Our group uses genetics and genomics to study informative families and populations in order to identify genes responsible for complex human conditions. Our primary areas of interest are inherited breast and ovarian cancer, the genetics of schizophrenia, and Mendelian disorders in children. We are particularly interested in disentangling genetic heterogeneity in complex traits, thereby discovering individually rare severe alleles that cause common disorders. Our lab also applies genomic sequencing to the identification of victims of human rights abuses. Some details with the most important papers in each area are given below.
Inherited breast cancer. For more than 40 years, my group has used approaches from genetics, genomics, statistics, and molecular biology to characterize inherited breast cancer. In 1990, we demonstrated that breast cancer is genetically inherited in some families by mapping to chromosome 17q21 the gene we named BRCA1. This project was the first to exploit linkage analysis to prove the existence of a major gene for a complex trait. My lab was not the first to positionally clone BRCA1, which was accomplished in 1994, but without our work, the search would not have been undertaken. Much more recently, with advances in genomic technologies, we developed a targeted capture and massively parallel sequencing approach (BROCA) to simultaneously detect all classes of mutations in all breast and ovarian cancer genes. BROCA is not patented and is used in laboratories worldwide. We are now carrying out whole genome sequencing to identify and characterize regulatory mutations in severely affected families with no mutations detectable by exome or CNV analysis.
Hall JM, Lee MK, Morrow J, Newman B, Anderson LA, Huey B, King M-C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684-1689, 1990
Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, King M-C. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet 8:399-404, 1994
King M-C, Marks JR, Mandell JB, The New York Breast Cancer Study Group. Risks of breast and ovarian cancer due to inherited mutations in BRCA1 and BRCA2. Science 302: 643-6, 2003
Walsh T, Lee MK, Casadei S, Thornton AM, Stray SM, Pennil C, Nord AS, Mandell JB, Swisher EM, King M-C. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 107: 12629-33, 2010
Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, Beeri R, Gal M, Grinshpun-Cohen J, Djemal K, Mandell JB, Lee MK, Beller U, Catane R, King M-C, Levy-Lahad E. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci USA 111: 14205-14210, 2014
De novo mutations in schizophrenia. Schizophrenia is a devastating disorder with significantly reduced reproductive fitness, yet remains common, with ~1% prevalence worldwide. This paradox led us to suggest that in many patients, specifically those from otherwise healthy families, the illness may result from de novo mutations in genes that affect brain development. We tested this hypothesis and showed that compared to their unaffected siblings, persons with schizophrenia are significantly more likely to harbor damaging de novo mutations in genes regulating neurogenesis in the prefrontal cortex. Furthermore, the genes harboring these de novo mutations in patients have a distinctive functional relationship: they are co-expressed in the dorsolateral and ventrolateral prefrontal cortex during fetal development. These genes are active in pathways critical to neurogenesis, including neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. Our results suggest that aberrant prefrontal cortical development is critical to the pathogenesis of schizophrenia. By integrating genomic analyses with brain mapping strategies, we were able to define possible disease-related processes and to identify potential targets for treatment.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King M-C, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539-43, 2008
McClellan J, King M-C. Genetic heterogeneity in human disease. Cell 141:210-7, 2010
Gulsuner S*, Walsh T*, Watts AC*, Lee MK, Thornton AM, Casadei S, Rippey CF, Shahin H, Consortium on the Genetics of Schizophrenia (COGS), PAARTNERS Study Group, Nimgaonkar VL, Go RCP, Savage RM, Swerdlow NR, Gur RE, Braff DL, King M-C, McClellan JM. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518-29, 2013
Rippey CF, Walsh T, Gulsuner S, Brodsky M, Nord AS, Gasperini M, Pierce SB, Spurrell C, Coe BP, Krumm N, Lee MK, Sebat J, McClellan JM, King M-C. Formation of chimeric genes by copy number variation as a mutational mechanism in schizophrenia. Am J Hum Genet 93:697-710, 2013
Mendelian disorders in Middle Eastern families With Israeli and Palestinian colleagues we have developed a partnership to identify the genetic causes of severe inherited disorders in Middle Eastern families. Recessive conditions, in particular, are exceptionally common in Middle Eastern communities given traditions of endogamy and consanguinity. Our partnership discovers the genes responsible for severe Mendelian disorders in families throughout the region. Our results are frequently used in combination with pre-gestational diagnosis so as to ensure that future pregnancies will lead to healthy children.
Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, Lee MK, Kanaan M, King M-C, Avraham KB. From flies' eyes to our ears: Mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci USA 99: 7518-7523, 2002
Shahin H, Walsh T, Sobe T, Abu Sa'ed J, Abu Rayan A, Lynch ED, Lee MK, Avraham KB, King M-C, Kanaan M. Mutations in a novel isoform of TRIOBP that encodes a filamentous TRIO and F-actin binding protein are responsible for DFNB28 recessive non-syndromic hearing loss. Am J Hum Genet 78:144-152, 2006
Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, Roeb W, Abu Rayyan A, Loulus S, Avraham KB, King M-C, Kanaan M. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of non-syndromic hearing loss DFNB82. Am J Hum Genet 87:90-94, 2010
Navon Elkan P, Pierce SB, Segel R, Walsh T, … King M-C, Levy-Lahad E. Mutant adenosine deaminase 2 (ADA2) in a polyarteritis nodosa vasculopathy. New Eng J Med 370:921-931, 2014
Forensic genetics and human rights Since 1983, our group has applied genetics and genomics to uncover and resolve human rights abuses. This work began with the Grandmothers of the Plaza de Mayo in Argentina in the search for their grandchildren who had been kidnapped by the Argentinean military after their parents were murdered. For this project, we developed the first application, in any field, of direct sequencing of PCR products of mitochondrial DNA (mtDNA) obtained from blood, first of discovered children and later from human remains. After sequencing, we matched children to families by comparing mtDNA sequences of children to mtDNA sequences of persons who might be their maternal relatives. We also established that teeth, whose enamel coating protects DNA in the dental pulp from degradation, offer a valuable source of DNA to identify remains, even long after death. We applied this approach to the identification of victims of extra-judicial execution on six continents. We also used mtDNA sequencing to identify American soldiers who went missing in action in Vietnam, Cambodia, and Korea, and in the Pacific and Europe during WWII. This approach is now used routinely in forensics worldwide. Our group now serves as consultant to the United nations Forensic Anthropology Team for cases that are particularly challenging for either technical or policial reasons.
DiLonardo AM, Darlu P, Baur M, Orrego C, King M-C. Human genetics and human rights: Identifying the families of kidnapped children. Am J Foren Med Pathol 5: 339-347, 1984
King M-C. An application of DNA sequencing to a human rights problem. Molec Genet Med 1:117-131, 1991
Ginther C, Issel-Tarver L, King M-C. Identifying individuals by sequencing mtDNA from teeth. Nature Genet 2:135-138, 1992