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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,6]]},"abstract":"<jats:p>\n                    Recombination of antibody genes in B cells can involve distant genomic loci and contribute a foreign antigen-binding element to form hybrid antibodies with broad reactivity for\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    . So far, antibodies containing the extracellular domain of the LAIR1 and LILRB1 receptors represent unique examples of cross-chromosomal antibody diversification. Here, we devise a technique to profile non-VDJ elements from distant genes in antibody transcripts. Independent of the preexposure of donors to malaria parasites, non-VDJ inserts were detected in 80% of individuals at frequencies of 1 in 10\n                    <jats:sup>4<\/jats:sup>\n                    to 10\n                    <jats:sup>5<\/jats:sup>\n                    B cells. We detected insertions in heavy, but not in light chain or T cell receptor transcripts. We classify the insertions into four types depending on the insert origin and destination: 1) mitochondrial and 2) nuclear DNA inserts integrated at VDJ junctions; 3) inserts originating from telomere proximal genes; and 4) fragile sites incorporated between J-to-constant junctions. The latter class of inserts was exclusively found in memory and in in\u00a0vitro activated B cells, while all other classes were already detected in na\u00efve B cells. More than 10% of inserts preserved the reading frame, including transcripts with signs of antigen-driven affinity maturation. Collectively, our study unravels a mechanism of antibody diversification that is layered on the classical V(D)J and switch recombination.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2205470119","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T15:13:40Z","timestamp":1661786020000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":18,"title":["Different classes of genomic inserts contribute to human antibody diversity"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3877-7195","authenticated-orcid":false,"given":"Mikhail","family":"Lebedin","sequence":"first","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"Department of Genomics of Adaptive Immunity, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russian Federation"},{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Foglierini","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera Italiana, Via Francesco Chiesa 5, 6500 Bellinzona, Switzerland"},{"name":"Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7873-2290","authenticated-orcid":false,"given":"Svetlana","family":"Khorkova","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"Department of Genomics of Adaptive Immunity, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russian Federation"},{"name":"Department of Molecular Technologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-7616","authenticated-orcid":false,"given":"Clara","family":"V\u00e1zquez Garc\u00eda","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5413-0730","authenticated-orcid":false,"given":"Christoph","family":"Ratswohl","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"Department of Biology, Chemistry and Pharmacy, Free University of Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey N.","family":"Davydov","sequence":"additional","affiliation":[{"name":"Central European Institute of Technology, Masaryk University, 601 77 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8874-0286","authenticated-orcid":false,"given":"Maria A.","family":"Turchaninova","sequence":"additional","affiliation":[{"name":"Department of Genomics of Adaptive Immunity, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russian Federation"},{"name":"Department of Molecular Technologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-0642","authenticated-orcid":false,"given":"Claudia","family":"Daubenberger","sequence":"additional","affiliation":[{"name":"Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, 4123 Allschwil, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0430-790X","authenticated-orcid":false,"given":"Dmitriy M.","family":"Chudakov","sequence":"additional","affiliation":[{"name":"Department of Genomics of Adaptive Immunity, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russian Federation"},{"name":"Department of Molecular Technologies, Pirogov Russian National Research Medical University, 117997 Moscow, Russian Federation"},{"name":"Central European Institute of Technology, Masaryk University, 601 77 Brno, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Lanzavecchia","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine, Universit\u00e0 della Svizzera Italiana, Via Francesco Chiesa 5, 6500 Bellinzona, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4809-3157","authenticated-orcid":false,"given":"Kathrin","family":"de la Rosa","sequence":"additional","affiliation":[{"name":"Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany"},{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,8,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115830"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1896"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00078-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16450"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23670"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03378-6"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.4049\/jimmunol.155.4.1911","article-title":"The Ig heavy chain switch region is a hotspot for insertion of transfected DNA","volume":"155","author":"Baar J.","year":"1995","unstructured":"J. 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Lazar I. Zwecker-Lazar R. Lazar Gel Analyzer 2010a: Freeware 1D gel electrophoresis image analysis software (2010). https:\/\/www.scienceopen.com\/document?vid=416d30b4-53d9-4565-a37d-e9d8709afd93. 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Lebedin . Sequencing of non-VDJ insertions in human antibody transcripts. NCBI SRA. https:\/\/www.ncbi.nlm.nih.gov\/sra\/?term=PRJNA638005. Accessed 22 August 2022."},{"key":"e_1_3_4_82_2","doi-asserted-by":"crossref","unstructured":"M. Foglierini Perez vdjinsertIllumina Pipeline and scripts to process PCR suppression products to find insert into V(D)J transcripts. Bitbucket. https:\/\/bitbucket.org\/mathildefog\/vdjinsertillumina\/src\/master\/. Deposited 16 June 2020.","DOI":"10.1371\/journal.pcbi.1007731"},{"key":"e_1_3_4_83_2","unstructured":"M. Foglierini Perez LAIR1vdjinsertIllumina \u00a0In-depth analysis of insert-containing antibody transcripts after running vdjinsertIllumina pipeline. Bitbucket. https:\/\/bitbucket.org\/mathildefog\/lair1vdjinsertillumina\/src\/master\/. 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