title: Detailed analysis of inversions predicted between two human genomes: errors, real polymorphisms, and their origin and population distribution.
abstract: The growing catalogue of structural variants in humans often overlooks inversions as one of the most difficult types of variation to study, even though they affect phenotypic traits in diverse organisms. Here, we have analysed in detail 90 inversions predicted from the comparison of two independently assembled human genomes: the reference genome (NCBI36/HG18) and HuRef. Surprisingly, we found that two thirds of these predictions (62) represent errors either in assembly comparison or in one of the assemblies, including 27 misassembled regions in HG18. Next, we validated 22 of the remaining 28 potential polymorphic inversions using different PCR techniques and characterized their breakpoints and ancestral state. In addition, we determined experimentally the derived allele frequency in Europeans for 17 inversions (DAF = 0.01-0.80), as well as the distribution in 14 worldwide populations for 12 of them based on the 1000 Genomes Project data. Among the validated inversions, nine have inverted repeats (IRs) at their breakpoints, and two show nucleotide variation patterns consistent with a recurrent origin. Conversely, inversions without IRs have a unique origin and almost all of them show deletions or insertions at the breakpoints in the derived allele mediated by microhomology sequences, which highlights the importance of mechanisms like FoSTeS/MMBIR in the generation of complex rearrangements in the human genome. Finally, we found several inversions located within genes and at least one candidate to be positively selected in Africa. Thus, our study emphasizes the importance of careful analysis and validation of large-scale genomic predictions to extract reliable biological conclusions.
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: David
authors.initials: D
authors.lastname: Vicente-Salvador
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.
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: Sarai
authors.initials: S
authors.lastname: Pacheco
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: Isaac
authors.initials: I
authors.lastname: Noguera
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.
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.|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: Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Spain.|Department of Experimental and Health Sciences, 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: Cristina
authors.initials: C
authors.lastname: Aguado
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.|Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de València, Paterna (València), Spain and.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Lucas-Lledó
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.|ICREA, Barcelona, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Cáceres
mesh_terms: D007446:Chromosome Inversion / Q000235:genetics*; D019143:Evolution, Molecular; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D058977:Molecular Sequence Annotation; D011110:Polymorphism, Genetic; D012641:Selection, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D057345:Sequence Inversion / Q000235:genetics*