Informatic approaches to evolutionary systems biology

The sheer complexity of evolutionary systems biology requires us to develop more sophisticated tools for analysis, as well as more probing and biologically relevant representations of the data. My research has focused on three aspects of evolutionary systems biology. I ask whether a gene's position in the human metabolic network affects the degree to which natural selection prunes variation in that gene. I estimated the selective constraint (the ratio of non-synonymous to synonymous nucleotide substitutions) on 80.2% of the genes in the metabolic network using a maximum likelihood model of codon evolution and compared this value to the betweenness centrality of each enzyme. Second, I have focused on the evolution of metabolic systems in the presence of gene and genome duplication. I show that increases in a particular gene's copy number are correlated with limiting metabolic flux in the reaction associated with that gene. Finally, I have investigated the proliferative cell programs present in 6 different cancers (breast, colorectal, gastrointestinal, lung, oral squamous and prostate cancers). I found an overabundance of genes that share expression between cancer and embryonic tissue and that these genes form modular units within regulatory, proteininteraction, and metabolic networks. This despite the fact that these genes, as well as the proteins they encode and reactions they catalyze show little overlap among cancers, suggesting parallel independent reversion to an embryonic pattern of gene expression.Includes bibliographical references (pages 84-99)

A Conserved Mammalian Protein Interaction Network

Physical interactions between proteins mediate a variety of biological functions, including signal transduction, physical structuring of the cell and regulation. While extensive catalogs of such interactions are known from model organisms, their evolutionary histories are difficult to study given the lack of interaction data from phylogenetic outgroups. Using phylogenomic approaches, we infer a upper bound on the time of origin for a large set of human protein-protein interactions, showing that most such interactions appear relatively ancient, dating no later than the radiation of placental mammals. By analyzing paired alignments of orthologous and putatively interacting protein-coding genes from eight mammals, we find evidence for weak but significant co-evolution, as measured by relative selective constraint, between pairs of genes with interacting proteins. However, we find no strong evidence for shared instances of directional selection within an interacting pair. Finally, we use a network approach to show that the distribution of selective constraint across the protein interaction network is non-random, with a clear tendency for interacting proteins to share similar selective constraints. Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.A˚.P.B. is supported by Ga˚lo¨stiftelsen Stipendium fo¨r ho¨gre utlandsstudier. C.M.H. is supported by a National Library of Medicine Biomedical and Health Informatics Training Fellowship [LM007089-19]. G.C.C. is supported by the Reproductive Biology Group of the Food for the 21st Century program at the University of Missouri. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Clustering Dipole of the Local Universe from the Two Micron All Sky Survey

The unprecedented sky coverage and photometric uniformity of the Two Micron All Sky Survey (2MASS) provides a rich resource for investigating the galaxies populating the local Universe. A full characterization of the large-scale clustering distribution is important for theoretical studies of structure formation. 2MASS offers an all-sky view of the local galaxy population at 2.15 micron, unbiased by young stellar light and minimally affected by dust. We use 2MASS to map the local distribution of galaxies, identifying the largest structures in the nearby universe. The inhomogeneity of these structures causes an acceleration on the Local Group of galaxies, which can be seen in the dipole of the Cosmic Microwave Background (CMB). We find that the direction of the 2MASS clustering dipole is 11 degrees from the CMB dipole, confirming that the local galaxy distribution accelerates the Local Group. From the magnitude of the dipole we find a value of the linear bias parameter b=1.37 +/- 0.3 in the K_s-band. The 2MASS clustering dipole is 19 degrees from the latest measurement of the dipole using galaxies detected by the Infrared Astronomical Satellite (IRAS) suggesting that bias may be non-linear in some wavebands.Comment: 7 pages, 4 figures, submitted to ApJ Letters, a version of the paper with full resolution figures can be found here http://daisy.astro.umass.edu/~ari

QTL analysis for growth and wood properties across multiple pedigrees and sites in Eucalyptus globulus

Eucalyptus globulus is the most widely planted species for pulpwood production in temperate regions of the world and there are breeding programs in numerous countries. There is interest in molecular approaches to breeding, particularly marker assisted selection of wood properties. QTL analysis has an important role in identifying positional candidate genes responsible for variation in wood properties. This is one approach to targeting genes which may harbour functional allelic variants (SNPs). The objective of this study was to detect and validate QTL across multiple sites and pedigrees, in order to identify genomic regions and genes affecting growth and wood properties with wide applicability in the species. We also aimed to determine the proportion of QTL which were stable in their expression across sites of contrasting productivity. Such information will be important to exploit the full potential of the impending Eucalyptus genome sequences. [Oral Presentation

