Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line

Abstract

Unlike single-gene mutations leading to Mendelian conditions, common human diseases are likely to be emergent phenomena arising from multilayer, multiscale and highly interconnected interactions. Atrial and ventricular septal defects are the most common forms of cardiac congenital anomalies in humans. Atrial septal defects (ASD) show an open communication between left and right atria postnatally, potentially resulting in serious hemodynamic consequences if untreated. A milder form of atrial septal defect, patent foramen ovale (PFO), exists in about one quarter of the human population, strongly associated with ischaemic stroke and migraine. The anatomic liabilities and genetic and molecular basis of atrial septal defects remain unclear. Here, we advance our previous analysis of atrial septal variation through quantitative trait locus (QTL) mapping of an advanced intercross line (AIL) established between the inbred QSi5 and 129T2/SvEms mouse strains, that show extremes of septal phenotypes. Analysis resolved 37 unique septal QTL with high overlap between QTL for distinct septal traits and PFO as a binary trait. Whole genome sequencing of parental strains and filtering identified predicted functional variants, including in known human congenital heart disease genes. Transcriptome analysis of developing septa revealed downregulation of networks involving ribosome, nucleosome, mitochondrial and extracellular matrix biosynthesis in the 129T2/SvEms strain, potentially reflecting an essential role for growth and cellular maturation in septal development. Analysis of variant architecture across different gene features, including enhancers and promoters, provided evidence for involvement of non-coding as well as protein coding variants. Our study provides the first high resolution picture of genetic complexity and network liability underlying common congenital heart disease, with relevance to human ASD and PFO.

Data availability

Sequencing data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession codes E-MTAB-11161 (DNA-seq) and E-MTAB-10929 (RNA-seq).

The following data sets were generated

Article and author information

Author details

  1. Mahdi Moradi Marjaneh

    Department of Infectious Disease, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9412-9029
  2. Edwin P Kirk

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Ralph Patrick

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0956-1026
  4. Dimuthu Alankerage

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. David T. Humphreys

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4140-0089
  6. Gonzalo Del Monte-Nieto

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Paola Cornejo-Paramo

    Victor Chang Cardiac Research Institute, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Vaibhao Janbandhu

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Tram B Doan

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Sally L Dunwoodie

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2069-7349
  11. Emily S Wong

    Victor Chang Cardiac Research Institute, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0315-2942
  12. Chris Moran

    Sydney School of Veterinary Science, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4550-5101
  13. Ian CA Martin

    Sydney School of Veterinary Science, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Peter C Thomson

    Sydney School of Veterinary Science, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4428-444X
  15. Richard P Harvey

    Victor Chang Cardiac Research Institute, Darlinghurst, Australia
    For correspondence
    r.harvey@victorchang.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9950-9792

Funding

National Health and Medical Research Council (0573705)

  • Richard P Harvey

New South Wales Government

  • Richard P Harvey

University of New South Wales (ID3263695)

  • Mahdi Moradi Marjaneh

University of New South Wales

  • Paola Cornejo-Paramo

National Health and Medical Research Council (1118576)

  • Richard P Harvey

National Health and Medical Research Council (2008743)

  • Richard P Harvey

National Institute of Heart Lung and Blood (1RO1HL68885-01)

  • Richard P Harvey

National Heart Foundation of Australia (G06S2575)

  • Richard P Harvey

National Heart Foundation of Australia (G0050738)

  • Richard P Harvey

National Health and Medical Research Council (354400)

  • Richard P Harvey

National Health and Medical Research Council (0573732)

  • Richard P Harvey

National Health and Medical Research Council (1074386)

  • Richard P Harvey

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

Reviewing Editor

  1. Aldons J Lusis, University of California, Los Angeles, United States

Ethics

Animal experimentation: Animals were bred and housed under Animal Care and Research Ethics approvals N00/4-2003/1/3745, N00/4-2003/2/3745 and N00/4-2003/3/3745 from the University of Sydney.

Version history

  1. Received: September 21, 2022
  2. Preprint posted: November 1, 2022 (view preprint)
  3. Accepted: June 2, 2023
  4. Accepted Manuscript published: June 5, 2023 (version 1)
  5. Version of Record published: June 21, 2023 (version 2)
  6. Version of Record updated: June 22, 2023 (version 3)

Copyright

© 2023, Moradi Marjaneh 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

  • 636
    views
  • 78
    downloads
  • 1
    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. Mahdi Moradi Marjaneh
  2. Edwin P Kirk
  3. Ralph Patrick
  4. Dimuthu Alankerage
  5. David T. Humphreys
  6. Gonzalo Del Monte-Nieto
  7. Paola Cornejo-Paramo
  8. Vaibhao Janbandhu
  9. Tram B Doan
  10. Sally L Dunwoodie
  11. Emily S Wong
  12. Chris Moran
  13. Ian CA Martin
  14. Peter C Thomson
  15. Richard P Harvey
(2023)
Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line
eLife 12:e83606.
https://doi.org/10.7554/eLife.83606

Share this article

https://doi.org/10.7554/eLife.83606

Further reading

    1. Developmental Biology
    Amandine Jarysta, Abigail LD Tadenev ... Basile Tarchini
    Research Article

    Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.

    1. Computational and Systems Biology
    2. Developmental Biology
    Gang Xue, Xiaoyi Zhang ... Zhiyuan Li
    Research Article

    Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.