Retroviral Integration Process in the Human Genome: Is It Really Non-Random? A New Statistical Approach
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{"title"=>"Retroviral integration process in the human genome: Is it really non-random? A new statistical approach", "type"=>"journal", "authors"=>[{"first_name"=>"Alessandro", "last_name"=>"Ambrosi", "scopus_author_id"=>"6701652173"}, {"first_name"=>"Claudia", "last_name"=>"Cattoglio", "scopus_author_id"=>"19638370400"}, {"first_name"=>"Clelia", "last_name"=>"Di Serio", "scopus_author_id"=>"18433571700"}], "year"=>2008, "source"=>"PLoS Computational Biology", "identifiers"=>{"issn"=>"1553734X", "pui"=>"352273831", "sgr"=>"50949111193", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "scopus"=>"2-s2.0-50949111193", "pmid"=>"18688267", "doi"=>"10.1371/journal.pcbi.1000144"}, "id"=>"79ef81cd-3fd8-30e3-a2ed-7d6d69869c34", "abstract"=>"Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' cells, since, once delivered to the nucleus, the genes of interest are stably inserted (integrated) into the target cell genome. There is now compelling evidence that integration of retroviral vectors follows non-random patterns in mammalian genome, with a preference for active genes and regulatory regions. In particular, Moloney Leukemia Virus (MLV)-derived vectors show a tendency to integrate in the proximity of the transcription start site (TSS) of genes, occasionally resulting in the deregulation of gene expression and, where proto-oncogenes are targeted, in tumor initiation. This has drawn the attention of the scientific community to the molecular determinants of the retroviral integration process as well as to statistical methods to evaluate the genome-wide distribution of integration sites. In recent approaches, the observed distribution of MLV integration distances (IDs) from the TSS of the nearest gene is assumed to be non-random by empirical comparison with a random distribution generated by computational simulation procedures. To provide a statistical procedure to test the randomness of the retroviral insertion pattern, we propose a probability model (Beta distribution) based on IDs between two consecutive genes. We apply the procedure to a set of 595 unique MLV insertion sites retrieved from human hematopoietic stem/progenitor cells. The statistical goodness of fit test shows the suitability of this distribution to the observed data. Our statistical analysis confirms the preference of MLV-based vectors to integrate in promoter-proximal regions.", "link"=>"http://www.mendeley.com/research/retroviral-integration-process-human-genome-it-really-nonrandom-new-statistical-approach", "reader_count"=>28, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>4, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>4, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Mathematics"=>1, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>4, "Physics and Astronomy"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Finland"=>1, "Brazil"=>1, "Italy"=>2, "Russia"=>1, "Spain"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/924122"], "description"=>"<p>Notice that in this particular case the transcription start site (TSS) of the nearest gene coincides with the nearest downstream (3′) TSS.</p>", "links"=>[], "tags"=>["mapped", "chromosome", "insertion"], "article_id"=>594573, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Example_of_integration_distance_calculation_for_one_integration_site_mapped_on_Chromosome_4_CB_RV51_insertion_site_in_20_dataset_/594573", "title"=>"Example of integration distance calculation for one integration site mapped on Chromosome 4 (CB-RV51 insertion site in [20] dataset).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:16:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/924714"], "description"=>"<p>Method of Moments and Maximum Likelihood <i>p</i> and <i>q</i> estimates (MME and MLE, respectively).</p>", "links"=>[], "tags"=>["moments", "estimates"], "article_id"=>595166, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.t001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Method_of_Moments_and_Maximum_Likelihood_p_and_q_estimates_MME_and_MLE_respectively_/595166", "title"=>"Method of Moments and Maximum Likelihood <i>p</i> and <i>q</i> estimates (MME and MLE, respectively).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-08-08 01:26:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/924271"], "description"=>"<p>In this picture, six hypothetical genes with different length and orientation (blue arrows) are scattered along a chromosome (x-axis). The purple piecewise linear function represents the distance from the TSS of the nearest gene. This function has discontinuities exactly in the middle of the intervals between two consecutive genes. Even assuming a series of random integrations in this setting, we obtain a distribution of distances from TSSs (projected on the y-axis, gray plot) which is a mixture of Uniform distributions. As a consequence, the bell-shape curve is observed. Notice that the ID distribution is asymmetric around zero, since gene orientations and gene lengths determine which is the TSS to be considered in computing the distances (a symmetric distribution would be observed plotting the distance from the nearest TSS instead of the nearest gene TSS, data not shown).</p>", "links"=>[], "tags"=>["nearest", "transcription"], "article_id"=>594727, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g004", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Integration_distance_ID_from_the_nearest_gene_transcription_start_site_TSS_/594727", "title"=>"Integration distance (ID) from the nearest gene transcription start site (TSS).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:18:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/924342"], "description"=>"<p>Solid black line represents the case of Uniform distribution (<i>p</i> = <i>q</i> = 1). Other curves are all consistent with the alternative hypothesis in <i>H</i><sub>1</sub>: <i>p</i>≠1 or <i>q</i>≠1.