title: Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript.
abstract: Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000-50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.
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: David
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Pantano
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: David
authors.initials: D
authors.lastname: Izquierdo
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: José Ignacio
authors.initials: JI
authors.lastname: Lucas-Lledó
authors.affiliation: Estonian Biobank, Estonian Genome Center, University of Tartu, Tartu, Estonia; Boston Children's Hospital, Harvard Medical School, and Broad Institute of Harvard and MIT, Boston, Massachusetts, United States of America.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
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: D056905:Chromosome Breakpoints; D007446:Chromosome Inversion / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D059766:DNA End-Joining Repair / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D014157:Transcription Factors