Margarida Cardoso Moreira

Publications (5) View all

• Article: Mutation spectrum of Drosophila CNVs revealed by breakpoint sequencing.

  Margarida Cardoso-Moreira, J Roman Arguello, Andrew G Clark
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  ABSTRACT: BACKGROUND: The detailed study of breakpoints associated with Copy Number Variants (CNVs) can elucidate the mutational mechanisms that generate them and the comparison of breakpoints across species can highlight differences in genomic architecture that may lead to lineage-specific differences in patterns of CNVs. Here, we provide a detailed analysis of Drosophila CNV breakpoints and contrast it with similar analyses recently carried out for the human genome. RESULTS: By applying split-read methods to a total of 10x coverage of 454 shotgun sequence across 9 lines of D. melanogaster and by re-examining a previously published dataset of CNVs detected using tiling arrays, we identified the precise breakpoints of more than 600 insertions, deletions and duplications. Contrasting these CNVs with those found in humans showed that in both taxa CNV breakpoints fall into three classes: blunt breakpoints; simple breakpoints associated with microhomology; and breakpoints with additional nucleotides inserted/deleted and no microhomology. In both taxa CNV breakpoints are enriched with non-B DNA sequence structures, which may impair DNA replication and/or repair. However, in contrast to human genomes, Non-Allelic Homologous-Recombination (NAHR) plays a negligible role in CNV formation in Drosophila. In flies, non-homologous repair mechanisms are responsible for simple, recurrent and complex CNVs, including insertions of de novo sequence as large as 60 bp. CONCLUSIONS: Humans and Drosophila differ considerably in the importance of homology-based mechanisms for the formation of CNVs, likely as a consequence of the differences in the abundance and distribution of both segmental duplications and transposable elements between the two genomes.
  Genome biology 12/2012; 13(12):R119. · 6.63 Impact Factor
• Article: Mutational bias shaping fly copy number variation: implications for genome evolution.

  Margarida M Cardoso-Moreira, Manyuan Long
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  ABSTRACT: Copy number variants (CNVs) underlie several genomic disorders and are a major source of genetic innovation. Consequently, any bias affecting their placement in the genome will impact our understanding of human disease and genome evolution. Here we report a mutational bias affecting CNVs that generates different probabilities of duplication and deletion across the genome in association with DNA replication time. We show that this mutational bias has important consequences for genome evolution by leading to different probabilities of gene duplication for different classes of genes and by linking the probability of gene duplication with the transcriptional activity of genes.
  Trends in Genetics 06/2010; 26(6):243-7. · 10.06 Impact Factor
• Article: The origin and evolution of new genes.

  Margarida Cardoso-Moreira, Manyuan Long
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  ABSTRACT: New genes are a major source of genetic innovation in genomes. However, until recently, understanding how new genes originate and how they evolve was hampered by the lack of appropriate genetic datasets. The advent of the genomic era brought about a revolution in the amount of data available to study new genes. For the first time, decades-old theoretical principles could be tested empirically and novel and unexpected avenues of research opened up. This chapter explores how genomic data can and is being used to study both the origin and evolution of new genes and the surprising discoveries made thus far.
  Methods in molecular biology (Clifton, N.J.) 01/2012; 856:161-86.
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  Available from: Margarida Cardoso Moreira

  Article: Drosophila duplication hotspots are associated with late-replicating regions of the genome.

  Margarida Cardoso-Moreira, J J Emerson, Andrew G Clark, Manyuan Long
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  ABSTRACT: Duplications play a significant role in both extremes of the phenotypic spectrum of newly arising mutations: they can have severe deleterious effects (e.g. duplications underlie a variety of diseases) but can also be highly advantageous. The phenotypic potential of newly arisen duplications has stimulated wide interest in both the mutational and selective processes shaping these variants in the genome. Here we take advantage of the Drosophila simulans-Drosophila melanogaster genetic system to further our understanding of both processes. Regarding mutational processes, the study of two closely related species allows investigation of the potential existence of shared duplication hotspots, and the similarities and differences between the two genomes can be used to dissect its underlying causes. Regarding selection, the difference in the effective population size between the two species can be leveraged to ask questions about the strength of selection acting on different classes of duplications. In this study, we conducted a survey of duplication polymorphisms in 14 different lines of D. simulans using tiling microarrays and combined it with an analogous survey for the D. melanogaster genome. By integrating the two datasets, we identified duplication hotspots conserved between the two species. However, unlike the duplication hotspots identified in mammalian genomes, Drosophila duplication hotspots are not associated with sequences of high sequence identity capable of mediating non-allelic homologous recombination. Instead, Drosophila duplication hotspots are associated with late-replicating regions of the genome, suggesting a link between DNA replication and duplication rates. We also found evidence supporting a higher effectiveness of selection on duplications in D. simulans than in D. melanogaster. This is also true for duplications segregating at high frequency, where we find evidence in D. simulans that a sizeable fraction of these mutations is being driven to fixation by positive selection.
  PLoS Genetics 11/2011; 7(11):e1002340. · 8.69 Impact Factor
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  Available from: Margarida Cardoso Moreira

  Article: Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster.

  J J Emerson, Margarida Cardoso-Moreira, Justin O Borevitz, Manyuan Long
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  ABSTRACT: The role that natural selection plays in governing the locations and early evolution of copy-number mutations remains largely unexplored. We used high-density full-genome tiling arrays to create a fine-scale genomic map of copy-number polymorphisms (CNPs) in Drosophila melanogaster. We inferred a total of 2658 independent CNPs, 56% of which overlap genes. These include CNPs that are likely to be under positive selection, most notably high-frequency duplications encompassing toxin-response genes. The locations and frequencies of CNPs are strongly shaped by purifying selection, with deletions under stronger purifying selection than duplications. Among duplications, those overlapping exons or introns, as well as those falling on the X chromosome, seem to be subject to stronger purifying selection.
  Science 07/2008; 320(5883):1629-31. · 31.20 Impact Factor