iPS models for interrogating how genes and alleles shape cellular function

Abstract

Tens of thousands of genetic variants shape human phenotypes, mostly by unknown cellular mechanisms. Human derived stem cells enable us to measure cellular phenotypes and their relationship to human genetic variation. Here, I provide a range of works focusing on leveraging these human stem cells to model functional genomics in an array of experimental paradigms. My efforts developing novel experimental systems now make population-scale (10s-100s of unique cell lines) experiments more feasible and accessible. I provide a new method for differentiating human stem cells into functional astrocytes, which are increasingly being implicated in a range of neuropsychiatric and neurological disorders. I then use these methods to understand astrocyte-neuron interactions and show that perturbations of this interaction may shed insights into mechanisms by which antipsychotic medications provide therapeutic benefit. I show state of the art imaging approaches are amenable to stem cell models and identify both common and rare genetic variants which mediate cell morphology. Last, I display functional and statistical convergence between rare and common genetic risk factors for neuropsychiatric phenotypes on Chromosome 22q. My work fills many gaps in the fields of stem cell biology, genomics, and human genetics to establish a strong foundation for other researchers to explore experimental biology at the scale of 100s to 1000s of genetically unique cell lines, across multiple levels of analysis, and develop new intellectual frameworks for investigating the functional consequences of human genetic variation.

Date of Award	1 Oct 2023
Original language	English
Awarding Institution	King's College London
Supervisor	Davide Danovi (Supervisor), Fiona Watt (Supervisor) & Ralda Nehme (Supervisor)