We propose a training program that will prepare an effective independent investigator in human genetics and neurobiology. The candidate has a DPhil/PhD from a joint graduate program with the University of Oxford and the National Institutes of Health focused on the characterization of common noncoding variation in human disease. She will extend her skills to include assaying genetic variation using novel sequencing technologies and functional neurobiological assays during a two-year program of organized mentorship and training followed by a structured three-year research program. The training program will promote use of sequencing technologies and functional assays to characterize human-specific duplicated genes and their roles in neurological traits and defects. Dr. Evan Eichler, Professor of Genome Sciences, will act as the primary mentor towards the scientific development of the candidate. Dr. Eichler is world-renowned in the field of genomics and disease genetics with pioneering work exploring complex regions of the genome. Dr. David Raible, Professor of Biological Structure and Adjunct Professor of Genome Sciences, will assist in mentoring the candidate in functional characterization of genes in neural development using zebrafish as a genetic tool. Additionally, the candidate will be supported by a team of investigators committed to preparing her for a career as an independent researcher. The Department of Genome Sciences at the University of Washington School of Medicine is an ideal setting to pursue training towards becoming an independent research investigator. The faculty is highly diverse and collaborative with expertise ranging from computational biology to experimental methods using model systems. Large-scale recurrent deletions and duplications mediated by segmental duplications are associated with autism, intellectual disability, epilepsy, and schizophrenia. Human-specific genes reside within these flanking segmental duplications that are missing or misannotated in the human reference build that exacerbate our understanding of the mechanisms that contribute to disease. To fully characterize these human-specific genes and their role in disease, we will (1) generate high-quality sequence of three genomic regions associated with neurodevelopmental disorders utilizing a haploid-genomic resource developed to assess regions of high sequence identity;(2) screen for mutations in cases with neurodevelopmental disorders;and (3) functionally characterize genes and identified variants using cell line assays and zebrafish. Many of the methodologies proposed here are novel to the candidate, including next-generation sequencing analysis to characterize disease variants and functional neurobiology assays using zebrafish. The experimental paradigm will be easily extended to characterize any gene implicated in neurological disease and will be essential in laying the foundation for the candidate's independent research program. !
Neurocognitive disorders are common in the population, representing a significant burden in all aspects of life and society. Studies aimed at discovering the causes of such disorders will lead to a better understanding of the underlying biological mechanisms, and in turn facilitate development of improved diagnostic methods and potential treatments.
| Chaisson, Mark J P; Huddleston, John; Dennis, Megan Y et al. (2015) Resolving the complexity of the human genome using single-molecule sequencing. Nature 517:608-11 |
| Huddleston, John; Ranade, Swati; Malig, Maika et al. (2014) Reconstructing complex regions of genomes using long-read sequencing technology. Genome Res 24:688-96 |
| Key, Felix M; Peter, Benjamin; Dennis, Megan Y et al. (2014) Selection on a variant associated with improved viral clearance drives local, adaptive pseudogenization of interferon lambda 4 (IFNL4). PLoS Genet 10:e1004681 |
| Antonacci, Francesca; Dennis, Megan Y; Huddleston, John et al. (2014) Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability. Nat Genet 46:1293-302 |
