Genome-complexity in terms of gene amplification: intriguing issues from reference species

Gene duplication (GD) and alternative splicing (AS) have emerged as two major processes supporting the functional diversification of the genes. My research project is mainly focused on the genome-scale analysis of these two important and complex mechanisms. Using comparative approaches and bioinformatics strategies I focused on the analysis of intragenome duplications, specifically focusing on Transcription Factors gene families in Plants and Homo sapiens. In particular, to investigate on gene duplication in Plants, the A.thaliana genome was used as a reference. The Arabidopsis genome underwent ancient whole genome duplication events (WGDs), followed by gene reduction and diploidization [Blanc G. et al 2000; Vision TJ, et al 2000; Simillion C. et al 2002; Cui L. et al., 2006; reviewed in Van de Peer and Meyer, 2005]. However, what dramatically increases its complexity are the extended genome rearrangements (i.e. deletions, inversions, translocations), which relocated and split up the retained portions around the genome [Tang H. et al., 2008], together with probable chromosome reductions within the Brassicaceae [Conner, J.A., et al., 1998]. Under the classical model for the evolution the duplicated genes may go for loss of function, neofunctionalization and subfunctionalization. In the first case, one member of the duplicated pair usually degenerates by accumulating deleterious mutations, while the other copy retains the original function. In the case of neofunctionalization, one duplicate may acquire a new adaptive function and the result is the preservation of both members of the pair, one with presenting the new function and the other retaining the old one. Functional divergence can occur even by subfunctionalization, that is the two copies act with a complementary effect to accomplish the functionalities of the ancestral gene. Duplicated genes also may interact through inter-locus recombination, gene conversion, or concerted evolution. In particular, we designed a bioinformatics pipeline to detect duplicated and singleton genes, taking into account several issues related to the computational methods applied. The implemented pipeline can provide a reference as tool for the detection of paralogy relationships in other genomes. Moreover, set of genes sharing one or more paralogs were organized in networks made available to the scientific community for small and large scale analyses, while single copy genes were deeply investigated since their presence represents an intriguing aspect in a so highly duplicated genome. A web accessible database (available at http://biosrv.cab.unina.it/athparalogs/main/index) allows access to the network organization, and the relevance of this resource either for evolutionary investigation or gene family analyses is here presented. In addition, our analysis underlines the need of a more accurate annotation process for the Arabidopsis genome and stirs up intriguing evolutionary issues related to the presence of single copy genes in a highly duplicated genome. Since the release 10 of the Arabidopsis genome [The Arabidopsis Information Resource, 2010] was recently made public, we confirmed and briefly described the main results concerning the TAIR9 also for this newest version. Transcription factor gene families (TFs) were analyzed considering the collection of networks obtained from A. thaliana. Due to their key roles in gene regulation, TFs are among the best examples of dosage-sensitive genes. This work provides support to the classification of transcription factors in A.thaliana and represents a step forward to understand TF families organization and evolution. Transcription factors were also analyzed in terms of alternative splicing. To further investigate on the impact of alternative splicing on transcriptional regulation, a genome-wide study of alternative splicing of TFs was also considered in the human genome, providing insights into the dynamic usage of splice isoforms and their regulatory impact in different cell types

Quantitative expression profiling of highly degraded RNA from formalin-fixed, paraffin-embedded breast tumor biopsies by oligonucleotide microarrays

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Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors.

Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions. We identify genes that correlate in expression with intrinsic and extrinsic PEER factors and associate outlier cell behavior with genes containing rare deleterious non-synonymous SNVs. Our study, thus, establishes a strategy for examining the genetic basis of inter-individual variability in cell behavior

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Measurement of the top quark mass using events with a single reconstructed top quark in pp collisions at root s=13 TeV

Abstract:A measurement of the top quark mass is performed using a data sample en-riched with single top quark events produced in thetchannel. The study is based on proton-proton collision data, corresponding to an integrated luminosity of 35.9 fb−1, recorded at√s= 13TeV by the CMS experiment at the LHC in 2016. Candidate events are selectedby requiring an isolated high-momentum lepton (muon or electron) and exactly two jets,of which one is identified as originating from a bottom quark. Multivariate discriminantsare designed to separate the signal from the background. Optimized thresholds are placedon the discriminant outputs to obtain an event sample with high signal purity. The topquark mass is found to be172.13+0.76−0.77GeV, where the uncertainty includes both the sta-tistical and systematic components, reaching sub-GeV precision for the first time in thisevent topology. The masses of the top quark and antiquark are also determined separatelyusing the lepton charge in the final state, from which the mass ratio and difference aredetermined to be0.9952+0.0079−0.0104and0.83+1.79−1.35GeV, respectively. The results are consistentwithCPTinvariance