Copy Number Variation of CCL3-like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (Macaca mulatta)
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{"title"=>"Copy number variation of CCL3-like genes affects rate of progression to simian-AIDS in rhesus macaques (Macaca mulatta)", "type"=>"journal", "authors"=>[{"first_name"=>"Jeremiah D.", "last_name"=>"Degenhardt", "scopus_author_id"=>"16238251700"}, {"first_name"=>"Paola", "last_name"=>"De Candia", "scopus_author_id"=>"57193009130"}, {"first_name"=>"Adrien", "last_name"=>"Chabot", "scopus_author_id"=>"16836022300"}, {"first_name"=>"Stuart", "last_name"=>"Schwartz", "scopus_author_id"=>"7403605019"}, {"first_name"=>"Les", "last_name"=>"Henderson", "scopus_author_id"=>"26025619400"}, {"first_name"=>"Binhua", "last_name"=>"Ling", "scopus_author_id"=>"7101795175"}, {"first_name"=>"Meredith", "last_name"=>"Hunter", "scopus_author_id"=>"7202148690"}, {"first_name"=>"Zhaoshi", "last_name"=>"Jiang", "scopus_author_id"=>"7404280187"}, {"first_name"=>"Robert E.", "last_name"=>"Palermo", "scopus_author_id"=>"35389457800"}, {"first_name"=>"Michael", "last_name"=>"Katze", "scopus_author_id"=>"7006672394"}, {"first_name"=>"Evan E.", "last_name"=>"Eichler", "scopus_author_id"=>"7005436796"}, {"first_name"=>"Mario", "last_name"=>"Ventura", "scopus_author_id"=>"7201763128"}, {"first_name"=>"Jeffrey", "last_name"=>"Rogers", "scopus_author_id"=>"7404268692"}, {"first_name"=>"Preston", "last_name"=>"Marx", "scopus_author_id"=>"7102894750"}, {"first_name"=>"Yoav", "last_name"=>"Gilad", "scopus_author_id"=>"6602166624"}, {"first_name"=>"Carlos D.", "last_name"=>"Bustamante", "scopus_author_id"=>"35228607000"}], "year"=>2009, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-59249106248", "isbn"=>"1553-7404 (Electronic)", "pmid"=>"19165326", "issn"=>"15537390", "sgr"=>"59249106248", "doi"=>"10.1371/journal.pgen.1000346", "pui"=>"354135270"}, "id"=>"6a111a34-b6bc-3caf-809a-c100217d020c", "abstract"=>"Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p<0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p<10(-6)) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se.", "link"=>"http://www.mendeley.com/research/copy-number-variation-ccl3like-genes-affects-rate-progression-simianaids-rhesus-macaques-macaca-mula", "reader_count"=>55, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>6, "Student > Doctoral Student"=>3, "Researcher"=>16, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>4, "Other"=>5, "Student > Bachelor"=>3, "Professor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>6, "Student > Doctoral Student"=>3, "Researcher"=>16, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>4, "Other"=>5, "Student > Bachelor"=>3, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>35, "Medicine and Dentistry"=>7, "Neuroscience"=>2, "Business, Management and Accounting"=>1, "Social Sciences"=>1, "Computer Science"=>2, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Neuroscience"=>{"Neuroscience"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Computer Science"=>{"Computer Science"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Austria"=>1, "United States"=>6, "United Kingdom"=>2, "France"=>2, "India"=>1}, "group_count"=>4}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/910937"], "description"=>"<p>“Variable” refers to a particular term in the regression model (i.e., CCL3L copy number, log of CCL3L copy number, or population of origin), “Data” refers to which subset of the data is considered (i.e., Combined = Indian-+Chinese-origin animals or Indian animals alone), and “Other factors in the model” refer to whether the regression coefficient is estimated alone or in the presence of other terms.</p>", "links"=>[], "tags"=>["coefficient", "estimates", "errors", "regression", "cox", "proportional", "models", "summarized"], "article_id"=>581366, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.t002", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Regression_coefficient_estimates_standard_errors_on_the_regression_coefficient_estimates_confidence_intervals_and_significance_for_terms_in_the_Cox_proportional_hazard_models_summarized_in_Table_1_/581366", "title"=>"Regression coefficient estimates (β), standard errors on the regression coefficient estimates, confidence intervals, and significance for terms in the Cox proportional hazard models summarized in Table 1.