An integrative cardio-informatics approach identifies positionally conserved ancestors of human lncRNA genes transcribed across vertebrate hearts
- 1German Cancer Research Center (DKFZ)
Abstract
The poor conservation of lncRNA genes limits their comprehensive functional studies, as genetic engineering of relevant animal models presupposes the presence of corresponding defined orthologs. This limitation is prominently evident in cardiovascular research, where heart-related lncRNAs are rarely conserved between humans and other vertebrates, despite the highly conserved nature of cardiac function. Because lncRNAs frequently regulate neighboring protein-coding genes essential for cardomyocyte function (herein termed cardiomyocyte indispensable, CMIs), we hypothesized that they are under evolutionary pressure to retain their genomic position and transcriptional activity, irrespective of sequence similarities to prototypical human lncRNA genes. By integrating mouse cardiac knockout phenotypes with human single-cell transcriptomics data, we systematically identified heart-expressed CMIs and their neighboring. lncRNA genes. Cross-species synteny analyses revealed regions flanking 109 CMIs with conserved relative positions and transcriptional orientations across vertebrate genomes. As most of these loci reside within poorly annotated non-coding regions, we developed VertLncRNAchecker, a neural network-based web interface, that predicts lncRNA-like genes within these regions, which we termed positional ancestors. Finally, we validated in situ that these positional ancestors express mature lncRNA transcripts in the hearts of mice, pigs, and frogs, mirroring the expression of their human lncRNA counterparts. We present an accurate and retrainable computational platform for cross-species lncRNA discovery that prioritizes conserved genomic position over sequence conservation or existing genome annotations. This pipeline revealed putative ancestors of human heart-related lncRNAs hidden within the vertebrate non-coding dark genome, providing novel insights into lncRNA biology and evolution.
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BibTeX
@misc{galow2026integrative,
title = {{An integrative cardio-informatics approach identifies positionally conserved ancestors of human lncRNA genes transcribed across vertebrate hearts}},
author = {A.-M. Galow and A. Pavlopoulou and E. Yildiz and S. Kuhn and S. Marquardt and J. Seco and O. Chabanovska and P. Vasudevan and C. Nesselmann and C. Etz and A. Rebl and R. David and S. Logotheti},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.759660},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.759660v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - An integrative cardio-informatics approach identifies positionally conserved ancestors of human lncRNA genes transcribed across vertebrate hearts
AU - A.-M. Galow
AU - A. Pavlopoulou
AU - E. Yildiz
AU - S. Kuhn
AU - S. Marquardt
AU - J. Seco
AU - O. Chabanovska
AU - P. Vasudevan
AU - C. Nesselmann
AU - C. Etz
AU - A. Rebl
AU - R. David
AU - S. Logotheti
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.759660
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.759660v1
AB - The poor conservation of lncRNA genes limits their comprehensive functional studies, as genetic engineering of relevant animal models presupposes the presence of corresponding defined orthologs. This limitation is prominently evident in cardiovascular research, where heart-related lncRNAs are rarely conserved between humans and other vertebrates, despite the highly conserved nature of cardiac function. Because lncRNAs frequently regulate neighboring protein-coding genes essential for cardomyocyte function (herein termed cardiomyocyte indispensable, CMIs), we hypothesized that they are under evolutionary pressure to retain their genomic position and transcriptional activity, irrespective of sequence similarities to prototypical human lncRNA genes. By integrating mouse cardiac knockout phenotypes with human single-cell transcriptomics data, we systematically identified heart-expressed CMIs and their neighboring. lncRNA genes. Cross-species synteny analyses revealed regions flanking 109 CMIs with conserved relative positions and transcriptional orientations across vertebrate genomes. As most of these loci reside within poorly annotated non-coding regions, we developed VertLncRNAchecker, a neural network-based web interface, that predicts lncRNA-like genes within these regions, which we termed positional ancestors. Finally, we validated in situ that these positional ancestors express mature lncRNA transcripts in the hearts of mice, pigs, and frogs, mirroring the expression of their human lncRNA counterparts. We present an accurate and retrainable computational platform for cross-species lncRNA discovery that prioritizes conserved genomic position over sequence conservation or existing genome annotations. This pipeline revealed putative ancestors of human heart-related lncRNAs hidden within the vertebrate non-coding dark genome, providing novel insights into lncRNA biology and evolution.
ER -