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Updated: Jul 13, 2025
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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Single-nucleotide variants within heart enhancers increase binding affinity and disrupt heart development
Granton A Jindal1, Alexis T Bantle2, Joe J Solvason3
1Department of Medicine, Health Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Developmental Cell
|October 17, 2023
Summary
Suboptimal binding sites in enhancers are crucial for precise gene expression. Single-nucleotide variants can alter binding affinity, leading to developmental defects and diseases.
Area of Science:
- Developmental Biology
- Genetics
- Evolutionary Biology
Background:
- Transcriptional enhancers regulate gene expression crucial for development and phenotypic variation.
- Identifying specific enhancer variants linked to gene expression changes and phenotypes remains a significant challenge.
- Low-affinity binding sites within enhancers are essential for precise developmental gene regulation.
Purpose of the Study:
- To investigate the role of suboptimal binding sites in enhancer function during heart development.
- To determine how single-nucleotide variants (SNVs) affecting binding affinity influence gene expression and phenotypes.
- To explore the implications of these findings in human disease and evolution.
Main Methods:
- Comparative analysis of enhancer sequences and binding sites in Ciona robusta.
- Functional assays using human induced pluripotent stem cell (iPSC)-derived cardiomyocytes.
- Assessment of gene expression changes and phenotypic outcomes following SNV introduction.
Main Results:
- Suboptimal ETS binding sites are necessary for precise heart development.
- SNVs that optimize ETS binding affinity lead to gain-of-function (GOF) gene expression.
- These GOF effects can cause cell migration defects, abnormal heart development (e.g., extra beating hearts), and altered cellular identity.
Conclusions:
- The presence of low-affinity sites in enhancers represents a vulnerability to SNVs.
- Affinity-optimizing SNVs can disrupt normal gene expression, leading to significant phenotypic consequences.
- These mechanisms may contribute to the evolution of new traits and the pathogenesis of diseases.
Keywords:
GATA4affinity-optimizing SNVscausal enhancer variantsenhanceropathiesenhancersheart developmentlow affinitysuboptimal affinitysuboptimizationMore Related Videos
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