Functional impact and evolution of a novel human polymorphic inversion that disrupts a gene and creates a fusion transcript
Puig Font, Marta (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Castellano Esteve, David (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pantano, Lorena (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Giner-Delgado, Carla (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Izquierdo Fontanills, David (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Gayà Vidal, Magdalena (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Lucas Lledó, José Ignacio (Universitat de València. Institut Cavanilles de Biodiversitat i Biologia Evolutiva)
Esko, Tõnu (Estonian Genome Center)
Terao, Chikashi (Kyoto University Graduate School of Medicine)
Matsuda, Fumihiko (Center for Genomic Medicine. Kyoto University Graduate School of Medicine)
Cáceres Aguilar, Mario (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Data:	2015
Resum:	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.
Ajuts:	European Commission 243212 Ministerio de Ciencia e Innovación BFU2007-60930
Nota:	Altres ajuts: a PIF PhD fellowship from the Universitat Autònoma de Barcelona (Spain) to CGD, and a Beatriu de Pinós Postdoctoral fellowship by the Commission for Universities and Research of the Ministry of Innovation, Universities and Enterprise of the Autonomous Government of Catalonia and the Cofund programme of the Marie Curie Actions of the FP7 to JILL.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Chromosome breakpoints ; Chromosome inversion ; Chromosomes, Human, Pair 19 ; DNA end-joining repair ; DNA transposable elements ; Evolution, Molecular ; Gene expression regulation ; Genetics, Population ; Genotype ; Humans ; Polymorphism, Single nucleotide ; Transcription factors
Publicat a:	PLoS Genetics, Vol. 11, issue 10 (2015) , art. e1005495, ISSN 1553-7404

DOI: 10.1371/journal.pgen.1005495
PMID: 26427027

28 p, 2.6 MB

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