Circular DNA intermediates in the generation of large human segmental duplications
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RESEARCH ARTICLE
Open Access
Circular DNA intermediates in the generation of large human segmental duplications Javier U. Chicote1, Marcos López-Sánchez2,3, Tomàs Marquès-Bonet4,5,6, José Callizo7, Luis A. Pérez-Jurado2,3,8* and Antonio García-España1*
Abstract Background: Duplications of large genomic segments provide genetic diversity in genome evolution. Despite their importance, how these duplications are generated remains uncertain, particularly for distant duplicated genomic segments. Results: Here we provide evidence of the participation of circular DNA intermediates in the single generation of some large human segmental duplications. A specific reversion of sequence order from A-B/C-D to B-A/D-C between duplicated segments and the presence of only microhomologies and short indels at the evolutionary breakpoints suggest a circularization of the donor ancestral locus and an accidental replicative interaction with the acceptor locus. Conclusions: This novel mechanism of random genomic mutation could explain several distant genomic duplications including some of the ones that took place during recent human evolution. Keywords: Segmental duplications, Circular DNA, Human genome evolution, X-Y transposed region, Chromoanasynthesis,, MMBIR/FoSTeS, NHEJ, Copy number variants
Background Gross genome rearrangements, such as deletions, amplifications, inversions and duplications, are an important source of genetic structural variation for natural selection. Genomic duplications constitute one of the main driving forces for acquiring novel gene functions [1]. Segmental duplications (SDs), which account for over 5% of the human genome, are defined by consensus as duplicated genomic sequences larger than 1-Kb and with an identity over 90% [2–4]. Among humans and great * Correspondence: [email protected]; [email protected] 2 Genetics Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain 1 Research Unit, Hospital Universitari de Tarragona Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, 43005 Tarragona, Spain Full list of author information is available at the end of the article
apes, recent SDs provide a substantial fraction of the genetic differences that might underlie the different phenotypes of these species [5, 6]. Additionally, SDs are also susceptibility factors for genomic disorders, a group of human genetic diseases characterized by recurrent genomic rearrangements mediated by non-allelic homologous recombination (NAHR) [7–9]. Understanding the mechanisms involved in SDs’ generation may provide new insights into evolutionary events associated with speciation, adaptation, polymorphic variation, and disease [5, 6, 10]. Proposed mechanisms for the origin of gene duplication include unequal crossing over, retrotransposition, and chromosomal or genome duplication [11]. While unequal crossing over could explain the generation of tandem duplications in proximity on the same chromosome, the generation of interspersed
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