Transcriptional consequences of genetic variation on single cells in development and cancer
type: CreativeWork
description: The study of genetic variation has long been central to understanding human disease. Genetic mutations, which constantly accumulate in cells through every cell division and may be inherited, can profoundly impact human development and health. A deeper understanding of their functional consequences, particularly those with adverse effects, may reveal insights to facilitate the development of new, highly-specific, and efficacious therapeutic strategies. While significant progress has been made, the complexity of genetic contributions to disease mechanisms means there is still much to uncover. A crucial starting point to study the impacts of mutations is the transcriptome. As the first and direct readout of the genetic code, the transcriptome offers a powerful lens to understand how genetic aberrations drive phenotypic changes. Decades of research and technological advancement have now enabled exploration of the transcriptional effects of genetic aberrations at unprecedented resolution, thereby delineating their contributions to disease. Motivated by this, my work throughout this thesis focuses on quantifying transcriptional changes as direct consequences of different genetic aberrations at single-cell resolution. I began with the development and benchmarking of alleleIntegrator, a computational tool designed to precisely identify cells carrying copy number variants (CNVs) in single-cell RNA sequencing (scRNA-seq) data. CNVs, frequently observed in human cancers, can serve as markers to track the development of cancer and subclones. By integrating the information from whole genome sequencing (WGS) data, alleleIntegrator definitively genotypes individual transcriptomes by assessing allelic imbalances of cancer-defining CNVs in RNA sequencing reads. This expression-independent approach provides a robust means for identifying cancer cells in scRNA-seq data. Next, to further explore the functional consequences of CNVs, I constructed three scRNA-seq atlases of fetal tissues…
abstract: The study of genetic variation has long been central to understanding human disease. Genetic mutations, which constantly accumulate in cells through every cell division and may be inherited, can profoundly impact human development and health. A deeper understanding of their functional consequences, particularly those with adverse effects, may reveal insights to facilitate the development of new, highly-specific, and efficacious therapeutic strategies. While significant progress has been made, the complexity of genetic contributions to disease mechanisms means there is still much to uncover. A crucial starting point to study the impacts of mutations is the transcriptome. As the first and direct readout of the genetic code, the transcriptome offers a powerful lens to understand how genetic aberrations drive phenotypic changes. Decades of research and technological advancement have now enabled exploration of the transcriptional effects of genetic aberrations at unprecedented resolution, thereby delineating their contributions to disease. Motivated by this, my work throughout this thesis focuses on quantifying transcriptional changes as direct consequences of different genetic aberrations at single-cell resolution. I began with the development and benchmarking of alleleIntegrator, a computational tool designed to precisely identify cells carrying copy number variants (CNVs) in single-cell RNA sequencing (scRNA-seq) data. CNVs, frequently observed in human cancers, can serve as markers to track the development of cancer and subclones. By integrating the information from whole genome sequencing (WGS) data, alleleIntegrator definitively genotypes individual transcriptomes by assessing allelic imbalances of cancer-defining CNVs in RNA sequencing reads. This expression-independent approach provides a robust means for identifying cancer cells in scRNA-seq data. Next, to further explore the functional consequences of CNVs, I constructed three scRNA-seq atlases of fetal tissues…
author: Trinh, Mi
language: eng
keywords: Genomics, Myeloid leukaemia in Down syndrome, ML-DS, Childhood cancers, Human development, Aneuploidy
license: https://www.repository.cam.ac.uk/bitstreams/a5185858-3828-4b36-b324-36069f7f616d/download
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
date published: 2025-01-29
date modified: 2026-07-22T22:24:13Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.121681