction or 'interactome' network remains uncharacterized. We built ...a bipartite graph composed of US Food and Drug Administration-approved drugs and proteins linked by drug-target binary associations. The resulting network connects most drugs into a highly interlinked giant component, with strong local clustering of drugs of similar types according to Anatomical Therapeutic Chemical classification. Topological analyses of this network quantitatively showed an overabundance of 'follow-on' drugs, that is, drugs that target already targeted proteins. By including drugs currently under investigation, we identified a trend toward more functionally diverse targets improving polypharmacology. To analyze the relationships between drug targets and disease-gene products, we measured the shortest distance between both sets of proteins in current models of the human interactome network. Significant differences in distance were found between etiological and palliative drugs. A recent trend toward more rational drug design was observed.
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