Circular DNA intermediates in the generation of large human segmental duplications

Chicote, Javier U.; López-Sánchez, Marcos; Callizo, José Ramón Ara; Pérez-Jurado, Luís A.; Garcı́a-España, Antonio

doi:10.1186/s12864-020-06998-w

Cited by 5 publications

(6 citation statements)

References 38 publications

(51 reference statements)

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“…Taken together, the structure observed is consistent with a duplication mechanism involving circular intermediates as recently established by Chicote et al (2020) . In the case described here recombination between two SVA elements mediates reintegration of the circular intermediate into the genome ( fig.…”

Section: Resultssupporting

confidence: 88%

“…Recently, SDs were found to be significantly overrepresented in sperm eccDNA ( Mouakkad-Montoya et al 2021 ). To date, only a relatively small number of duplication events generated by this mechanism has been characterized ( Chicote et al 2020 ; Takahashi and Innan 2020 ). Fundamental questions regarding circularization and integration are still unanswered.…”

Section: Discussionmentioning

confidence: 99%

“…Fundamental questions regarding circularization and integration are still unanswered. Based on the analysis published homology-based mechanisms did not appear to play a role in the integration process ( Chicote et al 2020 ). The structure of the NPIPB9 lcr16a copy analyzed here ( fig.…”

Section: Discussionmentioning

confidence: 99%

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SVA Retrotransposons and a Low Copy Repeat in Humans and Great Apes: A Mobile Connection

Damert

2022

Molecular Biology and Evolution

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Segmental duplications (SDs) constitute a considerable fraction of primate genomes. They contribute to genetic variation and provide raw material for evolution. Groups of SDs are characterized by the presence of shared core duplicons. One of these core duplicons, lcr16a, has been shown to be particularly active in the propagation of interspersed SDs in primates. The underlying mechanisms are, however, only partially understood. Alu short interspersed elements (SINEs) are frequently found at breakpoints and have been implicated in the expansion of SDs. Detailed analysis of lcr16a-containing SDs shows that the hominid-specific SVA (SINE-R-VNTR-Alu) retrotransposon is an integral component of the core duplicon in Asian and African great apes. In orang-utan it provides breakpoints and contributes to both inter- and intrachromosomal lcr16a mobility by inter-element recombination. Furthermore, the data suggest that in hominines (human, chimpanzee, gorilla) SVA recombination-mediated integration of a circular intermediate is the founding event of a lineage-specific lcr16a expansion. One of the hominine lcr16a copies displays large flanking direct repeats, a structural feature shared by other SDs in the human genome. Taken together, the results obtained extend the range of SVAs’ contribution to genome evolution from RNA-mediated transduction to DNA-based recombination. In addition, they provide further support for a role of circular intermediates in SD mobilization.

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Section: Resultssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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SVA Retrotransposons and a Low Copy Repeat in Humans and Great Apes: A Mobile Connection

Damert

2022

Molecular Biology and Evolution

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“…The fate of SD-bearing nscDNA (formation, reintegration, and degradation) in germ cells could be associated with genetic variations since SDs are subject to meiosis-specific DNA double-strand breaks ( 55 ), which would facilitate the integration of nscDNA into chromosomes. A trace of this mechanism can be found within SD clusters of the human genome ( 56 – 58 ). In yeast ( 59 ) and bovine ( 60 ), circular intermediates have been implicated in chromosomal amplifications or genic translocation events.…”

Section: Discussionmentioning

confidence: 99%

Quantitative assessment reveals the dominance of duplicated sequences in germline-derived extrachromosomal circular DNA

