Frazer Lab Department of Pediatrics, Genome Information Sciences

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Welcome to the Frazer Lab!

We are using two complementary approaches to achieve our goal of identifying and characterizing functional human genetic variants. Our first approach utilizes iPSCORE, a resource that was generated to enable both familial and association-based genetic studies of molecular and physiological phenotypes in induced pluripotent stem cells (iPSCs) and derived cell types. Our second approach involves conducting association studies in well-characterized cohorts with the goal of identifying variants that play roles in human disease and to assess their contributions to disease pathogenesis, progression, and prognosis.

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iPSCORE (iPSC Collection for Omics Research)

    Induced pluripotent stem cells (iPSCs), derived from human adult cells and capable of being differentiated to become a variety of cell types, are a powerful tool for studying how genetic variants associate with human molecular phenotypes. Over the past six years, our lab has systematically derived and characterized a unique collection of iPSC lines from 222 individuals - iPSCORE. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic CNVs) as determined using high-throughput RNA-seq and genotyping arrays, respectively. The participants were recruited to include 41 families, twins, and individuals of diverse ethnicity to enable genetic studies investigating the segregation of traits. Due to the fact that some of the individuals in the 41 families are only related by marriage, there are a total of 136 genetically unrelated individuals in the collection. All individuals in iPSCORE have whole genome sequence data. We are currently using these lines to conduct genotype-molecular phenotype correlations in both pluripotent stem cells and a variety of iPSC-derived cell types including cardiomyocytes (iPSC-CMs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). iPSCORE provides a powerful tool to examine how genetic variants influence molecular and physiological traits across a variety of derived cell types, as well as to functionally interrogate variants underlying a variety of GWAS phenotypes.

Human genetic studies

    We collaborate with Dr. Radha Ayyagari at the Shiley Eye Institute at UC San Diego to identify new genes involved in inherited retinal dystrophies (IRD). We have generated whole genome sequence (WGS) data for 454 individuals from 126 pedigrees segregating IRD; 227 subjects are affected by IRD and 227 are unaffected. Our analyses have identified new genes that can underlie IRD as well as new types of mutations that can be present in known IRD genes. The study is funded by the NEI and the Foundation Fighting Blindness.

    We also collaborate with Dr. John-Bjarne Hansen at the University of Tromsø to study the genetic underpinnings of venous thromboembolism (VTE). This multi-PI study is funded through the K.G. Jebsen Medical Foundation to analyze the Tromsø cohort, which is comprised of individuals who have been clinically followed for several decades. Our lab has sequenced over a thousand individuals in the Tromsø cohort and we are now analyzing these data to identify genetic associations with VTE.

iPSC-derived cell types

    iPSC-derived cardiomyocytes (iPSC-CMs): It has been postulated that all genetic variation that is functional in a disease-associated cell type may also be relevant for the disease; and thus, by comprehensively characterizing how genetic variation impacts molecular processes in cardiomyocytes, it could be possible to identify genetic variation important for cardiac disease. Hence, a thorough understanding of regulatory variation in cardiomyocytes would not only reveal the molecular effects of the majority of variants identified to date through cardiac trait genome-wide association studies (GWAS), but could also enable the identification of novel variants and provide insights into molecular processes underlying complex cardiac traits and disease. We have recently completed generating iPSC-CMs from 139 individuals and are in the process of analyzing how inherited coding and regulatory variants influence molecular phenotypes including gene expression, ATAC-seq peaks, and H3K27ac peaks. This CardiPS study was funded through the National Heart, Lung and Blood Institute (NHLBI) and the California Institute for Regenerative Medicine (CIRM).

    iPSC-derived pancreatic precursor cells (iPSC-PPCs): The Frazer lab is also involved in a multi-PI study to link pancreatic precursor cell phenotypes to genotypes through the generation of iPSC-PPCs. We will derive pancreatic progenitors from 100 human iPSCs in iPSCORE and generate ATAC-seq, H3K27ac ChIP-seq, RNA-seq, DNA methylation, and Hi-C chromatin conformation data, and combine with similar available datasets from human islets. These analyses will provide a comprehensive understanding of how genetic variants alter gene regulation and local chromatin states in pancreatic precursor cells. This study was funded through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and may provide insights into the roles that genetic variants play in the manifestation of diabetes.

    iPSC-derived retinal pigment epithelium cells (iPSC-RPEs). RPE dysfunction is the fulcrum of age-related macular degeneration (AMD) pathogenesis, and thus, by comprehensively characterizing the RPE epigenome, it could be possible to functionally annotate variation important for AMD. From six iPSCORE iPSCs, we have derived high-quality iPSC-RPEs that display many of the morphological and molecular characteristics of native RPE. We used RNA-seq to compare iPSC-RPE gene expression profiles to fetal RPEs, iPSCs, and another differentiated cell types via principle component analysis (PCA) of the RNA-seq data, and observed clustering of the iPSC-RPEs with fetal RPE that was driven by expression of gene sets associated with RPE functions. Using ATAC-seq, we found enrichment for relevant transcription factor motifs in iPSC-RPE accessible chromatin, including OTX2, LHX2, and MITF. We compared the iPSC-RPE ATAC-peaks to data from RPEs from adults with and without AMD and show that although they were highly similar, iPSC-RPE ATAC peaks were more strongly enriched for AMD GWAS association signal than adult RPE peak regions. We therefore used the iPSC-RPE chromatin accessibility profiles to prioritize regulatory AMD risk variants at GWAS loci and identified two variants in ATAC-peaks at the SLC12A5/MMP9 locus with a high posterior probability of being causally associated with AMD. Together, our work suggests that iPSC-RPE is an effective model system to identify functional regulatory variants associated with AMD. This study was funded by the National Eye Institute (NEI).

Kelly A Frazer, Ph D

    Dr. Frazer is an internationally renowned leader in the field of genome biology and medicine. She is the director of UC San Diego Institute for Genomic Medicine and founding chief of the Division of Genome Information Sciences in the Department of Pediatrics at UC San Diego.

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