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-01-23 00:22:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/910744"], "description"=>"<p>(A) Scatter plot of post SIV infection survival time (or censor time if animal is alive) by <i>CCL3L</i> copy number. Blue dots represent Chinese-origin rhesus macaques while green dots represent Indian origin. Filled in dots represent animals still alive at time of sampling. Fitted regression curve, <i>p</i>-value and relative-hazard (RH) from Cox proportional hazard model (model 1 in text). (B,C) Boxplots of <i>CCL3L</i> copy-number defining “low” copy number to be fewer than or equal to 8 copies per diploid genome, “intermediate” to be 9 and 14, and “high” to be more than 14 copies or low vs. intermediate+high. D-I) Estimated Kaplan-Meier survival curve for SIV-infected macaques with time measured from date of infection. The black curve represents “low”, the red curve “intermediate” or “intermediate+high”, and the blue curve “high” copy number for KM curves based on all animals (D,E), Indian-origin only (F,G), and Chinese-origin only (H,I). The <i>p</i>-values correspond to Harrington-Fleming tests of equality for survivorship curve using <i>ρ</i> = 0 which is equivalent to a log-rank or Mantel-Haenszel test. Relative-hazard (RH) for equivalent Cox proportional hazard model are also presented.</p>", "links"=>[], "tags"=>["macaque"], "article_id"=>581189, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.g003", "stats"=>{"downloads"=>4, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rhesus_macaque_survival_analysis_/581189", "title"=>"Rhesus macaque survival analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-01-23 00:19:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/910840"], "description"=>"<p>(A) Histograms and boxplots of <i>CCL3L</i> copy number distribution among the <i>n</i> = 57 animals used in the retrospective study as well as for a sample SIV-free Indian-origin (<i>n</i> = 16) and Chinese-origin rhesus macaques (<i>n</i> = 15). Red and light-red bars indicate Indian origin for the SIV and SIV-free populations, and blue and light-blue bars indicate the analogous for Chinese-origin animals. B) Box plot of copy number variation for 6 primate species: Human, Chimpanzee (<i>Pan troglodytes</i>), Orangutan (<i>Pongo pygmaeus</i>), Rhesus macaque (<i>Macaca mulatta</i>), African green monkey (<i>Cercocebus aethiops</i>), and Sooty mangabey (<i>Chlorocebus atys</i>). Whiskers indicate the upper and lower quartile with dots showing outliers. Estimates of species divergence times are from reference <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000346#pgen.1000346-Steiper1\" target=\"_blank\">[37]</a>.</p>", "links"=>[], "tags"=>["genetics and genomics/medical genetics", "immunology/genetics of the immune system", "infectious diseases/hiv infection and aids", "pathology/immunology"], "article_id"=>581270, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Population_and_species_level_copy_number_variation_/581270", "title"=>"Population and species level copy number variation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-01-23 00:21:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/910659"], "description"=>"<p>Histogram of the rtPCR estimated copy number of <i>CCL3</i>-like genes for the 57 retrospective samples of rhesus macaque. The histogram shows a large range of copy numbers found in this sample with copy number estimates from 5 to 31 copies per diploid genome.</p>", "links"=>[], "tags"=>["genetics and genomics/medical genetics", "immunology/genetics of the immune system", "infectious diseases/hiv infection and aids", "pathology/immunology"], "article_id"=>581095, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.g002", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histogram_of_copy_number_estimates_/581095", "title"=>"Histogram of copy number estimates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-01-23 00:18:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/450015", "https://ndownloader.figshare.com/files/450044", "https://ndownloader.figshare.com/files/450086", "https://ndownloader.figshare.com/files/450136", "https://ndownloader.figshare.com/files/450221", "https://ndownloader.figshare.com/files/450273", "https://ndownloader.figshare.com/files/450311", "https://ndownloader.figshare.com/files/450369", "https://ndownloader.figshare.com/files/450418", "https://ndownloader.figshare.com/files/450454", "https://ndownloader.figshare.com/files/450510", "https://ndownloader.figshare.com/files/450568"], "description"=>"<div><p>Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at <em>CCL3</em>-like genes (<em>CCL3L</em>), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that <em>CCL3L</em> CNV explains approximately 18% of the variance in time to simian-AIDS (<em>p</em><0.001) with lower <em>CCL3L</em> copy number associating with more rapid disease course. We also find that <em>CCL3L</em> copy number varies significantly (<em>p</em><10<sup>−6</sup>) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many <em>CCL3L</em> gene copies as Chinese-origin macaques. Lastly, we confirm that <em>CCL3L</em> shows variable copy number in humans and chimpanzees and report on <em>CCL3L</em> CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by <em>CCL3L</em> copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) <em>CCL3L</em> CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se.