1. Genetics and Genomics
  2. Microbiology and Infectious Disease

Genome duplication in Leishmania major relies on persistent subtelomeric DNA replication

  1. Jeziel Dener Damasceno  Is a corresponding author
  2. Catarina A Marques
  3. Dario Beraldi
  4. Kathryn Crouch
  5. Craig Lapsley
  6. Ricardo Obonaga
  7. Luiz R O Tosi
  8. Richard McCulloch  Is a corresponding author
  1. University of Glasgow, United Kingdom
  2. University of São Paulo, Brazil
https://doi.org/10.7554/eLife.58030
Share this article
Cite this article
  1. Jeziel Dener Damasceno
  2. Catarina A Marques
  3. Dario Beraldi
  4. Kathryn Crouch
  5. Craig Lapsley
  6. Ricardo Obonaga
  7. Luiz R O Tosi
  8. Richard McCulloch
(2020)
Genome duplication in Leishmania major relies on persistent subtelomeric DNA replication
eLife 9:e58030.
https://doi.org/10.7554/eLife.58030
  2. Download BibTeX
  3. Download .RIS

Abstract

DNA replication is needed to duplicate a cell's genome in S-phase and segregate it during cell division. Previous work in Leishmania detected DNA replication initiation at just a single region in each chromosome, an organisation predicted to be insufficient for complete genome duplication within S-phase. Here, we show that acetylated histone H3 (AcH3), base J and a kinetochore factor colocalise in each chromosome at only a single locus, which corresponds with previously mapped DNA replication initiation regions and is demarcated by localised G/T skew and G4 patterns. In addition, we describe previously undetected subtelomeric DNA replication in G2/M and G1 phase-enriched cells. Finally, we show that subtelomeric DNA replication, unlike chromosome-internal DNA replication, is sensitive to hydroxyurea and dependent on 9-1-1 activity. These findings indicate that Leishmania's genome duplication programme employs subtelomeric DNA replication initiation, possibly extending beyond S-phase, to support predominantly chromosome-internal DNA replication initiation within S-phase.

Data availability

Sequences used in this study have been deposited in the European Nucleotide Archive. Data can be accessed using the accession number PRJEB35027.

The following data sets were generated

Article and author information

Author details

  1. Jeziel Dener Damasceno

    The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    For correspondence
    jeziel.damasceno@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2077-3214

  2. Catarina A Marques

    The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1324-5448

  3. Dario Beraldi

    The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Kathryn Crouch

    The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9310-4762

  5. Craig Lapsley

    The Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Ricardo Obonaga

    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  7. Luiz R O Tosi

    Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
    Competing interests
    The authors declare that no competing interests exist.

  8. Richard McCulloch

    The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation,, University of Glasgow, Glasgow, United Kingdom
    For correspondence
    Richard.McCulloch@glasgow.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5739-976X

Funding

Biotechnology and Biological Sciences Research Council (BB/N016165/1)

  • Luiz R O Tosi
  • Richard McCulloch

Biotechnology and Biological Sciences Research Council (BB/R017166/1)

  • Richard McCulloch

European Commission (RECREPEMLE)

  • Jeziel Dener Damasceno

Wellcome (104111)

  • Richard McCulloch

Medical Research Council (MR/S019472/1)

  • Jeziel Dener Damasceno
  • Richard McCulloch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christine Clayton, DKFZ-ZMBH Alliance, Germany

Version history

  1. Received: April 17, 2020
  2. Accepted: September 7, 2020
  3. Accepted Manuscript published: September 8, 2020 (version 1)
  4. Version of Record published: September 23, 2020 (version 2)

Copyright

© 2020, Damasceno et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,860
    views
  • 248
    downloads
  • 9
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jeziel Dener Damasceno
  2. Catarina A Marques
  3. Dario Beraldi
  4. Kathryn Crouch
  5. Craig Lapsley
  6. Ricardo Obonaga
  7. Luiz R O Tosi
  8. Richard McCulloch
(2020)
Genome duplication in Leishmania major relies on persistent subtelomeric DNA replication
eLife 9:e58030.
https://doi.org/10.7554/eLife.58030

Share this article

https://doi.org/10.7554/eLife.58030

Categories and tags

Further reading

    1. Genetics and Genomics
    2. Neuroscience

    Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia

    Bohan Zhu, Richard I Ainsworth ... Javier González-Maeso
    Research Article

    Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.

    1. Cancer Biology
    2. Genetics and Genomics

    Convergent epigenetic evolution drives relapse in acute myeloid leukemia

    Kevin Nuno, Armon Azizi ... Ravindra Majeti
    Research Article

    Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

    1. Computational and Systems Biology
    2. Genetics and Genomics

    Haplotype function score improves biological interpretation and cross-ancestry polygenic prediction of human complex traits

    Weichen Song, Yongyong Shi, Guan Ning Lin
    Tools and Resources

    We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3619 independent HFS–trait associations with a significance of p < 5 × 10−8. Fine-mapping revealed 2699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with single-nucleotide polymorphism (SNP)-based analysis. HFS-based enrichment analysis uncovered 727 pathway–trait associations and 153 tissue–trait associations with strong biological interpretability, including ‘circadian pathway-chronotype’ and ‘arachidonic acid-intelligence’. Lastly, we applied least absolute shrinkage and selection operator (LASSO) regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1–39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.