title: Validation and genotyping of multiple human polymorphic inversions mediated by inverted repeats reveals a high degree of recurrence.
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.
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguado
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gayà-Vidal
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Villatoro
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Oliva
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: David
authors.initials: D
authors.lastname: Izquierdo
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Giner-Delgado
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Montalvo
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: García-González
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Alexander
authors.initials: A
authors.lastname: Martínez-Fundichely
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Capilla
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain; Departament de Biologia Celular, Fisiologia i Immunologia. Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Ruiz-Herrera
authors.affiliation: Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Puig
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Cáceres
mesh_terms: D000818:Animals; D007446:Chromosome Inversion / Q000235:genetics*; D002874:Chromosome Mapping; D019143:Evolution, Molecular; D015894:Genome, Human; D060148:HapMap Project; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics*; D002679:Pan troglodytes / Q000235:genetics; D011110:Polymorphism, Genetic; D056916:Segmental Duplications, Genomic / Q000235:genetics*