</p></div>", "links"=>[], "tags"=>["genes", "affects", "progression", "simian-aids", "rhesus", "macaques"], "article_id"=>148681, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000346.s001", "https://dx.doi.org/10.1371/journal.pgen.1000346.s002", "https://dx.doi.org/10.1371/journal.pgen.1000346.s003", "https://dx.doi.org/10.1371/journal.pgen.1000346.s004", "https://dx.doi.org/10.1371/journal.pgen.1000346.s005", "https://dx.doi.org/10.1371/journal.pgen.1000346.s006", "https://dx.doi.org/10.1371/journal.pgen.1000346.s007", "https://dx.doi.org/10.1371/journal.pgen.1000346.s008", "https://dx.doi.org/10.1371/journal.pgen.1000346.s009", "https://dx.doi.org/10.1371/journal.pgen.1000346.s010", "https://dx.doi.org/10.1371/journal.pgen.1000346.s011", "https://dx.doi.org/10.1371/journal.pgen.1000346.s012"], "stats"=>{"downloads"=>8, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Copy_Number_Variation_of_CCL3_like_Genes_Affects_Rate_of_Progression_to_Simian_AIDS_in_Rhesus_Macaques_Macaca_mulatta_/148681", "title"=>"Copy Number Variation of <em>CCL3-</em>like Genes Affects Rate of Progression to Simian-AIDS in Rhesus Macaques (<em>Macaca mulatta</em>)", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-01-23 02:24:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/911002"], "description"=>"<p>The test statistics are asymptotically χ<sup>2</sup> distributed.</p>", "links"=>[], "tags"=>["variables", "contributing", "survivorship", "cox", "proportional"], "article_id"=>581435, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.t001", "stats"=>{"downloads"=>6, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Likelihood_ratio_test_statistics_for_analysis_of_multiple_variables_contributing_to_survivorship_based_on_Cox_proportional_hazard_model_/581435", "title"=>"Likelihood ratio test statistics for analysis of multiple variables contributing to survivorship based on Cox proportional hazard model.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-01-23 00:23:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/910549"], "description"=>"<p>(A) Metaphase FISH image of A431 cell line confirming diploid copy number of two <i>CCL3L1</i> genes (Note: Therefore using our assay we consider the A431 cell line to have a diploid copy number of four genes since it also contains two copies of <i>CCL3</i>). (B) Whole-genome shotgun read depth analysis showing estimation of <i>CCL3L</i> copy number in the rhesus macaque genome donor as 6 copies per diploid genome based on rheMac2 assembly. Green and orange lines denote shotgun reads aligned to <i>CCL3L</i> region of the January 2006 assembly of the rhesus macaque reference genome with orange lines showing those that likely represent regions of duplications based on the read-depth analysis (See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000346#s4\" target=\"_blank\">Methods</a>). (C) Interphase FISH image of the MMU2 9133 rhesus macaque cell line, which has an estimated diploid copy number of 10 copies of <i>CCL3L</i>. (D) Validation of rtPCR estimates of <i>CCL3L</i> copy number. Black dots represent rtPCR copy number estimates for the A431 human cell line, the rhesus genome donor, and MMU2 9133 rhesus cell line. Red dots represent an independent estimate of copy number for all three samples based on either FISH or WGS analysis. See supplemental material for additional information regarding the copy number estimation methods.</p>", "links"=>[], "tags"=>["verification", "rtpcr"], "article_id"=>580988, "categories"=>["Immunology", "Medicine", "Genetics"], "users"=>["Jeremiah D. Degenhardt", "Paola de Candia", "Adrien Chabot", "Stuart Schwartz", "Les Henderson", "Binhua Ling", "Meredith Hunter", "Zhaoshi Jiang", "Robert E. Palermo", "Michael Katze", "Evan E. Eichler", "Mario Ventura", "Jeffrey Rogers", "Preston Marx", "Yoav Gilad", "Carlos D. Bustamante"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000346.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Calibration_and_verification_of_rtPCR_copy_number_/580988", "title"=>"Calibration and verification of rtPCR copy number.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-01-23 00:16:28"}

PMC Usage Stats | Further Information

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