UW Genome Sciences

Our group uses approaches from genetics, genomics, molecular and cell biology, mathematics, and computational biology in order to identify and characterize genes responsible for complex human conditions. Our primary areas of interest are inherited breast, ovarian, and prostate cancer; schizophrenia and related severe mental illness; and severe inherited disorders in children.  We are particularly interested in disentangling the genetic heterogeneity of complex traits, so as to discover clinically meaningful mutations that cause common diseases. Our philosophy is described in this commentary:

McClellan J and King M-C. Genetic heterogeneity in human disease. Cell 2010;141:210-217

Our current projects are described below.  

Inherited breast and ovarian cancer. We are interested in understanding the genetic bases of inherited predisposition to breast, ovarian, prostate, and pancreatic cancer. We develop genomic and transcriptomic tools to discover previously undetectable classes of mutations, then apply these tools to understanding cancer in severely affected families with no previous genetic diagnosis. We are now developing approaches based on long-read genomic DNA sequencing and direct RNA sequencing, and are integrating Fiber-seq (developed by Andrew Stergachis) with genomic analysis of families.

Representative publications:

Walsh T, Casadei S, Munson KM, Eng M, Mandell JB, Gulsuner S, King M-C. A CRISPR-Cas9 / long-read-sequencing approach to identify cryptic mutations in BRCA1 and other tumor suppressor genes. J Med Genet 2021;58(12):850-852.

Casadei S*, Gulsuner S*, Shirts BH, Mandell JB, Kortbawi HM, Norquist BS, Swisher EM, Lee MK, Goldberg Y, O’Connor R, Tan Z, Pritchard CC, King M-C, Walsh T. Characterization of splice-altering mutations in inherited predisposition to cancer. Proc Natl Acad Sci USA 2019;116:26798-807

Zheng Y*, Walsh T*, Gulsuner S, Casadei S, Lee MK, Ogundiran TO, Ademola A, Falusi AG, Adebamowo CO, Babalola CP, Ojengbede OA, Odedina S, Anetor I, Wang S, Huo D, Yoshimatsu TF, Zhang J, Felix GES, King M-C, Olopade OI.  Inherited breast cancer in Nigerian women. J Clin Oncol 2018;36:2820-25

Stewart MD, Zelin E, Dhall A, Walsh T, Upadhyay E, Corn JE, Chatterjee C, King M-C, Klevit RE. BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes.  Proc Natl Acad Sci USA 2018;115:1316-21

Weinberg-Shukron A, Rachmiel M, Renbaum P, Gulsuner S, Walsh T, Lobel O, Dreifuss A, Ben-Moshe A, Zeligson S, Segel R, Shore T, Kalifa R, Goldberg M, King M-C, Gerlitz O, Levy-Lahad E, Zangen D.  Essential role for BRCA2 in ovarian development and function. New Engl J Med 2018;379:1042-49

Genetics of schizophrenia. Schizophrenia is a devastating disorder with significantly reduced reproductive fitness, yet remains common, with ~1% prevalence worldwide. This paradox led our group to suggest that in persons from otherwise healthy families, the illness often results from the occurrence of de novo mutations in genes that affect brain development. We tested this hypothesis in families, demonstrating that compared to their unaffected siblings, persons with schizophrenia are significantly more likely to harbor damaging de novo mutations in genes regulating neurogenesis in fetal prefrontal cortex. Even more striking was the distinctive functional relationship among the genes harboring mutations. The genes disrupted by damaging de novo mutations in patients formed a network defined by co-expression 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 suggested that aberrant prefrontal cortical development is critical to the pathogenesis of schizophrenia. By integrating genomic analyses with brain mapping strategies, we are able to define possible disease-related processes and to identify potential targets for treatment.

Representative publications:

McClellan JM, King M-C. A tipping point in neuropsychiatric genetics. [Commentary]. Neuron 2021;109(9):1411-13.

Gulsuner S, Stein DJ, Susser E, Sibeko G, Pretorius A, Walsh T, Majara L, Mndini MM, Mqulwana SG, Ntola OA, Casadei S, Ngqengelele LL, Korchina V, vanderMerwe C, Malan M, Fader KM, Feng M, Willoughby E, Muzny D, Baldinger A, Andrews HF, Gur RC, Gibbs RA, Zingela Z, Nagdee M, Ramesar RS, King M-C, McClellan JM. Genetics of schizophrenia in the South African Xhosa. Science 2020;367:569-73

McClellan JM, Lehner T, King M-C. Gene discovery for complex traits: Lessons from Africa. [Commentary] Cell 2017;171:261-64

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 2013;154:518-29

Genetic bases of Mendelian and complex disorders of children. Returning again to the theme of genetic heterogeneity, we are interested in discovery and characterization of genes responsible for severe inherited disorders in children. Much of this work is collaborative with our partners in Israel and Palestine.

Representative publications:

Carlson RJ, Walsh T, Mandell JB, Aburayyan A, Lee MK, Gulsuner S, Horn DL, Ou HC, Sie KCY, Mancl L, Rubinstein J, King MC. Association of genetic diagnoses for childhood-onset hearing loss with cochlear implant outcomes. JAMA Otolaryngol HNS. 2023;149(3):212-22

Baxter SK, Walsh T, Casadei S, Eckert MM, Allenspach EJ, Hagin D, Segundo G, Lee MK, Gulsuner S, Shirts BH, Sullivan KE, Keller MD, Torgerson TR, King M-C. Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy and enteropathy; and implications for clinical management. J Allergy Clin Immunol 2022;149:327-39

Yechieli M, Gulsuner S, Ben Pazi H, Fattal-Valevski A, Aran A, Kuzminsky A, Sagi L, Guttman D, Schneebaum Sender N, Gross-Tsur V, Klopstock T, Walsh T, Renbaum P, Zeligson S, Shemer ML, Lev D, Shmueli D, Blumkin L, Lahad A, King M-C, Levy-Lahad E, Segel R. Diagnostic yield of chromosomal microarray and trio whole-exome sequencing in cryptogenic cerebral palsy. J Med Genet 2022;59(8):759-67

Abu Rayyan A, Kamal L, Casadei S, Brownstein Z, Zahdeh F, Shahin H, Canavati C, Dweik D, Jaraysa T, Rabie G, Carlson RJ, Gulsuner S, Lee MK, Avraham KB, Walsh T, King M-C, Kanaan MN. Genomic analysis of inherited hearing loss in the Palestinian population. Proc Natl Acad Sci USA 2020;117:20070-76

Seo A, Gulsuner S, Pierce S, Ben-Harosh M, Shalev H, Walsh T, Krasnov T, Dgany O, Doulatov S, Tamary H, Shimamura A, King M-C. Inherited thrombocytopenia associated with mutation of udp-galactose-4-epimerase (GALE). Hum Molec Genet 2019;28:133-42

Navon Elkan P*, Pierce SB*, Segel R*, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes P, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom T, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King M-C, Levy-Lahad E. Mutant adenosine deaminase 2 (ADA2) in a polyarteritis nodosa vasculopathy. New Engl J Med 2014;370:921-31

We welcome to the lab geneticists who are interested in working with us in these areas. Please contact Dr. King.