NLM IRP Seminar Schedule
UPCOMING SEMINARS
RECENT SEMINARS
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April 16, 2024 Jaya Srivastava
Regulatory plasticity of the human genome -
April 11, 2024 Sergey Shmakov
Comprehensive survey of the TnpB RNA-guided nucleases -
April 2, 2024 Yifan Yang
Fairness and Bias in Biomedical AI -
March 28, 2024 Joseph Schafer
Evolutionary selection of proteins with two folds -
March 26, 2024 Sanasar Babajanyan
Microbial diversity and ecological complexity emerging from environmental variation and horizontal gene transfer in a simple mathematical model
Scheduled Seminars on May 16, 2023
Contact NLM_IRP_Seminar_Scheduling@mail.nih.gov with questions about this seminar.
Abstract:
PCOS is a complex disorder manifesting as reproductive and metabolic abnormalities in women. The undefined etiology stems from our incomplete understanding of genetic aberrations contributing to the diseased phenotype. This has resulted in speculations surrounding the cause-consequence relationship between phenotypic features of PCOS and limited our knowledge of comprehensive genetic signatures of PCOS.
Pleiotropic effects are salient features of genetic regulation in mammalian genomes. The contribution of a set of regulatory elements (REs) to upregulation of a single gene, or the genetic control of multigene loci by a single RE, give rise to heterogenous phenotypes. Enhancers in particular dictate the spatio-temporal scale of gene expression by controlling transcription factor (TF) binding events. The complex traits of PCOS are suggestive of pleiotropy originating from genetic and epigenetic changes that arise from nucleotide variations in REs of the genome. Genome Wide Association Studies (GWAS) have identified ~100 risk variants associated with PCOS and implicated the involvement of several genes such as FSHB/R, THADA, DENND1A, etc. However, mechanisms by which they contribute to pathophysiology are unknown. Additionally, twin studies have implicated the heritability of PCOS to be ~80% and yet, the heritability from GWAS variants accounts for less than 10%. Experimental data may account for the ‘missing heritability problem’ specifically through rare variants that are missed in GWAS.
To address this issue, we developed a Deep Learning model of gene regulation in PCOS identifying hundreds of active REs orchestrating the activity of PCOS genes. We also established a foundation for quantifying the impact of single-nucleotide noncoding mutations on TF binding and RE activity. By combining thousands of experimental assays associated with many biological events such as tissue-specific epigenetic maps of the human genome, multi-tissue profiling of TF binding and gene expression using data from high throughput experiments, we have devised a strategy to accurately identify functionally map causative mutations in the GWAS loci of PCOS genes.