Abstract

The rapid advancement of sequencing technologies over the last two decades has delivered unprecedented insight into the biology of the human genome. Most strikingly, the proven single-molecule longread sequencing technologies have delivered the complete, gapless T2T human genome reference in recent years, while significant reductions in costs associated with the production of high-output, highly accurate shortread data in recent months is expected to accelerate the scale and resolution of single-cell, single-molecule, multi-omics analyses. All together, these technology innovations have placed us at the beginning of an exciting era when the knowledge of human genomes can be realized at populational scale to address the unmet needs in human diseases and precision medicine.

At the Northwest Genomics Center (NWGC), we have pioneered a suite of state-of-the-art genomic technologies ranging from long-read sequencing, single-cell multiomics, 3D chromatin organization survey, and spatial omics. Together with advances in data science aimed at systematically characterizing the functional consequences of disease-associated genetic variation, we have applied these approaches to facilitate multiple NIH precision medicine initiatives, including rare disease studies in GREGoR, genomic somatic variation analysis in SMaHT, and population-based genomic characterization in the All of Us Research Program. Our efforts have catalyzed research into the mechanistic underpinnings of health and disease. I will present how these technologies unlock the genetic alterations affected Mendelian conditions and derive mechanistic insights into how pathogenic variants induce 3D chromatin changes in oncogenic transformation.


Short Bio

Chia-Lin Wei, PhD, focuses her research on the mammalian genome, which is extensively folded to form complex three-dimensional (3D) chromatin organization to facilitate functional interactions. These 3D structures and functional interactions are dynamic. Understanding these complex functional interactions and their variations will not only advance fundamental biological knowledge but also provide novel insights into human disease that could lead to new treatment paradigms.

Dr. Wei's research specifically concentrates on the development and application of advanced genomic technologies to decipher genome structures, their 3D organizations, and how they modulate molecular phenotypes and complex traits. Her lab pioneered pair-end-tag (PET) sequencing strategies to advance the understanding of genome variation and transcription regulation in shaping cellular behavior.

In recent years, the lab developed a suite of approaches including ChIA-PET, ChIA-Drop, and ChIATAC to map 3D chromatin conformation. These methods have transformed the understanding of how noncoding elements regulate transcription during development and disease states. Dr. Wei and her team further improved these assays to derive single-cell and single-molecule resolution for studying complex genome structural variation, specifically, the extrachromosomal DNA (ecDNA) function in cancer. In addition, as one of the pioneers in establishing long-read technologies, Dr. Wei leverages advances in single-molecule, long-read sequencing methods to better identify complex structural variants of ecDNA, their evolution, and impacts on ecDNA functions