Biology subjects

Akbari, V.

Publications and source records attributed to Akbari, V..

6 recordsLinked to original sources

bioRxiv2025

HuBIE: The Human Blood Immunome Encyclopedia Of TCRs and BCRs in Bloodstream Infections and Cancer

T and B cells are central to adaptive immunity, where they identify and neutralize foreign antigens and cancer neo-antigens. Large-scale elucidation of T- and B-cell receptors (TCRs and BCRs) through immune-repertoire sequencing promises novel diagnostics, prognostic markers, and therapeutic strategies. However, progress is hampered by small cohort sizes, a lack of real-world patient diversity, and heterogeneous sample processing, impeding cross-study comparability. To overcome these limitations, here we introduce the Human Blood Immunome Encyclopedia (HuBIE), comprising immune-repertoire data from 2,614 samples collected from 1,941 participants. The cohort includes a range of bloodstream infections, several cancer types, and control participants, with many individuals providing longitudinal samples. We employed Roches immune receptor Primer Extension Target Enrichment (immunoPETE) platform to perform simultaneous targeted sequencing of T-cell receptor {beta} chains (TRB), T-cell receptor {delta} chains (TRD), and immunoglobulin heavy chains (IGH), thereby profiling TCRs and BCRs in all participants. We provide a comprehensive description of immune-repertoire diversity in cancer and bloodstream infections and examine variations across demographic variables such as age and race. We find significant differences in TRB and IGH composition across ethnic groups, and show that the fall in repertoire diversity with age follows distinct patterns for TRB, TRD, and IGH and is accompanied by age-related differences in VJ gene usage. Finally we demonstrate that greater immunological diversity is associated with improved survival but only for elderly participants. HuBIE thus constitutes a valuable resource for the immune-repertoire community, enabling large-scale mapping of the human immunome to accelerate development of diagnostics, prognostic biomarkers, and innovative therapeutic strategies.

immunology↗

bioRxiv2023

Genomic structures and regulation patterns at HPV integration sites in cervical cancer

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

genomics↗

bioRxiv2023

Profiling Chromatin Accessibility in Humans Using Adenine Methylation and Long-Read Sequencing

Chromatin accessibility demonstrates accessible DNA regions that usually have regulatory function. Several studies have demonstrated DNA accessibility profiling using nanopore sequencing and GpC or adenine modification. However, the GpC dinucleotide is not evenly distributed across the genome and there are regions sparse in GpC. 6mA studies have demonstrated chromatin accessibility in yeast using nanopore based sequencing, although a high-false positive in 6mA detection rate and low coverage have previously precluded the effective use in mammalian sized genomes. Here, we have developed accurate 6mA base calling and demonstrated high-resolution profiling of accessible regions and simultaneous CpG methylation detection in humans using long read sequencing.

genomics↗

bioRxiv2023

IMPALA: A Comprehensive Pipeline for Detecting and Elucidating Mechanisms of Allele Specific Expression in Cancer

SummaryAllele-specific expression (ASE), where transcripts from one allele are more abundant than transcripts from the other, can arise from various genetic mechanisms and has implications for gene regulation and disease. We present IMPALA (Integrated Mapping and Profiling of Allelically-expressed Loci with Annotations), a versioned and containerized pipeline for detecting ASE in samples including cancer genomes. IMPALA leverages RNA sequencing data and, optionally, phased variant, copy number variant (CNV), allelic methylation, and mutation data to identify ASE genes and uncover underlying regulatory mechanisms. IMPALA incorporates the MBASED framework for ASE detection, and outputs a comprehensive summary table and informative figures to visualize the genomic distribution of ASE genes and their correlation with potential regulatory causes. We applied IMPALA to a cancer sample and identified thousands of genes with ASE and highlighted potential somatic events that may have influenced ASE of these genes. ASE data can be used to detect the downstream consequences of genomic alterations, which facilitates the identification of dysregulated cancer-related genes. IMPALA thus provides researchers with a powerful tool for both ASE analysis and for investigating genetic factors correlated with ASE. Availability and implementationIMPALA is licensed under GNU General Public License v3.0 and freely available at https://github.com/bcgsc/IMPALA and https://doi.org/10.5281/zenodo.8019168 with documentation and tutorial. Contactsjones@bcgsc.ca Supplemental informationSupplemental materials are available at Bioinformatics online. Issue section: Gene expression

bioinformatics↗

bioRxiv2022

Parent-of-origin detection and chromosome-scale haplotyping using long-read DNA methylation sequencing and Strand-seq

Hundreds of loci in human genomes have alleles that are methylated differentially according to their parent of origin. These imprinted loci generally show little variation across tissues, individuals, and populations. We show that such loci can be used to distinguish the maternal and paternal homologs for all autosomes, without the need for the parental DNA. We integrate methylation-detecting nanopore sequencing with the long-range phase information in Strand-seq data to determine the parent of origin of chromosome-length haplotypes for both DNA sequence and DNA methylation in five trios with diverse genetic backgrounds. The parent of origin was correctly inferred for all autosomes with an average mismatch error rate of 0.31% for SNVs and 1.89% for indels. Because our method can determine whether an inherited disease allele originated from the mother or the father, we predict that it will improve the diagnosis and management of many genetic diseases.

genomics↗

bioRxiv2021

Genome-Wide Detection of Imprinted Differentially Methylated Regions Using Nanopore Sequencing

Imprinting is a critical part of normal embryonic development in mammals, controlled by defined parent-of-origin (PofO) differentially methylated regions (DMRs) known as imprinting control regions. As we and others have shown, direct nanopore sequencing of DNA provides a mean to detect allelic methylation and to overcome the drawbacks of methylation array and short-read technologies. Here we leverage publicly-available nanopore sequence data for 12 standard B-lymphocyte cell lines to present the first genome-wide mapping of imprinted intervals in humans using this technology. We were able to phase 95% of the human methylome and detect 94% of the well-characterized imprinted DMRs. In addition, we found 28 novel imprinted DMRs (12 germline and 16 somatic), which we confirmed using whole-genome bisulfite sequencing (WGBS) data. Analysis of WGBS data in mus musculus, rhesus macaque, and chimpanzee suggested that 12 of these are conserved. We also detected subtle parental methylation bias spanning several kilobases at seven known imprinted clusters. These results expand the current state of knowledge of imprinting, with potential applications in the clinic. We have also demonstrated that nanopore long reads, can reveal imprinting using only parent-offspring trios, as opposed to the large multi - generational pedigrees that have previously been required.

genomics↗