Research:

The Villén Lab seeks to develop and apply novel technologies for proteome characterization to answer fundamental questions in cell biology and disease. We use quantitative mass spectrometry to measure dynamic changes in protein abundances, protein post-translational modification states, and to characterize interaction partners across multiple cellular states.

We are particularly interested in studying protein phosphorylation as a general regulatory mechanism in the cell involved in a myriad of functions: how phosphorylation is integrated into the multiple responses to shape the proteome, and how signaling circuits evolved to accommodate proteome functional complexity.

Selected Publications:

Beausoleil, S. A., Villen, J., Gerber, S. A., Rush, J. & Gygi, S. P. (2006). A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol 24, 1285-1292.

Villen, J., Beausoleil, S. A., Gerber, S. A. & Gygi, S. P. (2007). Large-scale phosphorylation analysis of mouse liver. Proc. Natl. Acad. Sci. U. S. A. 104, 1488-1493.

Guo, A., Villen, J., Kornhauser, J., Lee, K. A., Stokes, M. P., Rikova, K., Possemato, A., Nardone, J., Innocenti, G., Wetzel, R., Wang, Y., MacNeill, J., Mitchell, J., Gygi, S. P., Rush, J., Polakiewicz, R. D. & Comb, M. J. (2008). Signaling networks assembled by oncogenic EGFR and c-Met. Proc. Natl. Acad. Sci. U. S. A. 105, 692-697.

Villen, J. & Gygi, S. P. (2008). The SCX/IMAC enrichment approach for global phosphorylation analysis by mass spectrometry. Nat Protoc 3, 1630-1638.

Villen, J., Beausoleil, S. A. & Gygi, S. P. (2008). Evaluation of the utility of neutral-loss-dependent MS3 strategies in large-scale phosphorylation analysis. Proteomics 8, 4444-4452.

Baek, D.*, Villen, J.*, Shin, C.*, Camargo, F. D., Gygi, S. P. & Bartel, D. P. (2008). The impact of microRNAs on protein output. Nature 455, 64-71. (* equal contribution)

Holt, L. J.*, Tuch, B. B.*, Villen, J.*, Johnson, A. D., Gygi, S. P. & Morgan, D. O. (2009). Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325, 1682-1686. (* equal contribution)

Gail Jarvik MD, PhD is the Arno G. Motulsky Endowed Chair in Medicine, Joint Professor of Medicine and Genome Sciences, and Head of the Division of Medical Genetics (only the third since the founding of the division in 1957) at the UW Medical Center (UWMC) and an Affiliate Member of the Fred Hutchinson Cancer Research Center. Her honors include being a Pew Scholar in the Biomedical Sciences, and has been made a Lifetime National Associate of the National Academies, “In recognition of extraordinary service to the National Academy of Science.” She has been designated “A Local Legend from Washington” by Senator Maria Cantwell, in association with the American Medical Women’s Association and the U.S. National Library of Medicine. Her abilities as a scholar and a leader have been recognized by her election as 2021 President of the American Society of Human Genetics. In addition to that service, leading the Division of Medical Genetics and actively pursuing her own research, she continues to be a practicing clinician in Internal Medicine and Medical Genetics. 

Clinical activity:

Dr. Jarvik sees adult patients in the UW Genomic Medicine clinic.

Trainees:

Dr. Jarvik works with trainees at all levels from undergraduate to postdoctoral.

Research:

Dr. Jarvik is interested in the genetic basis of complexly inherited disease and has a long-standing interest in biomedical ethics. In addition to many collaborations, including GWAS studies of multiple phenotypes and genomic analyses of Mendelian disorders, Dr. Jarvik’s ongoing research focuses on these major areas: 

Complex disease discovery and prediction

Exome sequence and genome-wide association studies (GWAS) of phenotypes from clinical electronic medical records in the electronic Medical Records and GEnomics  (eMERGE) consortium. This consortium includes over 105,000 participants at 10 sites. Phenotypes of interest include colorectal cancer, white blood cell count, susceptibility to infection, lipid disorders and carotid artery disease. 

