An epigenomic investigation of atrial fibrillation in a matched left and right atrial human cohort

Rodriguez-Gonzalez, A.; Frost, S.; Thomas, A. M.; Fernandez-Aroca, D. M.; Choudhury, J.; Tikkas, G.; Tinker, A. M.; Munroe, P. B.; Bell, C. G.; Villar, D.

doi:10.1101/2025.08.29.673028

bioRxiv · 10.1101/2025.08.29.673028

An epigenomic investigation of atrial fibrillation in a matched left and right atrial human cohort

Rodriguez-Gonzalez, A.·Frost, S.·Thomas, A. M.·Fernandez-Aroca, D. M.·Choudhury, J.·Tikkas, G.·Tinker, A. M.·Munroe, P. B.·Bell, C. G.·Villar, D.

View original source ↗Export metadata ↓

Abstract

As the most prevalent cardiac arrythmia, atrial fibrillation is an important contributor to cardiovascular morbidity and mortality. Human population findings increasingly support its complex genetic architecture, with most genetic association signals for atrial fibrillation found in the non-coding genome. In this study, we integrated genome-wide histone modification, gene expression and DNA methylation levels in a paired left and right atrial cohort comprising permanent atrial fibrillation patients and sinus rhythm controls. First, we first identified epigenomic regions enriched in histone H3 lysine 27 acetylation (H3K27ac) across left and right atria from patients and controls, and associated them with differentially expressed genes to derive a set of dysregulated candidate loci - including NPPB and SCX. Second, by incorporating an independent replication cohort, we were able to validate gene expression and epigenomic differences for a subset of these candidate loci. Third, we profiled base-resolution DNA methylation levels and identified differentially-methylated regions (DMRs) between atrial fibrillation and sinus rhythm samples. Integration of these data with histone modification levels and gene expression allowed us to propose epigenetic mechanisms underlying transcriptomic and epigenomic changes across dysregulated loci, such as disruption of transcription factor binding by DNA methylation at the LRRC4B locus. The data and analyses we report constitute a systematic investigation of gene regulatory alterations across the left and right atria in permanent atrial fibrillation.

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Rodriguez-Gonzalez, A., Frost, S., Thomas, A. M., Fernandez-Aroca, D. M., Choudhury, J., Tikkas, G., Tinker, A. M., Munroe, P. B., Bell, C. G., Villar, D.. 2025-09-02. An epigenomic investigation of atrial fibrillation in a matched left and right atrial human cohort. https://doi.org/10.1101/2025.08.29.673028

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Genomic correlates of metastatic competence and progression in human melanoma

Genomic events and their timing that grant a primary tumour the competence to disseminate remain poorly defined. We performed sequencing of 247 stage I/II primary cutaneous melanomas (CMs) and 60 matched metastases without intervening therapy from a prospectively followed registry cohort with a median followup of 92 months, integrating copy-number, mutational, protein and spatial-transcriptomic analyses. Relapse was not distinguished by oncogenic point mutations, which were largely shared between primaries and metastases, but by somatic copy-number alterations (SCNAs) and global chromosomal instability. We defined OncoCycle, a six-gene copy-number signature (amplification of CDK4, MCL1 and CD276; biallelic loss of CDKN2A, CDKN2B and TP53BP1) that predicted relapse independently of established clinicopathological features in melanoma, and a pan-cancer analysis. In matched pairs, metastatic progression was driven by continued copy-number evolution and reduction in intra-tumoural heterogeneity, rather than by acquired point mutations, and OncoCycle alterations from primary tumours were preserved in metastasis seeding clones. Clonal reconstruction revealed both monoclonal and polyclonal metastasis seeding, and spatial transcriptomics resolved copy-number-defined metastatic subclones occupying and programming distinct immune and stromal niches. Thus, metastatic competence was primed early by focal SCNAs on a background of chromosomal instability, elaborated by continued copy-number evolution during dissemination and spatio-temporal interactions with the tumour-microenvironment.

genomics↗

bioRxiv2026

PfPHAST: Plasmodium falciparum Public Health Amplicon Sequencing Tool, a Streamlined Panel for Malaria Genomic Surveillance

Genomic tools can support malaria control policy through surveillance of Plasmodium falciparum populations, tracking antimalarial drug resistance, pfhrp2/3 deletions that compromise rapid diagnostic tests, and selection at the circumsporozoite protein (PfCSP) vaccine target, as well as through molecular correction of therapeutic efficacy studies (TES). Multiplex Amplicons for Drug, Diagnostic, Diversity, and Differentiation Haplotypes using Targeted Resequencing (MAD4HatTeR), a comprehensive amplicon sequencing panel covering up to 276 targets, supports these applications but is tailored to research rather than routine programmatic use. We developed P. falciparum Public Health Amplicon Sequencing Tool (PfPHAST), a 56-target derivative of MAD4HatTeR spanning drug resistance loci, pfhrp2/3 deletion, PfCSP genotyping, non-falciparum species identification, and 20 high-heterozygosity microhaplotype loci for TES classification. We compared PfPHAST and MAD4HatTeR using laboratory strain controls, including two-strain dilution series and a five-strain mixture, across parasite densities of 100 to 10,000 parasites/L. At matched per-target depth, PfPHAST achieved a higher quality-control pass rate than MAD4HatTeR (94.4% versus 90.0%) and distributed reads more evenly across targets. The panels showed comparable recall and precision for drug resistance codons and microhaplotypes, reaching near-complete recall above 40% within-sample allele frequency (WSAF) at all densities, with reduced sensitivity for minor alleles below 10% WSAF at low parasite density in both panels. Observed and expected WSAF correlated strongly for both panels, and both resolved a five-strain polyclonal mixture, including a 5% minor strain. By concentrating sequencing capacity on targets of greatest programmatic relevance, PfPHAST offers a scalable, lower-cost alternative to comprehensive research panels without sacrificing performance on shared targets, complementing MAD4HatTeR for routine molecular malaria surveillance.

genomics↗

bioRxiv2026

Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

Somatic mosaicism contributes to genomic variation, yet postzygotic structural variants remain under-characterized. We performed long- and short-read WGS from multiple individuals (n=47 normal tissues; n=168 samples) and identified mosaic structural variants in all individuals and germ layers, impacting a median 285.2 kb/genome. Nearly half of breakpoints were independently validated, with tissue distributions reflecting both early and late developmental origins. Most mosaic variants were repeat-mediated and 8.3% overlapped functional elements, an enrichment compared to germline variants. To extend these analyses in samples where long-read sequencing is infeasible, we measured repeat alterations from short-read sequencing, recapitulating mosaic tissue-specific differences. We characterized tumor- and tissue- specific variation in repeats across 15 cancer types and found tumor-related repeat variation to be similar in scale to that of normal mosaic variation. Tracking repeat changes in cell-free DNA provided a noninvasive approach for tumor monitoring. Our analyses revealed widespread repeat-driven structural variation in health and disease.

genomics↗