Project summary The primary focus of research in my laboratory centers on unraveling the causal relationship between common genetic variants in humans and susceptibility to complex diseases. We aim to understand how single nucleotide polymorphisms (SNPs), often residing in the non-coding portion of the genome, influence cellular physiology, the determination of cell fate, and the alterations in cell state. We employ a unique human-specific genetic framework, utilizing induced pluripotent stem cells (iPSCs) and genome editing techniques to investigate non-coding regions of the genome whose functions are not yet defined. SNPs frequently exhibit correlations with neighboring variants, forming clusters known as haplotypes through a phenomenon called linkage disequilibrium. Haplotypes are shared within the same ancestral group and exhibit significant variations across different genetic ancestries. This genomic diversity translates into varying degrees of correlation between genetic variants and the risk of developing complex diseases across diverse ancestries. While this genomic diversity is deeply rooted in human evolutionary history, our understanding of its functional implications at the cellular level remains incomplete. The elucidation of haplotypes function and the effect of their diversity are crucial to uncover unexplored biological processes impacted by the non-coding genome and for enhancing the accuracy of predicting complex disease risk within different populations. In this proposal, we outline a research strategy to investigate human-specific haplotype diversity and its cellular consequences across diverse cell types. Our overarching goal is to determine the physiological significance of haplotype diversity in cell fate determination and the maintenance of cell states, shedding light on haplotype functionality and its role in disease susceptibility. By examining the impact of ancestrally diverse haplotypes at the cellular level, this proposal aims to identify critical factors contributing to ethnicity-based disease risk and cell-type-specific vulnerabilities. We will employ human iPSCs obtained from diverse ancestral backgrounds, induce differentiation into various cell types, perform haplotype editing, and utilize a wide range of assays to evaluate how diversity at specific genomic loci influences cell fate determination and the maintenance of cell states in response to various stimuli. The tools we develop will serve as a versatile platform for investigating non-coding genetic risk factors in various complex diseases, expediting the translation of functional genomics findings into advancements in human health.