Genomic medicine implementation

Dr. Jarvik is a PI of the network funded by NHGRI. In addition to a large legacy dataset, eMERGE is now evaluating the outcomes of implementing polygenic risk scores for 10 common disease in 25,000 participants across 10 sites, including 2600 UWMC patients. These participants are being followed to determine the impact of this information on their clinical outcomes. Dr. Jarvik has long been interested in the return of genomic results to research participants and the rate of genomic incidental findings.
UDN: Dr. Jarvik is PI in the Undiagnosed Disease Network, funded by the NIH. Patients who have remained undiagnosed despite long diagnostic journeys are evaluated by multiple methods, including multi-omics, to try to discover the cause of their illness.
All of Us: Dr. Jarvik is a PI with Drs. Wei and Eichler as a sequencing center in the national genomic medicine cohort study. 

Selected Publications:

Genomic data in the All of Us Research Program. All of Us Research Program Genomics Investigators. Nature. 2024 Mar;627(8003):340-346. doi: 10.1038/s41586-023-06957-x. Epub 2024 Feb 19. (PMID: 38374255)

Linder JE, Allworth A, Bland ST, Caraballo PJ, Chisholm RL, Clayton EW, Crosslin DR, Dikilitas O, DiVietro A, Esplin ED, Forman S, Freimuth RR, Gordon AS, Green R, Harden MV, Holm IA, Jarvik GP, et al.   Returning integrated genomic risk and clinical recommendations: The eMERGE study. Genet Med. 2023 Jan 6;25(4):100006. doi: 10.1016/j.gim.2023.100006. Epub 2023 Jan 6. (PMID: 36621880)

Rosenthal EA, Wei WQ, Luo Y, Namjou-Khales B, Schaid DJ, Esplin ED, Lape M, Kottyan L, Pacheco JA, Weng C, Gordon AS, Kullo IJ, Crosslin DR, Grady WM, Hsu L, Peters U, Jarvik GP. Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer. Hum Genomics. 2025 Jul 9;19(1):77. doi: 10.1186/s40246-025-00791-0.PMID: 40635049

Gordon AS, Zouk H, Venner E, Eng CM, , Funke BH, Amendola LM, Carrell DS, Chisholm RL, Chung WK, Denny JC, Fedotov, A, Hakonarson H, Kullo IJ, Larson EB, Leduc MS, Leppig KA, Lennon NJ, Linder JE, Muzny DM, Prows CA, Rasmussen-Torvik LJ, PhD, Rasouly HM, Roden DM, Rosenthal EA, Smith ME, Stanaway IB, Van Driest SL, Walker K, Wiesner GL, Williams MS, Witkowski L, Crosslin DR, Gibbs RA, Rehm HL, The eMERGE Clinical Annotation Working Group, and Jarvik GP. Frequency of genomic incidental findings among 21,915 eMERGE network participants. Genet Med. 22(9):1470-77, 2020. (PMID: 32546831. PMCID: PMC7713503.)

Vollger MR, Korlach J, Eldred KC, Swanson E, Underwood JG, Bohaczuk SC, Mao Y, Cheng YH, Ranchalis J, Blue EE, Schwarze U, Munson KM, Saunders CT, Wenger AM, Allworth A, Chanprasert S, Duerden BL, Glass I, Horike-Pyne M, Kim M, Leppig KA, McLaughlin IJ, Ogawa J, Rosenthal EA, Sheppeard S, Sherman SM, Strohbehn S, Yuen AL, Stacey AW; University of Washington Center for Rare Disease Research; Undiagnosed Diseases Network; Reh TA, Byers PH, Bamshad MJ, Hisama FM, Jarvik GP, Sancak Y, Dipple KM, Stergachis AB. Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.
Nat Genet. 2025 Feb;57(2):469-479. doi: 10.1038/s41588-024-02067-0. Epub 2025 Jan 29.PMID: 39880924 

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.

Research

The focus of our research is in the development of stable isotope and mass spectrometry based approaches to improve our understanding of biology on a molecular, cellular, and whole organism level. Presently, individuals in the laboratory are working on technology for 1) automating biochemical sample preparation methods for the analysis of protein mixtures; 2) developing in vivo stable isotope methods for studying protein metabolism; 3) increasing the dynamic range of liquid chromatography-mass spectrometry for the analysis of peptides; and 4) developing computational tools for the automated conversion of mass spectrometry data into biologically meaningful results. These technologies are presently being demonstrated in the model organisms C. elegans and S. cerevisiae. Although our current research interests are presently in model systems, our long-term goal is have technologies robust enough to handle the automated high-throughput characterization of human clinical samples.

Selected Publications

Searle BC, Lawrence RT, MacCoss MJ, Villén J. Thesaurus: quantifying phosphopeptide positional isomers. Nat Methods. 2019 Aug;16(8):703-706. doi: 10.1038/s41592-019-0498-4. Epub 2019 Jul 29. PubMed PMID: 31363206.

Amodei D, Egertson J, MacLean BX, Johnson R, Merrihew GE, Keller A, Marsh D, Vitek O, Mallick P, MacCoss MJ. Improving Precursor Selectivity in Data-Independent Acquisition Using Overlapping Windows. J Am Soc Mass Spectrom. 2019 Apr;30(4):669-684. doi: 10.1007/s13361-018-2122-8. Epub 2019 Jan 22. PubMed PMID: 30671891; PubMed Central PMCID: PMC6445824.

Chalkley RJ, MacCoss MJ, Jaffe JD, Röst HL. Initial Guidelines for Manuscripts Employing Data-independent Acquisition Mass Spectrometry for Proteomic Analysis. Mol Cell Proteomics. 2019 Jan;18(1):1-2. doi: 10.1074/mcp.E118.001286. PubMed PMID: 30602589; PubMed Central PMCID: PMC6317474.

Searle BC, Pino LK, Egertson JD, Ting YS, Lawrence RT, MacLean BX, Villén J, MacCoss MJ. Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry. Nat Commun. 2018 Dec 3;9(1):5128. doi: 10.1038/s41467-018-07454-w. PubMed PMID: 30510204; PubMed Central PMCID: PMC6277451.

Pino LK, Searle BC, Huang EL, Noble WS, Hoofnagle AN, MacCoss MJ. Calibration Using a Single-Point External Reference Material Harmonizes Quantitative Mass Spectrometry Proteomics Data between Platforms and Laboratories. Anal Chem. 2018 Nov 6;90(21):13112-13117. doi: 10.1021/acs.analchem.8b04581. Epub 2018 Oct 23. PubMed PMID: 30350613.

MacLean BX, Pratt BS, Egertson JD, MacCoss MJ, Smith RD, Baker ES. Using Skyline to Analyze Data-Containing Liquid Chromatography, Ion Mobility Spectrometry, and Mass Spectrometry Dimensions. J Am Soc Mass Spectrom. 2018 Nov;29(11):2182-2188. doi: 10.1007/s13361-018-2028-5. Epub 2018 Jul 25. PubMed PMID: 30047074; PubMed Central PMCID: PMC6191345.

Research:

Cells are continually reshaped throughout evolution allowing for animals to adapt to an everchanging environment. Studies on the evolution of development have largely focused on morphology at the whole-animal level. Moreover, most of our mechanistic insights into how animals evolve are at the microevolutionary scale and involve the loss or gain of traits due to changes in allele frequencies. My lab will focus on the evolution of novel cell types and cellular behaviors by comparing homologous cells across distantly related chordate species. I will study how cells evolve at the levels of individual fate specification to multicellular morphogenesis. My goal is to reconstruct how cellular innovations emerge through evolution and use this knowledge to create novel cell types and behaviors at will in the lab.

My lab will explore these questions in instances of known developmental innovation. Specifically, I will analyze cellular innovation in the annual killifish Nothobranchius furzeri, whose embryos evolved under strong selection pressure imposed by their environment that evaporates during the dry season. Their radical dispersed cell stage and ability to enter diapause distinguish them uniquely from other teleosts and make them ideal for studying novelty. In parallel, I will delve further into how vertebrate-specific cell types such as neurogenic placodes evolved from invertebrate chordates, using the tunicate model Ciona robusta. Having multiple, highly tractable models that are ideal for both genetics and imaging will allow me to understand how cellular innovations emerge and how to synthetically create them.

Selected Publications:

Abitua PB, Stump LM, Aksel DC, Schier AF. 2024. Axis formation in annual killifish: Nodal and β-catenin regulate morphogenesis without Huluwa prepatterning. Science. PMID: 38843334.

Lord, N. D., Carte, A.N., Abitua, P.B., Schier, A.F. 2021. The pattern of Nodal morphogen signaling is shaped by co-receptor expression. eLife 10:e54894. PMID: 34036935.

Abitua, P.B., Gainous, T.B., Kaczmarczyk, A.N., Winchell, C. J., Hudson, C., Kamata, K., Nakagawa, M., Tsuda, M., Kusakabe, T. G., and Levine, M. 2015. The pre-vertebrate origins of neurogenic placodes. Nature 524, 462-465.

Haupaix, N*., Abitua, P.B*., Sirour, C., Yasuo, H., Levine, M., and Hudson, C. 2014. Ephrin-mediated restriction of ERK1/2 activity delimits the number of pigment cells in the Ciona CNS. Developmental Biology 394, 170-180.

Abitua, P.B., Wagner, E., Navarrete I.A., and Levine, M. 2012. Identification of a rudimentary neural crest in a non-vertebrate chordate. Nature 492, 104-107.

* These authors contributed equally to the publications.

Research:

The Miller laboratory is focused on defining the molecular basis of bacterial pathogenesis and interactions with eukaryotic cells. The laboratory has a particular interest in bacterial interactions with innate immunity. This work involves the use of animal and tissue culture (mice, macrophages, epithelial cells) models of infection using Salmonella, Pseudomonas, and Yersinia. Research interests include Salmonellae-induced typhoid fever and gastroenteritis, the chronic Pseudomonas airway disease of cystic fibrosis patients, and Gram-negative organisms important to biodefense, including Francisella tularensis and the plague bacillis Yersinia pestis.

The lab is organized into research groups focusing on the study of: (1) The effect of bacterial type III effector proteins on mammalian cells; (2) The assembly and regulation of the type III secretion system of Salmonella typhimurium, which translocates proteins into mammalian cells on contact; (3) The environmental remodeling of the gram-negative bacterial surface that occurs when bacteria infect host tissues; and (4) The characterization of the phenotypic adaptation of Pseudomonas aeruginosa to the unique environmental niche of the CF airway; (5) Analysis of bacterial genes and proteins using bioinformatics; (6) Development of new antimicrobial compounds inhibiting pathogenic factors. Current projects organized by group include the study of: (1) Salmonellae translocated effectors (which are delivered across the phagosome membrane and recruited to the actin cytoskeleton, nucleus, and phagosome) (2) Assembly of the type III secretion system inner membrane ring of the needle complex and structure-function analysis of the type III secretion chaperone InvB; (3) Remodeling of the surface of lipid A after bacterial infection of host tissues and analysis of the recognition of diverse lipid A by human Toll-like receptor 4; (4) Proteomic analysis and transcriptional profiling of Pseudomonas aeruginosa adaptation during CF; (5) Bioinformatic analysis and comparison of Francisella genomes; (6) Screening for chemical compounds that inhibit aminoarabinose modification of Lipid A.

Selected Publications:

Guina T, Purvine SO, Yi EC, Eng J, Goodlett DR, Aebersold R, Miller SI. Quantitative proteomic analysis indicates increased synthesis of a quinolone by Pseudomonas aeruginosa isolates from cystic fibrosis airways. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2771-6.

Miao EA, Brittnacher M, Haraga A, Jeng RL, Welch MD, Miller SI. Salmonella effectors translocated across the vacuolar membrane interact with the actin cytoskeleton. Mol Microbiol. 2003 Apr;48(2):401-15.

Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol. 2005 Jan;3(1)36-46.

Bader MW, Sanowar S, Daley ME, Schneider AR, Cho U, Wenqing X, Klevit RE, Moual H, Miller SI. Recognition of antimicrobial peptides by a bacterial sensor kinase. Cell, in press.

Hoffman L, D’Argenio D, MacCoss M, Zhang Z, Jones RA, and Miller SI. Aminoglycoside antibiotics induce bacterial biofilm formation. Nature. 2005 Aug 25;436(7054):1171-5.

Calvin K. Yip, Tyler G. Kimbrough, Heather B. Felise, Marija Vuckovic, Nikhil A. Thomas, Richard A. Pfuetzner, Elizabeth A. Frey, B. Brett Finlay,, Samuel I. Miller,, Natalie C.J. Strynadka. Structural characterization of the molecular platform for type III secretion system assembly. Nature. 2005 Jun 2;435(7042):702-7.

additional publication listings available via PubMed

Research

My research group is focused on building robust and scalable enabling technologies to study the organization of chromosomes in 3D space, the interactions they participate in at the inter- and intra-chromosomal level, and the associated RNAs and proteins that occupy functionally relevant sites. The motivation for this work is to better understand the mechanisms by which the organization and composition of genomic intervals relevant for health and disease impact the essential DNA transactions of transcription, replication, and repair. We also are committed to building ecosystems supported by open-source software, low-cost hardware, and extensive documentation to democratize the adoption of advanced single cell and spatial approaches in order to facilitate their application in a broad range of research settings.

Selected Publications

Liu, Y.*, McGann, C.D.*, Krebs, M., Perkins Jr., T.A., Fields, R., