Functional Genomics and GWAS Team
The Functional Genomics Team is focused on the use of next generation sequencing methods to identify candidate genes from genome wide-association studies (GWAS). Currently over 30 GWAS regions have been identified for ovarian cancer, and we are now focused on understanding how to link these GWAS loci with their most likely causal gene. Current projects include identifying various regions of the genome with functional effects on the transcriptome,with regards to ovarian cancer risk. Using epigenetic profiling methods, our plan is to provide a comprehensive landscape of the genetic determinants of gene expression in ovarian cancer in order to best prioritize genes and loci for further functional follow up.
Identification of functional variants in ovarian GWAS regions
GWAS studies have identified thousands of common variants associated with numerous diseases but for the vast majority of genetic associations, the underlying functional mechanisms are unknown. Unlike Mendelian disorders, ~90% of trait and risk-associated alleles lie out sideof protein coding regions, suggesting that common variants lie in regulatory regions and cause disease by regulating target gene expression. In post GWAS studies, the overall problem becomes identifying i) the correct susceptibility gene(s) for each locus and their functional role in disease pathogenesis and ii) the causal genetic variant(s) which drive disease development. Common variants that influence the activity of specific regulatory elements such as enhancers,may affect target gene expression through direct, physical interactions. We use 3C/4C technologies to identify physical interactions between susceptibility cell lines. Using epigenetic profiling spanning all ovarian cancer histotypes, we are establishing histotype specific enhancer profiles. Enhancer marks that overlap with positive 3C/4C SNP interaction are are later validated in in vitro neoplastic models of ovarian cancer.
Identifying candidate susceptibility genes associated with prostate, breast and ovarian cancer risk loci
Prostate, breast and ovarian cancer share common genetic and lifestyle/environmental etiologies, both epidemiological (hormonal risk factors) and genetic (BRCA1,BRCA2). This shared genetic background suggests similar biological mechanisms drive the development of these cancers. By determining the function of pleiotropic loci, we expect to identify similar mechanisms underlying these different cancer types. Using expression quantitative trait locus(eQTL) analysis, integrated with genetic fine mapping and regulatory profiling, we have identified candidate causal variants at 11 pleiotropic risk loci for prostate, ovarian and breast cancer. We use chromosome conformation capture techniques (3C and 4C) to identify physical interactions between these risk loci and target genes in experimental models of prostate,breast and ovarian normal and tumor tissues. Positive interactions are then prioritized for further characterization in genome editing assays to confirm function of these plausible functional variants in regulatory regions.
- Identifying target genes of pleiotropic risk loci (breast, prostate and ovarian) using chromosome capture technologies
- Epigenetic profiling of histotypes and cells of origin for ovarian cancer using various ChIPseq marks (including H3K27Ac, H3K4me, H3K4me3 and ovarian cancer specific transcription factors)
- Establishing Tissue ChIP seq techniques for epigenomic profiling of ovarian tumors
- Developing new chromatin technologies (HiC, ChIAPET) to identify histotype specific topologically associated domains (TADs) in ovarian cancer
Jasmine Plummer, PhD Project Scientist (Jasmine.Plummer@cshs.org)
Dr. Plummer completed her HonBSc in Biology and Chemistry at University of Toronto, Toronto, Canada where she worked with Dr. JJB Smith on sensory circuitry.Dr. Plummer joined the Department of Physiology and Biophysics, at Dalhousie University (Halifax, Canada) in the laboratory of Dr. Croll. She completed her Masters of Science (MSc) in neuroscience, specializing in comparative neurobiology and neuro development. In her PhD work under the supervision of Dr. Culotti(Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto), Dr.Plummer took a genetic approach to identifying new genes that regulate the development of the nervous system. She moved to Dr. Levitt’s laboratory at Children’s Hospital Los Angeles for her postdoctoral work. Dr. Plummer’s post-doctoral fellowship focused on systems biology approaches to understanding genetic risk of neurodevelopmental disorders. As an Autism Speaks postdoctoral fellow, her research primarily focused on the discovery and function of gene regulatory networks involving autism risk genes. Her research also broadened to include and interrogate other neuropsychiatric disorder loci., including schizophrenia, ADHD, bipolar disorder and major depressive disorder. In 2016 Dr.Plummer joined the Center for Bioinformatics and Functional Genomics to lead the Functional Genomics and GWAS team together with Dr. Gayther.
Stephanie Chen, Research Associate III (Stephanie.Chen2@cshs.org)
Stephanie Chen has worked extensively in the ovarian cancer field, first at the University of Southern California with Dr. Susan Ramus. At USC, Stephanie used the Nanostring nCounter technology to detect gene expression, and analyzed over 1920 ovarian tumor samples from FFPE material for tumor profiling. She also performed targeted sequencing and Loss of Heterozygosity analysis of breast cancer cases with both BRCA1 and BRCA2 mutations. Now at Dr. Simon Gayther’s group, Stephanie has taken on the position as lab manager, and has helped develop and perform functional genomic techniques including chromosome conformation capture methods (3C/4C) on breast, ovarian and prostate cancer lines. Stephanie also uses ChIPseq to identify transcription factor binding sites, for key transcriptional regulators of ovarian cancer.
Brian Davis, Research Associate III (Brian.Davis@cshs.org)
Brian Davis joined the Dr Gayther laboratory recently as a Research Associate III after working at the Molecular Genomics Core at the University of Southern California. At USC MGC core, Brian oversaw library preparations to be run on Illumina’s Next-Generation Sequencing Systems, the NextSeq500 and MiSeq platform. Along with sequencing, Brian is adept at SNP genotyping and gene and miRNA expression. He has had much experience with sample extractions and movement, using various liquid handling Tecan robotics. Brian extracts and prepares all samples for our ongoing transcriptome projects. He also oversees our epigenetic profiling (ChIPseq) projects with goals to establish Tissue ChIPseq for ovarian and breast cancer tumor analyses.
- Plummer, JT, Gordon, AJ and P Levitt. The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside Frontiers in Psychiatry. 7:142. PMCID: PMC4992686
- Plummer, JT, Evgrafov, OV, Bergman, MY, Friez, M, Haiman, CA, Levitt, P, KA Aldinger.Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. Translational Psychiatry 3:1-8. PMCID: PMC3818007
- Aldinger, KA, Plummer, JT and P Levitt. Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene. Journal of Neurodevelopmental Disorders. 5:15. PMCID: PMC38700820
- Aldinger, KA, Plummer, JT, Qiu, SF, and P Levitt. SnapShot: Genetics of Autism. Neuron 72(2):418.PMID: 22017998
- Rebbeck TR, Friebel TM, Mitra N, Wan F, Chen S, [120 authors] Easton D, Chenevix-Trench G,Antoniou AC, Nathanson KL, Ramus SJ. Inheritance of Deleterious Mutations at Both BRCA1 and BRCA2 in an International Sample of 32,295 Women. Breast Cancer Research 2016,
- Talhouk A, Kommoss S, Mackenzie R, Cheung M, Leung S, Chiu DS, Kalloger SE, Huntsman DG,Chen S, Intermaggio M, Gronwald J, Chan FC, Ramus SJ, Steidl C, Scott DW, Anglesio MS. Single-patient molecular testing with NanoString nCounter Data using a reference-based strategy for batch effect correction. PLOS One. 2015.
- Levine AJ, Lee W, Figueiredo JC, Conti DV, Vandenberg DJ, Davis BD, Edlund CK, Henning SM,Heber D, Stern MC, Haile RW. Variation in folate pathway genes and distal colorectal adenomarisk: a sigmoidoscopy-based case-control study. Cancer Causes Control. 2011 Apr;22(4):541-52. doi: 10.1007/s10552-011-9726-7.
- Levine AJ, Ihenacho U, Lee W, Figueiredo JC, Vandenberg DJ, Edlund CK, Davis BD, Stern MC,Haile RW. Genetic variation in insulin pathway genes and distal colorectal adenoma risk. Int J Colorectal Dis. 2012 Dec;27(12):1587-95. doi: 10.1007/s00384-012-1505-8.