Dear UCSC Genome Informatics Group,
I am writing to you to inquire about including a data track on the Genome Browser from the Developmental Genome Anatomy Project (http://dgap.harvard.edu <http://dgap.harvard.edu/> ). The Developmental Genome Anatomy Project (DGAP) is a NIH-funded program project based in four Harvard Medical School laboratories (Drs. Cynthia Morton, James Gusella, Richard Maas, and Brad Quade). Our goal is to identify genes important for human development and our strategy is based on identifying humans with congenital abnormalities (birth defects) and chromosomal rearrangements. We essentially use these naturally occurring "human knock-out experiements" collected from around the U.S. and globe to find new developmentally important genes and, over time, annotate the functional/developmental genome, without any of the biases inherent in analyzing large populations or families. Using such rearrangements as positional markers, we identify candidate genes by mapping those rearrangements with a variety of methods from FISH to whole genome sequencing, study temporal and tissue-specific expression of candidate genes near the chromosomal breakpoints, look for corresponding point mutations in chromosomally normal, affected individuals, and in selected cases, develop animal models that reproduces the human phenotype. To date, we now have collected well over 200 hundred cases, and with the inclusion of genome-level sequencing, the rate that we are able to identify candidate genes has grown tremendously! Over the last five years, we have used Genome Browser custom tracts to share our results (including extensive unpublished data). For example, here is a link to a case page: http://www.bwhpathology.org/DGAP/LookUpCase.aspx?case=097&chr=X <http://www.bwhpathology.org/DGAP/LookUpCase.aspx?case=097&chr=X> . This page has some summary information about each case, as well as links to PDFs with more detailed information and candidate gene mapping information (using the Genome Browser!). Other pages on our web site allow DGAP database searches by phenotypic information or chromosomal location. I am in the process of updating the architecture of our web site to accommodate the faster pace of data production (primarily due to genome sequencing). With this effort, it is a good time to inquire about creating a DGAP tract directly on Genome Browser, probably within the Phenotype and Disease Association cluster of tracks. We know that there is substantial interest in the scientific and medical genetics communities based on our broad effort to collect DGAP cases. We also know that the NIH and our peer reviewers think that this would be a great way to make our data, of which a substantial fraction is unpublished or pre-publication, more accessible to a wider number of investigators. We also believe that it would enhance the Genome Browser by adding another rich source of functional, developmentally relevant annotation. I will be attending the ASHG 61st annual meeting / 12th International Congress of Human Genetics in Montreal next week (Tues., Oct. 11- Friday, Oct 14). Perhaps it would be possible to meet and discuss this proposal in person? Also, the DGAP group has a project-wide poster presentation next Friday afternoon (abstract 1270F, text pasted below in rust color). Come check us out! I look forward to exploring this exciting opportunity for collaboration further! Sincerely, Brad Quade Bradley J. Quade, M.D., Ph.D. Associate Professor of Pathology (Harvard Medical School) Division of Women's and Perinatal Pathology Department of Pathology Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 mailto:[email protected] <mailto:[email protected]> Tel: (617) 732-5475 Fax: (617) 738-6996 Administrative Assistant: Amanda Wild mailto:[email protected] <mailto:[email protected]> Tel: (617) 732-7980 Fax: (617) 738-6996 1270F The Developmental Genome Anatomy Project (DGAP): Annotating the Genome by Cytogenetic and Sequencing Approaches. A.M. Lindgren1, M.E. Talkowski2,3, C. Hanscom2, C. Chiang2, C. Ernst2,3, S. Ahsan1, B.B. Currall1, L. Yuan1, S. Lachke4, I. Saadi4, D.J. Harris5, R.L. Maas4, B.J. Quade1, J.F. Gusella2,3, C.C. Morton1. 1) Depts. of Ob/Gyn and Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 2) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 3) Depts. of Genetics and Neurology, Harvard Medical School, Boston, MA; 4) Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 5) Children's Hospital Boston, Harvard Medical School, Boston, MA. The Developmental Genome Anatomy Project (DGAP, dgap.harvard.edu) is a collaborative endeavor to identify genes critical in human development and disease. Balanced chromosomal rearrangements are the biological resource for gene discovery in DGAP as they may indicate the location of disrupted or dysregulated genes that lead to an abnormal phenotype. DGAP analyzes the correlation between genotype and phenotype through FISH-based breakpoint localization, various sequencing methods, candidate gene identification and functional analysis in model organisms. Of 235 cases enrolled to date, breakpoints are FISH mapped in 88 cases, 116 of which are localized to a single clone. Seventy-six breakpoint sequences are determined in 36 cases and 57 disrupted genes identified for which 24 animal models have been evaluated. Notable cases under active investigation include DGAP100 [46,X,t(X;5)(p11.3;q35.2)], a nonverbal 16 year-old female with septo-optic dysplasia, cleft palate, severe myopia, neuromuscular scoliosis, hearing impairment, and a history of seizures. KDM6A, a histone 3 lysine 27 demethylase, is disrupted at Xp11.3, and qRT-PCR reveals ~50% reduction in KDM6A expression compared to control lymphoblast cell lines, suggesting haploinsufficiency of KDM6A is pathogenetic in the phenotype. Zebrafish knockdowns are underway and preliminary analyses show craniofacial anomalies. DGAP120 [46,XY,t(6;11)(q24.3;q21)] is a 12 year-old male with low-to-mid frequency sensorineural hearing loss, intermittent exotropia and craniofacial defects; C6ORF103 is disrupted at 6q24.3. DGAP191 [46,XY,t(5;7)(q14.3;q21.3)], a 3 year-old male, has sensorineural hearing loss, mental retardation, hypotonia and seizures. Although no genes are directly disrupted, the 5q14.3 breakpoint is ~500 kb upstream of MEF2C and the 7q21.3 breakpoint is 2.86 kb upstream of COL1A2. Normal expression of MEF2C and over-expression of COL1A2, as determined by qRT-PCR, suggest dysregulation of COL1A2 as etiologic in the phenotype. Chromosomal rearrangements remain a rich resource for identifying genes and regulatory elements underlying human disease and traits. In conjunction with development of affordable sequencing methods, the study of balanced chromosome rearrangements in phenotypically abnormal individuals is imperative in rapid annotation of the human genome. 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