The goal of the 1000 Genomes Project is to provide a comprehensive database on human genetic variation. As part of the 1000 Genomes Project SV Group, our laboratory works to comprehensively and accurately identify structural variants (SVs) in the 2,535 human genomes from various ethnic populations around the world using specialized computer programs, DNA sequencing methods and other molecular technologies (e.g., Iafrate, et al., Nature Genetics 36:949, 2004, Mills et al. Nature 470:59, 2011).
We are currently studying the genetic etiology of two congenital birth defects. First is congenital diaphragmatic hernia (CDH), a defect in the diaphragm that allows the stomach and intestines to move into the chest cavity and cause underdevelopment of the lungs (pulmonary hypoplasia). The incidence of CDH is approximately 1 in 2,500 newborns. More than 80 percent of the patients are not associated with any known genetic syndrome, and the underlying mechanisms for their condition remain unknown. In collaboration with Dr. Patricia Donahoe’s group at MGH, we have already identified many genes that are associated with this disorder (e.g., Longoni et al. PNAS USA-In Press). Second is spina bifida, a defect due to incomplete closing of the neural tube during embryonic development. Spina bifida is one of the most common types of neural tube defect (NTD), affecting an estimated 1 in 2,500 newborns worldwide. It is a complex disorder that is likely caused by the interaction of multiple genetic and environmental factors. Some of these factors (e.g., a deficiency of folate and folic acid-related gene MTHFR) have been identified, but many remain unknown.
Our laboratory has had a long-standing interest in developing new diagnostic assays and platforms for genomic medicine (e.g. Lee et al. Lancet 357: 1240, 2001, Turke et al; Cancer Cell 17:77, 2010). In particular, we have been engaged in studies of cancer genome sequences and structures to provide insights for understanding cancer biology, diagnosis and therapy. In addition to our studies on cancer cytogenetics (e.g., Demichelis et al. Proc Natl Acad Sci USA 109:6686, 2012) we have initiated a large-scale project on mouse patient-derived xenografts (PDX) and cancer avatars for tumors from Asian patients. The "mouse avatar" is a personalized animal model of a patient's tumor, transplanted into immune-deficient mice, and subsequently used in both co-clinical trials for drug efficacy as well as the development of databases for genomic profiles and clinical outcomes. Essentially, this model allows oncologists to screen and/or identify the most effective anti-cancer drugs for a patients cancer.
Recent studies have demonstrated that structural variants constitute a greater portion of human genomic variation than single nucleotide variants (Conrad et al., Nature 464:704, 2010) and play an important role not only in human disease but also in genome evolution (e.g. Perry et al., Nature Genetics 39:1256,2007) To investigate this further, our laboratory has generated comprehensive genomic structural variation maps in multiple primate species including chimpanzees, orangutans, and rhesus macaques by using massively parallel DNA sequencing technology. Linking gene expression data with species-specific gene duplications, we have already described several instances where gene duplicates seem to lead to a gain of function in new tissues where the gene is not otherwise usually expressed (e.g., Gokcumen et al., Proc Natl Acad Sci USA. 110:15764, 2013).