Defending Our Public Biological Databases as a Global Critical Infrastructure

Progress in modern biology is being driven, in part, by the large amounts of freely available data in public resources such as the International Nucleotide Sequence Database Collaboration (INSDC), the world's primary database of biological sequence (and related) information. INSDC and similar databases have dramatically increased the pace of fundamental biological discovery and enabled a host of innovative therapeutic, diagnostic, and forensic applications. However, as high-value, openly shared resources with a high degree of assumed trust, these repositories share compelling similarities to the early days of the Internet. Consequently, as public biological databases continue to increase in size and importance, we expect that they will face the same threats as undefended cyberspace. There is a unique opportunity, before a significant breach and loss of trust occurs, to ensure they evolve with quality and security as a design philosophy rather than costly “retrofitted” mitigations. This Perspective surveys some potential quality assurance and security weaknesses in existing open genomic and proteomic repositories, describes methods to mitigate the likelihood of both intentional and unintentional errors, and offers recommendations for risk mitigation based on lessons learned from cybersecurity

Duloxetine in the treatment of major depressive disorder: an open-label study

<p>Abstract</p> <p>Background</p> <p>Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined.</p> <p>Methods</p> <p>Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD₁₇total score, HAMD₁₇subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale.</p> <p>Results</p> <p>The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD₁₇, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment.</p> <p>Conclusion</p> <p>In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.</p> <p>Trial registration</p> <p>NCT00036309.</p

Consistency of high-fidelity two-qubit operations in silicon

The consistency of entangling operations between qubits is essential for the performance of multi-qubit systems, and is a crucial factor in achieving fault-tolerant quantum processors. Solid-state platforms are particularly exposed to inconsistency due to the materials-induced variability of performance between qubits and the instability of gate fidelities over time. Here we quantify this consistency for spin qubits, tying it to its physical origins, while demonstrating sustained and repeatable operation of two-qubit gates with fidelities above 99% in the technologically important silicon metal-oxide-semiconductor (SiMOS) quantum dot platform. We undertake a detailed study of the stability of these operations by analysing errors and fidelities in multiple devices through numerous trials and extended periods of operation. Adopting three different characterisation methods, we measure entangling gate fidelities ranging from 96.8% to 99.8%. Our analysis tools also identify physical causes of qubit degradation and offer ways to maintain performance within tolerance. Furthermore, we investigate the impact of qubit design, feedback systems, and robust gates on implementing scalable, high-fidelity control strategies. These results highlight both the capabilities and challenges for the scaling up of spin-based qubits into full-scale quantum processors

Selection for Higher Gene Copy Number after Different Types of Plant Gene Duplications

The evolutionary origins of the multitude of duplicate genes in the plant genomes are still incompletely understood. To gain an appreciation of the potential selective forces acting on these duplicates, we phylogenetically inferred the set of metabolic gene families from 10 flowering plant (angiosperm) genomes. We then compared the metabolic fluxes for these families, predicted using the Arabidopsis thaliana and Sorghum bicolor metabolic networks, with the families' duplication propensities. For duplications produced by both small scale (small-scale duplications) and genome duplication (whole-genome duplications), there is a significant association between the flux and the tendency to duplicate. Following this global analysis, we made a more fine-scale study of the selective constraints observed on plant sodium and phosphate transporters. We find that the different duplication mechanisms give rise to differing selective constraints. However, the exact nature of this pattern varies between the gene families, and we argue that the duplication mechanism alone does not define a duplicated gene's subsequent evolutionary trajectory. Collectively, our results argue for the interplay of history, function, and selection in shaping the duplicate gene evolution in plants

Evidence for Limited Genetic Compartmentalization of HIV-1 between Lung and Blood

BACKGROUND:HIV-1 is frequently detected in the lungs of infected individuals and is likely important in the development of pulmonary opportunistic infections. The unique environment of the lung, rich in alveolar macrophages and with specialized local immune responses, may contribute to differential evolution or selection of HIV-1. METHODOLOGY AND FINDINGS:We characterized HIV-1 in the lung in relation to contemporaneous viral populations in the blood. The C2-V5 region of HIV-1 env was sequenced from paired lung (induced sputum or bronchoalveolar lavage) and blood (plasma RNA and proviral DNA from sorted or unsorted PBMC) from 18 subjects. Compartmentalization between tissue pairs was assessed using 5 established tree or distance-based methods, including permutation tests to determine statistical significance. We found statistical evidence of compartmentalization between lung and blood in 10/18 subjects, although lung and blood sequences were intermingled on phylogenetic trees in all subjects. The subject showing the greatest compartmentalization contained many nearly identical sequences in BAL sample, suggesting clonal expansion may contribute to reduced viral diversity in the lung in some cases. However, HIV-1 sequences in lung were not more homogeneous overall, nor were we able to find a lung-specific genotype associated with macrophage tropism in V3. In all four subjects in whom predicted X4 genotypes were found in blood, predicted X4 genotypes were also found in lung. CONCLUSIONS:Our results support a picture of continuous migration of HIV-1 between circulating blood and lung tissue, with perhaps a very limited degree of localized evolution or clonal replication