Biology subjects

Swanson, E. G.

Publications and source records attributed to Swanson, E. G..

7 recordsLinked to original sources

bioRxiv2026

Myeloma and therapy reshape the bone marrow niche to durably constrain immune reconstitution and vaccine responsiveness

Infections are the most common cause of non-relapse mortality in multiple myeloma (MM), but the basis of persistent immune dysfunction is obscured by patient heterogeneity and complex treatment regimens, including autologous stem cell transplant (ASCT). We performed longitudinal multi-omic profiling of matched bone marrow and peripheral blood from MM patients across diagnosis, induction, ASCT, and recovery. We found the tumor imposes a compartment-specific immune program where the marrow exhibits metabolic and inflammatory changes that bias hematopoiesis and alter cytotoxic effector programs not mirrored in blood. Adaptive immune reconstitution is impaired up to two years post-ASCT. Half of patients fail to mount IgG responses to high-dose non-adjuvanted influenza vaccine, a defect overcome by the lipid nanoparticle (LNP) adjuvanted COVID mRNA vaccine, which elicited responses in all patients, supporting adjuvanted influenza vaccine strategies in MM. Together these findings define how myeloma and its treatment durably reshape immunity from the marrow outward. HighlightsO_LIMultiple Myeloma marrow and blood show opposing metabolic and inflammatory states C_LIO_LIInduction therapy selects durable myeloma plasma-cell transcriptional states C_LIO_LIB cell and follicular helper T deficits blunt antigen responses after transplant C_LIO_LICOVID-19 vaccination builds immune memory with variable responses to flu vaccination C_LI eTOCMultiple myeloma and its treatment leave a lasting imprint on the bone marrow niche. By profiling bone marrow and blood longitudinally at diagnosis, through induction, autologous transplant, and recovery, we show that marrow-local metabolic and inflammatory constraints persist and help explain why influenza vaccination often fails while mRNA vaccination succeeds.

cancer biology↗

bioRxiv2026

Donor-specific assemblies enhance somatic structural variant detection in complex genomic regions

Structural variants (SVs) contribute substantially to genomic variation and disease, but detecting somatic SVs (sSVs) remains difficult due to reference bias, mosaicism, and enrichment in repetitive regions. Linear reference genomes, like GRCh38 and CHM13, do not fully capture individual genomic structure, which can obscure true somatic variation. Donor-specific assemblies (DSAs) generated from the same genome where sSVs are being assayed provide a personalized alternative, yet their performance for sSV detection has not been systematically assessed. As part of the Somatic Mosaicism across Human Tissues (SMaHT) Network, we benchmark a DSA for sSV discovery in the COLO829 melanoma cell line with a matched normal sample from the same individual. We compare sSV detection across GRCh38, CHM13, and the COLO829BL_DSA using three different sSV callers (Delly, Severus, and Sniffles2) and sequence data from multiple long-read platforms. The COLO829BL_DSA identifies 1.8-fold more manually validated sSVs than linear references, in regions both shared with GRCh38 and CHM13 and unique to the COLO829BL_DSA. Variants detected only with the COLO829BL_DSA are often found in satellite and other repeat-rich regions that are difficult to resolve using standard references. In addition, several COLO829BL_DSA-specific sSVs are located in genes, some of which are associated with cancer. Overall, these results underscore the utility of DSAs in improving sSV detection.

genomics↗

bioRxiv2025

A telomere-to-telomere map of somatic mutation burden and functional impact in cancer

Oncogenesis involves widespread genetic and epigenetic alterations, yet the full spectrum of somatic variation genome-wide remains unresolved. We generated a near-telomere-to-telomere (T2T) diploid assembly of a donor paired with deep short- and long-read sequencing of their melanoma. This revealed that 16% of somatic variants occur in sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-induced damage due to sequence-intrinsic mutability and inefficient repair. Centromere kinetochore domains emerged as focal sites of structural, genetic, and epigenetic variation, leading to remodeling of centromere kinetochore binding domains during tumor evolution. Single-molecule telomere reconstructions uncovered cycles of attrition, deletion, and telomerase-mediated extension that shape cancer telomeres. Finally, diploid chromatin maps exposed that copy number alterations and epimutations, rather than point mutations, predominate in rewiring cancer regulatory programs. These findings define the full landscape of a cancers somatic variation and their functional impact, establishing a blueprint for T2T studies of mosaicism.

genomics↗

bioRxiv2024

Deaminase-assisted single-molecule and single-cell chromatin fiber sequencing

Gene regulation is mediated by the co-occupancy of numerous proteins along individual chromatin fibers. However, our tools for deeply profiling how proteins co-occupy individual fibers, especially at the single-cell level, remain limited. We present Deaminase-Assisted single-molecule chromatin Fiber sequencing (DAF-seq), which leverages a non-specific double-stranded DNA deaminase toxin A (SsDddA) to efficiently stencil protein occupancy along DNA molecules via selective deamination of accessible cytidines, which are preserved via C-to-T transitions upon DNA amplification. We demonstrate that DAF-seq enables [~]200,000-fold enrichment of target loci for single-molecule footprinting at near single-nucleotide resolution, enabling the precise delineation of the regulatory logic guiding neighboring proteins to cooperatively occupy chromatin fibers. Furthermore, DAF-seq enables the synchronous identification of single-molecule chromatin and genetic architectures - resolving the functional impact of rare somatic variants, as well as transitional chromatin states guiding haplotype-selective promoter actuation. Finally, we demonstrate that single-cell DAF-seq enables the accurate reconstruction of the diploid genome and epigenome from a single cell, revealing that a cells accessible regulatory landscape can diverge by as much as 63% while still retaining the cells identity. Overall, DAF-seq enables the comprehensive characterization of protein occupancy and chromatin accessibility across entire chromosomes with single-nucleotide, single-molecule, single-haplotype, and single-cell precision.

genomics↗

bioRxiv2024

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules--a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with [~]10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated {gamma}-globin (HBG1/HBG2) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

genomics↗

bioRxiv2024

A haplotype-resolved view of human gene regulation

Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq Inferred Regulatory Elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing novel imprinted elements lacking underlying parent-of-origin CpG methylation differences, and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.

genomics↗

bioRxiv2022

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

Discoveries of RNA roles in cellular physiology and pathology are raising the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an "RNA-privileged" chemical space. Biennial updates of the database and the establishment of a website platform (rbind.chem.duke.edu) have provided new insights and tools to design small molecules based on the analyzed physicochemical and spatial properties. In this report and R-BIND 2.0 update, we refined the curation approach and ligand classification system as well as conducted analyses of RNA structure elements for the first time to identify new targeting strategies. Specifically, we curated and analyzed RNA target structural motifs to determine properties of small molecules that may confer selectivity for distinct RNA secondary and tertiary structures. Additionally, we collected sequences of target structures and incorporated an RNA Structure Search algorithm into the website that outputs small molecules targeting similar motifs without a priori secondary structure knowledge. Cheminformatic analyses revealed that, despite the 50% increase in small molecule library size, the distinguishing properties of R-BIND ligands remained significantly different to that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.

biochemistry↗