Nature and contribution of noncoding, regulatory mutations in neurodevelopmental disorders

项目总结

Project Summary This proposal for a Pathway to Independence Award focuses on the training of Dr. Tychele Turner to become an independent investigator of large-scale genomics and human genetics. Dr. Turner has a Bachelor's Degree from Michigan State University in Genomics and Molecular Genetics and a Ph.D. in Human Genetics and Molecular Biology from the Johns Hopkins University School of Medicine. Proposed studies will advance her genomics training into long-read based technologies and massively parallel reporter assays (MPRAs) to assess function of variants discovered in genomes from individuals with neurodevelopmental disorders (NDDs). Another essential piece will be the development of a collaboration for assessing function of these variants in vivo. The training program will consist of two years of mentored training in the laboratory of Dr. Evan Eichler and three years of funding for her independent laboratory. Specifically, the training program will center on the study of noncoding variants in NDDs by identifying these variants and assessing their function. The mentored work will take place under the supervision of the primary mentor, Dr. Evan Eichler, and the co-mentor, Dr. Jay Shendure, both at the University of Washington (UW) Department of Genome Sciences (GS). Both the mentor and co-mentor are well-established experts in the characterization of genomes and high-throughput functional assays of genomic variation, respectively. Dr. Turner will also gain advice from a formal advisory committee as well as through activities arranged by the Department of GS. This department is an optimal place for the mentored training providing the candidate with access to a number of high caliber scientists in areas ranging from basic science, model organisms, disease genomics, population genetics, development and high throughput functional assessment of genomes. While there has been considerable progress in our understanding of the genetics of NDDs through the use of exome and array technologies there still remains an appreciable gap in understanding of their genetic architecture. In proposed studies, we will assess NDDs via a genome-first strategy coupled with functional- based assays to determine the role of noncoding variation in NDDs. We will approach this by (1) calling and statistical assessment of variants from whole-genome sequencing data in 14,000 families; (2) variant prioritization via single-cell based assays identifying regulatory sites in the brain; and (3) by MPRAs of variant function coupled with in vivo functional characterization of a subset of these variants in mice. The skills learned in this proposal are on the cutting-edge and many are unique to the setting of the UW Department of GS. The candidate will amass a great amount of knowledge in new areas of genomics, which will be applicable to many diseases and critical to the candidate's future independent laboratory.