</p>", "links"=>[], "tags"=>["probability", "functions", "parameter"], "article_id"=>594792, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g005", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Beta_probability_distribution_functions_for_different_parameter_combinations_/594792", "title"=>"Beta probability distribution functions for different parameter combinations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:19:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/455947"], "description"=>"<div><p>Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' cells, since, once delivered to the nucleus, the genes of interest are stably inserted (integrated) into the target cell genome. There is now compelling evidence that integration of retroviral vectors follows non-random patterns in mammalian genome, with a preference for active genes and regulatory regions. In particular, Moloney Leukemia Virus (MLV)–derived vectors show a tendency to integrate in the proximity of the transcription start site (TSS) of genes, occasionally resulting in the deregulation of gene expression and, where proto-oncogenes are targeted, in tumor initiation. This has drawn the attention of the scientific community to the molecular determinants of the retroviral integration process as well as to statistical methods to evaluate the genome-wide distribution of integration sites. In recent approaches, the observed distribution of MLV integration distances (IDs) from the TSS of the nearest gene is assumed to be non-random by empirical comparison with a random distribution generated by computational simulation procedures. To provide a statistical procedure to test the randomness of the retroviral insertion pattern, we propose a probability model (Beta distribution) based on IDs between two consecutive genes. We apply the procedure to a set of 595 unique MLV insertion sites retrieved from human hematopoietic stem/progenitor cells. The statistical goodness of fit test shows the suitability of this distribution to the observed data. Our statistical analysis confirms the preference of MLV-based vectors to integrate in promoter-proximal regions.</p></div>", "links"=>[], "tags"=>["retroviral"], "article_id"=>149813, "categories"=>["Genetics", "Cancer"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Retroviral_Integration_Process_in_the_Human_Genome_Is_It_Really_Non_Random_A_New_Statistical_Approach/149813", "title"=>"Retroviral Integration Process in the Human Genome: Is It Really Non-Random? A New Statistical Approach", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-08-08 02:43:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/924628"], "description"=>"<p>Goodness of fit was assessed by Kolmogorov Smirnov test (MME <i>p-value</i> = 0.909, MLE <i>p-value</i> = 0.8012).</p>", "links"=>[], "tags"=>["observed", "fitted", "distributions", "moments", "estimators", "dashed"], "article_id"=>595079, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_between_the_observed_Y_distribution_and_the_fitted_distributions_of_Method_of_Moments_Estimators_MMEs_red_dashed_line_and_Maximum_Likelihood_Estimators_MLEs_blue_dashed_line_/595079", "title"=>"Comparison between the observed <i>Y</i><sup>*</sup> distribution and the fitted distributions of Method of Moments Estimators (MMEs, red dashed line) and Maximum Likelihood Estimators (MLEs, blue dashed line).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:24:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/924196"], "description"=>"<p>The solid line is the kernel density estimate plotted within a ±30 kb window for a better graphical visualization of the ”bell-shape” curve.</p>", "links"=>[], "tags"=>["distances", "transcription", "nearest", "randomly", "generated"], "article_id"=>594649, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_1_250_000_integration_distances_kb_from_the_transcription_start_site_TSS_of_the_nearest_gene_Y_randomly_generated_from_a_Uniform_distribution_/594649", "title"=>"Distribution of 1,250,000 integration distances (kb) from the transcription start site (TSS) of the nearest gene (<i>Y</i>) randomly generated from a Uniform distribution.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:17:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/924040"], "description"=>"<p>The empirical comparison between simulated (dotted line) and observed distribution leads the authors to conclude in favour of non-randomness of retroviral integration.</p>", "links"=>[], "tags"=>["moloney", "leukemia", "simian", "immunodeficiency", "sites", "centered", "transcription", "nearest"], "article_id"=>594487, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_Moloney_Leukemia_Virus_MLV_and_Simian_Immunodeficiency_Virus_SIV_integration_sites_centered_on_transcription_start_sites_of_the_nearest_gene_/594487", "title"=>"Distribution of Moloney Leukemia Virus (MLV) and Simian Immunodeficiency Virus (SIV) integration sites centered on transcription start sites of the nearest gene.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:14:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/924510"], "description"=>"<p>Loglikelihood function related to the distribution of <i>Y</i><sup>*</sup> observed in human hematopoietic/stem progenitor cells showing the Maximum Likelihood Estimator (MLE) for the parameters <i>p</i> and <i>q</i>.</p>", "links"=>[], "tags"=>["observed", "progenitor", "cells", "estimator"], "article_id"=>594962, "categories"=>["Genetics", "Infectious Diseases"], "users"=>["Alessandro Ambrosi", "Claudia Cattoglio", "Clelia Di Serio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000144.g006", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Loglikelihood_function_related_to_the_distribution_of_Y_observed_in_human_hematopoietic_stem_progenitor_cells_showing_the_Maximum_Likelihood_Estimator_MLE_for_the_parameters_p_and_q_/594962", "title"=>"Loglikelihood function related to the distribution of <i>Y</i><sup>*</sup> observed in human hematopoietic/stem progenitor cells showing the Maximum Likelihood Estimator (MLE) for the parameters <i>p</i> and <i>q</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-08-08 01:22:42"}

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