Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrence

Aguado, Cristina; Gayà Vidal, Magdalena; Villatoro, Sergi; Oliva, Meritxell; Izquierdo, David; Giner Delgado, Carla; Montalvo, Víctor; García González, Judit; Martínez Fundichely, Alexander, 1978-; Capilla, Laia; Ruiz Herrera, Aurora; Estivill, Xavier, 1955-; Puig, Marta; Cáceres Aguilar, Mario

Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrence

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dc.contributor.author Aguado, Cristinaca
dc.contributor.author Gayà Vidal, Magdalenaca
dc.contributor.author Villatoro, Sergica
dc.contributor.author Oliva, Meritxellca
dc.contributor.author Izquierdo, Davidca
dc.contributor.author Giner Delgado, Carlaca
dc.contributor.author Montalvo, Víctorca
dc.contributor.author García González, Juditca
dc.contributor.author Martínez Fundichely, Alexander, 1978-ca
dc.contributor.author Capilla, Laiaca
dc.contributor.author Ruiz Herrera, Auroraca
dc.contributor.author Estivill, Xavier, 1955-ca
dc.contributor.author Puig, Martaca
dc.contributor.author Cáceres Aguilar, Marioca
dc.date.accessioned 2016-06-13T14:12:01Z
dc.date.available 2016-06-13T14:12:01Z
dc.date.issued 2014
dc.description.abstract In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6-24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ∼ 12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.ca
dc.description.sponsorship This work was supported by the European Research Council (ERC) Starting Grant 243212 (INVFEST) under the European Union Seventh Research Framework Programme (FP7) to MC, a FPI PhD fellowship from the Ministerio de Educación y Ciencia (Spain) to MO, a PIF PhD fellowship from the Universitat Autònoma de Barcelona (Spain) to CGD, a MAEC-AECI PhD fellowship from the Ministerio de Asuntos Exteriores y Cooperación (Spain) to AMF, and a research PRIC grant from the Barcelona Zoo (Ajuntament de Barcelona, Spain) to ARH.
dc.format.mimetype application/pdfca
dc.identifier.citation Aguado C, Gayà-Vidal M, Villatoro S, Oliva M, Izquierdo D, Giner-Delgado C et al. Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrence. PLoS Genetics. 2014;10(3):e1004208. DOI: 10.1371/journal.pgen.1004208ca
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1004208
dc.identifier.issn 1553-7390
dc.identifier.uri http://hdl.handle.net/10230/26912
dc.language.iso engca
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLoS Genetics. 2014;10(3):e1004208
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/243212
dc.rights © 2014 Aguado et al. 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 author and source are credited.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
dc.subject.other Ximpanzés -- Genèticaca
dc.subject.other Genètica humanaca
dc.title Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrenceca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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