Multidisciplinary approach to studying genomic variation on genome function and phenotype

Project Summary The long-term goal of our laboratory is tackling a fundamental question in the field of Genetics: How do genetic variants drive functional changes at the molecular, cellular, and phenotypic levels? In essence, we aim to unravel the intricate consequences of genomic variation on genome function and phenotypes. This undertaking is particularly challenging, primarily because most variants associated with phenotypes or diseases are located in non-coding regions, indicating their likely involvement in the regulation of gene expression. The noncoding nature of most loci introduces another layer of complexity, characterized by cell-type specificity, developmental dynamism, residence at considerable distances from their target genes, and often a lack of conservation across different model systems. Additional challenges arise from allelic heterogeneity and linkage disequilibrium. This complexity forms a bottleneck, hindering progress in understanding the genetic basis of dynamic gene expression programs crucial for specifying distinct cell types, modulating tissue homeostasis, and influencing diseases. Our proposal builds upon past research achievements and adopts a multidisciplinary approach that integrates cutting-edge technologies, including computational analysis, single-cell analysis, iPSC system, and genetic screening. The objective is to create an integrative platform for systematically investigating the genetic architecture of complex traits and the impact of genomic variation on function. Over the next five years, we plan to thoroughly and mechanistically characterize the effects of genomic variation on genome function and phenotypes. We will define and systematically characterize genetic dynamics profiling to explore the impact of allelic heterogeneity on complex traits. Additionally, our proposal aims to characterize the role of genetic variants in cellular programs relevant to human diseases by using high-content microscopy imaging. Our research holds the promise of providing valuable insights into the dynamic landscape of genetic regulation and its profound impact on human health and disease.