Biology subjects

Sedeno-Cortes, A. E.

Publications and source records attributed to Sedeno-Cortes, A. E..

7 recordsLinked to original sources

bioRxiv2026

Single-molecule variation in telomeric sequence and structure across humans

The repetitive architectures of telomeric and subtelomeric regions have obscured studies of their genetic variation and chromatin organization across the human population. Here, we integrate near-complete diploid genome assemblies from 212 individuals with matched long-read sequencing data to construct an atlas of 316,146 telomere-spanning molecules across 12,080 chromosome-end-resolved telomere arrays. This atlas reveals that nearly every chromosome end harbors a structured and unique pattern of telomere variant repeats (TVR), or TVR code, with subtelomere-proximal TVR codes being heritable, somatically stable, and influenced by subtelomeric TAR1 regulatory elements. Despite ongoing cycles of telomere shortening and elongation in the germline, proximal TVR codes are maintained across the human population. These TVR codes expose rare telomerase-independent events that lengthen telomeres in the germline, including interchromosomal telomere exchange and recurrent internal duplications within telomere arrays. Furthermore, single-molecule chromatin fiber sequencing across 26,972 molecules spanning the telomere-subtelomere boundary confirms that TVR-rich regions adopt telomeric chromatin but introduce discrete discontinuities into otherwise compact telomeric chromatin fibers. Together, our results link chromosome-end sequence variation to telomere cap formation and telomerase-independent telomere extension mechanisms in the human germline.

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↗

bioRxiv2025

Genetic diversity and regulatory features of human-specific NOTCH2NL duplications

NOTCH2NL (NOTCH2-N-terminus-like) genes arose from ape-specific chromosome 1 segmental duplications implicated in human brain cortical expansion, including an incomplete NOTCH2 gene. Genetic characterization of these loci and their regulation is complicated because they are embedded in large, nearly identical duplications that predispose to recurrent microdeletion syndromes. Using near-complete long-read assemblies generated from 70 human and 12 ape haploid genomes, we show independent recurrent duplication among apes with protein-coding copies emerging in humans 2.2-3.7 million years ago. We distinguish NOTCH2NL paralogs present in every human haplotype (NOTCH2NLA) from copy number variable ones. We also characterize large-scale structural variation, including gene conversion, for 28% of haplotypes leading to a previously undescribed paralog, NOTCH2tv. Finally, we apply Fiber-seq and long-read transcript sequencing to human dorsal forebrain organoids to characterize the regulatory landscape and find that the most fixed paralogs, NOTCH2 and NOTCH2NLA, harbor the greatest number of paralog-specific elements potentially driving their regulation.

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↗

bioRxiv2023

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have also revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and the astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity across transgenes and in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

neuroscience↗

bioRxiv2020

A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation

The isocortex and hippocampal formation are two major structures in the mammalian brain that play critical roles in perception, cognition, emotion and learning. Both structures contain multiple regions, for many of which the cellular composition is still poorly understood. In this study, we used two complementary single-cell RNA-sequencing approaches, SMART-Seq and 10x, to profile [~]1.2 million cells covering all regions in the adult mouse isocortex and hippocampal formation, and derived a cell type taxonomy comprising 379 transcriptomic types. The completeness of coverage enabled us to define gene expression variations across the entire spatial landscape without significant gaps. We found that cell types are organized in a hierarchical manner and exhibit varying degrees of discrete or continuous relatedness with each other. Such molecular relationships correlate strongly with the spatial distribution patterns of the cell types, which can be region-specific, or shared across multiple regions, or part of one or more gradients along with other cell types. Glutamatergic neuron types have much greater diversity than GABAergic neuron types, both molecularly and spatially, and they define regional identities as well as inter-region relationships. For example, we found that glutamatergic cell types between the isocortex and hippocampal formation are highly distinct from each other yet possess shared molecular signatures and corresponding layer specificities, indicating their homologous relationships. Overall, our study establishes a molecular architecture of the mammalian isocortex and hippocampal formation for the first time, and begins to shed light on its underlying relationship with the development, evolution, connectivity and function of these two brain structures.

neuroscience↗

bioRxiv2018

Monitoring changes in the Gene Ontology and their impact on genomic data analysis

The Gene Ontology (GO) is one of the most widely used resources in molecular and cellular biology, largely through the use of \"enrichment analysis\". To facilitate informed use of GO, we present GOTrack (https://gotrack.msl.ubc.ca), which provides access to historical records and trends in the Gene Ontology and GO annotations (GOA). GOTrack gives users access to gene- and term-level information on annotations for nine model organisms as well as an interactive tool that measures the stability of enrichment results over time for user-provided \"hit lists\" of genes. To document the effects of GO evolution on enrichment, we analyzed over 2500 published hit lists of human genes (most over 9 years old). 53% of hit lists were considered to yield significantly stable enrichment results. Because stability is far from assured for any individual hit list, GOTrack can lead to more informed and cautious application of GO to genomics research.

bioinformatics↗