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      The importance of the whole: Topological data analysis for the network neuroscientist

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          Abstract

          Data analysis techniques from network science have fundamentally improved our understanding of neural systems and the complex behaviors that they support. Yet the restriction of network techniques to the study of pairwise interactions prevents us from taking into account intrinsic topological features such as cavities that may be crucial for system function. To detect and quantify these topological features, we must turn to algebro-topological methods that encode data as a simplicial complex built from sets of interacting nodes called simplices. We then use the relations between simplices to expose cavities within the complex, thereby summarizing its topological features. Here we provide an introduction to persistent homology, a fundamental method from applied topology that builds a global descriptor of system structure by chronicling the evolution of cavities as we move through a combinatorial object such as a weighted network. We detail the mathematics and perform demonstrative calculations on the mouse structural connectome, synapses in C. elegans, and genomic interaction data. Finally, we suggest avenues for future work and highlight new advances in mathematics ready for use in neural systems.

          Author Summary

          For the network neuroscientist, this exposition aims to communicate both the mathematics and the advantages of using tools from applied topology for the study of neural systems. Using data from the mouse connectome, electrical and chemical synapses in C. elegans, and chromatin interaction data, we offer example computations and applications to further demonstrate the power of topological data analysis in neuroscience. Finally, we expose the reader to novel developments in applied topology and relate these developments to current questions and methodological difficulties in network neuroscience.

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          Most cited references49

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          A mesoscale connectome of the mouse brain.

          Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
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            Hi-C: A Method to Study the Three-dimensional Architecture of Genomes.

            The three-dimensional folding of chromosomes compartmentalizes the genome and and can bring distant functional elements, such as promoters and enhancers, into close spatial proximity 2-6. Deciphering the relationship between chromosome organization and genome activity will aid in understanding genomic processes, like transcription and replication. However, little is known about how chromosomes fold. Microscopy is unable to distinguish large numbers of loci simultaneously or at high resolution. To date, the detection of chromosomal interactions using chromosome conformation capture (3C) and its subsequent adaptations required the choice of a set of target loci, making genome-wide studies impossible 7-10. We developed Hi-C, an extension of 3C that is capable of identifying long range interactions in an unbiased, genome-wide fashion. In Hi-C, cells are fixed with formaldehyde, causing interacting loci to be bound to one another by means of covalent DNA-protein cross-links. When the DNA is subsequently fragmented with a restriction enzyme, these loci remain linked. A biotinylated residue is incorporated as the 5' overhangs are filled in. Next, blunt-end ligation is performed under dilute conditions that favor ligation events between cross-linked DNA fragments. This results in a genome-wide library of ligation products, corresponding to pairs of fragments that were originally in close proximity to each other in the nucleus. Each ligation product is marked with biotin at the site of the junction. The library is sheared, and the junctions are pulled-down with streptavidin beads. The purified junctions can subsequently be analyzed using a high-throughput sequencer, resulting in a catalog of interacting fragments. Direct analysis of the resulting contact matrix reveals numerous features of genomic organization, such as the presence of chromosome territories and the preferential association of small gene-rich chromosomes. Correlation analysis can be applied to the contact matrix, demonstrating that the human genome is segregated into two compartments: a less densely packed compartment containing open, accessible, and active chromatin and a more dense compartment containing closed, inaccessible, and inactive chromatin regions. Finally, ensemble analysis of the contact matrix, coupled with theoretical derivations and computational simulations, revealed that at the megabase scale Hi-C reveals features consistent with a fractal globule conformation.
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              8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC.

              The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.
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                Author and article information

                Contributors
                Journal
                Netw Neurosci
                Netw Neurosci
                netn
                Network Neuroscience
                MIT Press (One Rogers Street, Cambridge, MA 02142-1209USAjournals-info@mit.edu )
                2472-1751
                2019
                2019
                : 3
                : 3 , Focus Feature: Topological Neuroscience
                : 656-673
                Affiliations
                [1]Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, USA
                [2]Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, USA
                [3]Department of Mathematics, College of Arts and Sciences, University of Pennsylvania, Philadelphia, USA
                [4]Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, USA
                [5]Department of Physics & Astronomy, College of Arts and Sciences, University of Pennsylvania, Philadelphia, USA
                [6]Department of Electrical & Systems Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, USA
                [7]Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                * Corresponding Author: dsb@ 123456seas.upenn.edu

                Handling Editor: Giovanni Petri

                Author information
                https://orcid.org/0000-0003-1031-5535
                https://orcid.org/0000-0002-6183-4493
                Article
                netn_a_00073
                10.1162/netn_a_00073
                6663305
                31410372
                42c015f5-b72f-43c1-b13b-87b8588bccbb
                © 2018 Massachusetts Institute of Technology

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. For a full description of the license, please visit https://creativecommons.org/licenses/by/4.0/legalcode.

                History
                : 21 June 2018
                : 17 October 2018
                Page count
                Figures: 6, Equations: 1, References: 75, Pages: 18
                Funding
                Funded by: John D. and Catherine T. MacArthur Foundation (US);
                Funded by: Alfred P. Sloan Foundation, FundRef http://dx.doi.org/10.13039/100000879;
                Funded by: Paul G. Allen Family Foundation (US);
                Funded by: Army Research Laboratory (US);
                Award ID: W911NF-10-2-0022
                Funded by: Army Research Office (US);
                Award ID: Bassett-W911NF-14-1-0679, Grafton-W911NF-16-1-0474, DCIST-W911NF-17-2-0181
                Funded by: Office of Naval Research, FundRef http://dx.doi.org/10.13039/100000006;
                Funded by: National Institute of Mental Health, FundRef http://dx.doi.org/10.13039/100000025;
                Award ID: 2-R01-DC-009209-11, R01 – MH112847, R01-MH107235, R21-M MH-106799
                Funded by: National Institute of Child Health and Human Development, FundRef http://dx.doi.org/10.13039/100000071;
                Award ID: 1R01HD086888-01
                Funded by: National Institute of Neurological Disorders and Stroke, FundRef http://dx.doi.org/10.13039/100000065;
                Award ID: R01 NS099348
                Funded by: National Science Foundation, FundRef http://dx.doi.org/10.13039/100000001;
                Award ID: BCS-1441502, BCS-1430087, NSF PHY-1554488 and BCS-1631550
                Funded by: ISI Foundation;
                Funded by: National Science Foundation and National Institute of General Medical Sciences;
                Award ID: 1562665
                Funded by: Office of Naval Research, FundRef http://dx.doi.org/10.13039/100000006;
                Award ID: N00014-16-1-2010
                Categories
                Research Articles
                Custom metadata
                Sizemore, A. E., Phillips-Cremins, J. E., Ghrist, R., & Bassett, D. S. (2019). The importance of the whole: Topological data analysis for the network neuroscientist. Network Neuroscience, 3(3), 656–673. https://doi.org/10.1162/netn_a_00073

                topological data analysis,applied topology,persistent homology

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