Balanced chromosomal rearrangements represent both clinical diagnosticquandaries and exceptional experimental opportunities in human genetics as they offer a unique window intothe impact of single locus hemizygosity in human disease. However, their contribution to complex disordersremains largely unquantified as they are not detected by conventional association approaches. Failure toconsider BCRs bypasses a powerful complement to conventional association approaches in complex diseaseas they can directly implicate a causal locus or sequence motif, and may help explain a portion of the missingheritability in disorders such as autism spectrum disorders (ASDs). In this proposal, the candidate will delveinto this unexplored genomic space by leveraging novel sequencing techniques innovated during his currentNRSA to evaluate the full spectrum chromosomal aberrations that can impact human developmentalabnormalities such as ASD, their inheritance, and the mechanism by which they arise. The proposed studieswere carefully designed to develop expertise in three primary training domains; mechanism of DNA breakagerepair and formation of chromosomal aberrations, clinical genetics and heterogeneous phenotypicpresentation, and the molecular genetic consequences of chromosomal abnormalities on gene expression(transcriptomics). These skills are needed to establish expertise required to become a leader in the genomicsof human neurodevelopmental abnormalities and chromosomal aberrations.Hypotheses: The aims of this proposal were designed to test the specific hypotheses supported by thepreliminary data that: (1) inverted genomic segments represent an underappreciated and profound genetic riskfactor mediating human chromosomal aberrations and complex chromosomal rearrangements by aberrantrepair of small de novo or inherited local inversions (Aim 1), (2) phenotypic discordance from highly penetrantgenetic lesions is mitigated by unrecognized genetic structure (Aim 2), and (3) balanced chromosomalaberrations underlie a meaningful portion of the unexplained genetic etiology of children with autism and nodetectable dosage imbalance (Aim 3).Training: All research will be conducted within the Center for Human Genetic Research at MGH, HarvardMedical School, and the Broad Institute under the mentorship of James F. Gusella, Ph.D., an establishedleader in the field with a prolific record of discovery in human genetics. Training will be carried out in threeprimary domains with contributing experts in each field, including A) studying the mechanism of DNA breakrepair and chromosomal rearrangements with James Lupski, Ph.D., external advisory panel member, B) deeptraining in clinical genetics to understand the diverse phenotypes associated with neurodevelopmentalabnormalities with Cynthia Morton, Ph.D., advisory panel member and Director of Cytogenetics at HarvardMedical School, and C) molecular genetics, transcriptomics, and the impact of chromosomal aberrations ongene expression with James Gusella, Ph.D. Director of the Center for Human Genetic Research and a leaderin the molecular genetics of human disease and Mark J. Daly, Chief of the Analytical and TranslationalGenetics Unit of CHGR, expert in computational genomics, and emerging leader in autism genetics research.In addition to research training, the candidate will undertake coursework through Harvard University and MIT,participate in regular seminars and symposia, continue to lead an autism genomics group, and attend annualscientific meetings.Significance: The impact of balanced chromosomal aberrations in autism and other human developmentalabnormalities is largely unknown as they remain completely undetectable by most genetic research designs.As the population prevalence of autism continues to increase, estimates at cytogenetic resolution suggest theimpact of chromosomal abnormalities in these children is potentially high (estimated at an approximately six-fold increase in the development of autism). These studies will fulfill a vital need in the study of humandevelopmental abnormalities and could provide significant insight into the mechanism by which these eventsoccur and ultimately yield sequence specificity and predictive diagnostics to the patients studied in Aim 3.Overall, the training environment is exceptional, the proposed studies are innovative, the science is timely, thehypotheses address unresolved and important questions in the field that could yield seminal findings in autismgenetics, the genomics of chromosomal organization, and the implementation of clinical diagnostics. Thementoring and research skills developed over the course of this award will undoubtedly provide a strongfoundation for the candidate to become a successful independent scientist and leader in understanding thegenomics underlying human developmental abnormalities. Indeed, the candidate's enthusiasm is very high forthe remarkable training and research opportunities afforded in this application.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
