Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line
- Imperial College London, United Kingdom
- Victor Chang Cardiac Research Institute, Australia
- University of Sydney, Australia
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).
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DNA-seq of the QSi5 and 129T2/SvEms mouse strainsArrayExpress E-MTAB-11161.
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RNA-seq of dissected cardiac septa from a mouse developmental time courseArrayExpress and E-MTAB-10929.
Article and author information
Author details
Mahdi Moradi Marjaneh
David T. Humphreys
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
- 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
- Received: September 21, 2022
- Preprint posted: November 1, 2022 (view preprint)
- Accepted: June 2, 2023
- Accepted Manuscript published: June 5, 2023 (version 1)
- Version of Record published: June 21, 2023 (version 2)
- 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.
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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
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