Dennis, S. R. | bioRxiv Science

bioRxiv2025

DNA methylation patterns in breast cancer, paired benign tissue from ipsilateral and contralateral breast, and healthy controls.

BackgroundEpigenetic changes, particularly DNA methylation, are crucial to breast cancer development. Tumor-adjacent normal (AN) tissue frequently serves as a reference for characterizing genomic alterations but is reported to share some characteristics with tumors. However, it is unclear whether ANs epigenetic profiles reflect a predisposition to cancer or a response to the presence of the tumor. We address this gap by systematically comparing methylation profiles of tumor, AN, and matched-benign tissues from both breasts, as well as to healthy donated breast tissue. MethodsWe studied four different sample categories from 69 cancer cases: tumor (TU), AN, ipsilateral opposite quadrant (OQ), and contralateral unaffected breast (CUB); and healthy donated breast (HDB) tissue from 182 cancer-unaffected donors. These constitute a "tumor proximity axis" (TPxA): HDB[->]CUB[->]OQ[->]AN[->]TU. Methylation profiles were assayed using Illuminas Infinium Methylation EPICv1.0 BeadChip. Differential methylation (DM) analysis was conducted, and the significantly DM CpGs were analyzed for enrichment of transcription factor binding sites (TFBS) and other features. ResultsFollowing data processing and quality control, there were 69 TU, 60 AN, 67 OQ, 68 CUB, and 182 HDB samples for analysis. DM analysis showed distinct methylation profiles of TU relative to benign tissues, whereas case-benign tissues were similar to each other but distinct from HDB. Hypomethylated sites in case-benign versus HDB were enriched for TF binding sites of TP63, GATA3, ESR1, PR, AR, NR3C1, and GREB1. TU hypermethylation events were enriched for Polycomb-repressive complex 2 (PRC2) binding, including EZH2, SUZ12, and JARID2, with hypermethylation enrichment for PRC2-related binding motifs in both ER+ and ER- tumors. TU methylation profiles were otherwise highly distinct by ER status: TFBS enrichment of hypomethylation events for hormone receptor-related pathways in ER+ tumors and for hematopoiesis/immune-related pathways in ER- tumors. We found no differential methylation between benign tissues from patients with ER+ vs. ER- tumors. ConclusionsDNA methylation profiles differ profoundly at two points: tumor to case-benign and case-benign to HDB, with clear distinction between ER+ and ER- tumors. Case-benign tissues are not epigenetically "normal", are similar across both breasts, and do not differ by ER status of paired tumors.

cancer biology↗

bioRxiv2021

Hybridization dynamics and extensive introgression in the Daphnia longispina species complex: new insights from a high-quality Daphnia galeata reference genome

Hybridization and introgression are recognized as an important source of variation that influence adaptive processes; both phenomena are frequent in the genus Daphnia, a keystone zooplankton taxon in freshwater ecosystems that comprises several species complexes. To investigate genome-wide consequences of introgression between species, we provide here the first high-quality genome assembly for a member of the Daphnia longispina species complex, Daphnia galeata. We further re-sequenced 49 whole genomes of three species of the complex and their interspecific hybrids both from genotypes sampled in the water column and from single resting eggs extracted from sediment cores. Populations from habitats with diverse ecological conditions offered an opportunity to study the dynamics of hybridization linked to ecological changes and revealed a high prevalence of hybrids. Using phylogenetic and population genomic approaches, we provide first insights into the intra- and interspecific genome-wide variability in this species complex and identify regions of high divergence. Finally, we assess the length of ancestry tracts in hybrids to characterize introgression patterns across the genome. Our analyses uncover a complex history of hybridization and introgression reflecting multiple generations of hybridization and backcrossing in the Daphnia longispina species complex. Overall, this study and the new resources presented here pave the way for a better understanding of ancient and contemporary gene flow in the species complex and facilitate future studies on resting egg banks accumulating in lake sediment.

evolutionary biology↗