cyTRON and cyTRON/JS: two Cytoscape-based applications for the inference of cancer evolution models

The increasing availability of sequencing data of cancer samples is fueling the development of algorithmic strategies to investigate tumor heterogeneity and infer reliable models of cancer evolution. We here build up on previous works on cancer progression inference from genomic alteration data, to deliver two distinct Cytoscape-based applications, which allow to produce, visualize and manipulate cancer evolution models, also by interacting with public genomic and proteomics databases. In particular, we here introduce cyTRON, a stand-alone Cytoscape app, and cyTRON/JS, a web application which employs the functionalities of Cytoscape/JS. cyTRON was developed in Java; the code is available at https://github.com/BIMIB-DISCo/cyTRON and on the Cytoscape App Store http://apps.cytoscape.org/apps/cytron. cyTRON/JS was developed in JavaScript and R; the source code of the tool is available at https://github.com/BIMIB-DISCo/cyTRON-js and the tool is accessible from https://bimib.disco.unimib.it/cytronjs/welcome

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

The detection of dynamical organization in cancer evolution models

Many systems in nature, society and technology are composed of numerous interacting parts. Very often these dynamics lead to the formation of medium-level structures, whose detection could allow a high-level description of the dynamical organization of the system itself, and thus to its understanding. In this work we apply this idea to the “cancer evolution” models, of which each individual patient represents a particular instance. This approach - in this paper based on the RI methodology, which is based on entropic measures - allows us to identify distinct independent cancer progression patterns in simulated patients, planning a road towards applications to real cases

Rare and low-frequency coding variants alter human adult height

Pathophysiology, epidemiology and therapy of agein

Publisher Correction:Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (vol 50, pg 26, 2017)

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity (vol 50, pg 26, 2018)

A.P.R. was supported by R01DK089256. A.W.H. is supported by an NHMRC Practitioner Fellowship (APP1103329). A.K.M. received funding from NIH/NIDDK K01DK107836. A.T.H. is a Wellcome Trust Senior Investigator (WT098395) and an NIH Research Senior Investigator. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (WT098017). A.R.W. is supported by the European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). A.U.J. is supported by the American Heart Association (13POST16500011) and the NIH (R01DK089256, R01DK101855, K99HL130580). B.K. and E.K.S. were supported by the Doris Duke Medical Foundation, the NIH (R01DK106621), the University of Michigan Internal Medicine Department, Division of Gastroenterology, the University of Michigan Biological Sciences Scholars Program and the Central Society for Clinical Research. C.J.W. is supported by the NIH (HL094535, HL109946). D.J.L. is supported by R01HG008983 and R21DA040177. D.R.W. is supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. V. Salomaa has been supported by the Finnish Foundation for Cardiovascular Research. F.W.A. is supported by Dekker scholarship–Junior Staff Member 2014T001 Netherlands Heart Foundation and the UCL Hospitals NIHR Biomedical Research Centre. F.D. is supported by the UK MRC (MC_UU_12013/1-9). G.C.-P. received scholarship support from the University of Queensland and QIMR Berghofer. G.L. is funded by the Montreal Heart Institute Foundation and the Canada Research Chair program. H.Y. and T.M.F. are supported by the European Research Council (323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). I.M.H. is supported by BMBF (01ER1206) and BMBF (01ER1507m), the NIH and the Max Planck Society. J. Haessler was supported by NHLBI R21HL121422. J.N.H. is supported by NIH R01DK075787. K.E.N. was supported by the NIH (R01DK089256, R01HD057194, U01HG007416, R01DK101855) and the American Heart Association (13GRNT16490017). M.A.R. is supported by the Nuffield Department of Clinical Medicine Award, Clarendon Scholarship. M.I.M. is a Wellcome Trust Senior Investigator (WT098381) and an NIH Research Senior Investigator. M.D. is supported by the NCI (R25CA94880, P30CA008748). P.R.N. is supported by the European Research Council (AdG; 293574), the Research Council of Norway, the University of Bergen, the KG Jebsen Foundation and the Helse Vest, Norwegian Diabetes Association. P.T.E. is supported by the NIH (1R01HL092577, R01HL128914, K24HL105780), by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). P.L.A. was supported by NHLBI R21HL121422 and R01DK089256. P.L.H. is supported by the NIH (NS33335, HL57818). R.S.F. is supported by the NIH (T32GM096911). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). S.A.L. is supported by the NIH (K23HL114724) and a Doris Duke Charitable Foundation Clinical Scientist Development Award. T.D.S. holds an ERC Advanced Principal Investigator award. T.A.M. is supported by an NHMRC Fellowship (APP1042255). T.H.P. received Lundbeck Foundation and Benzon Foundation support. V.T. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). Z.K. is supported by the Leenaards Foundation, the Swiss National Science Foundation (31003A-143914) and SystemsX.ch (51RTP0_151019). Part of this work was conducted using the UK Biobank resource (project numbers 1251 and 9072)