Mouakkad-Montoya

Murata

Sulovari

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Extrachromosomal circular DNA (eccDNA) originates from linear chromosomal DNA in various human tissues under physiological and disease conditions. The genomic origins of eccDNA have largely been investigated using in vitro–amplified DNA. However, in vitro amplification obscures quantitative information by skewing the total population stoichiometry. In addition, the analyses have focused on eccDNA stemming from single-copy genomic regions, leaving eccDNA from multicopy regions unexamined. To address these issues, we isolated eccDNA without in vitro amplification (naïve small circular DNA, nscDNA) and assessed the populations quantitatively by integrated genomic, molecular, and cytogenetic approaches. nscDNA of up to tens of kilobases were successfully enriched by our approach and were predominantly derived from multicopy genomic regions including segmental duplications (SDs). SDs, which account for 5% of the human genome and are hotspots for copy number variations, were significantly overrepresented in sperm nscDNA, with three times more sequencing reads derived from SDs than from the entire single-copy regions. SDs were also overrepresented in mouse sperm nscDNA, which we estimated to comprise 0.2% of nuclear DNA. Considering that eccDNA can be integrated into chromosomes, germline-derived nscDNA may be a mediator of genome diversity.

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“…Several findings show that elevated transcription increases the chance of a gene duplication mutation (Hull et al, 2017;Wilson et al, 2015;Thomas and Rothstein, 1989;Aguilera and Gaillard, 2014;Hamperl et al, 2017), likely by local destabilization of the genome (Aguilera, 2002;Gómez-González and Aguilera, 2019) followed by downstream mechanisms involving RNA (Kaessmann et al, 2009) or DNA intermediates (Chicote et al, 2020;Durkin et al, 2012;Takahashi and Innan, 2020). A direct connection between transcription and gene duplication mutation rates was exemplified in yeast, where copy number amplification of the CUP1 gene results in adaptation to high copper concentration: by replacing the CUP1 promoter sequence with a galactose-inducible promoter, Hull et al (2017) have shown that CUP1 transcription induces gene copy number amplification under galactose stimulation and in the absence of copper selection, suggesting that copy number amplification of the wild-type CUP1 can be caused mechanistically by transcription.…”

Section: Gene Duplication As Mutational Replacementmentioning

confidence: 99%

Evolutionary Honing in and Mutational Replacement: How Long-Term Directed Mutational Responses to Specific Environmental Pressures Are Possible

Livnat¹,

Melamed²

2022

Preprint

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Recent results have shown that the human malaria-resistant hemoglobin S mutation originates de novo more frequently in the gene and in the population where it is of adaptive significance, namely, in the hemoglobin subunit beta gene compared to the non-resistant but otherwise identical 20A>T mutation in the hemoglobin subunit delta gene, and in sub-Saharan Africans, who have been subject to intense malarial pressure for many generations, compared to Northern Europeans, who have not. This finding raises a fundamental challenge to the traditional notion of accidental mutation. Here we address this finding with the replacement hypothesis, according to which pre-existing genetic interactions can lead directly and mechanistically to mutations that simplify and replace them. Thus, a gradual evolutionary process under selection can hone in on interactions of importance for the currently evolving adaptations, from which large-effect mutations follow that are relevant to these adaptations. We exemplify this hypothesis using multiple types of mutation, including gene fusion mutations, gene duplication mutations, A>G mutations in RNA-edited sites and transcription-associated mutations, and place it in the broader context of a system-level view of mutation origination called Interaction-based Evolution. Potential consequences include that similarity of mutation pressures may contribute to parallel evolution in genetically related species, that the evolution of genome organization may be driven by mutational mechanisms, that transposable element movements may also be explained by replacement, and that long-term directional mutational responses to specific environmental pressures are possible. Such responses need to be further tested by future studies in natural and artificial settings.

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Circular DNA intermediates in the generation of large human segmental duplications

Cited by 5 publications

References 38 publications

SVA Retrotransposons and a Low Copy Repeat in Humans and Great Apes: A Mobile Connection

SVA Retrotransposons and a Low Copy Repeat in Humans and Great Apes: A Mobile Connection

Quantitative assessment reveals the dominance of duplicated sequences in germline-derived extrachromosomal circular DNA

Evolutionary Honing in and Mutational Replacement: How Long-Term Directed Mutational Responses to Specific Environmental Pressures Are Possible

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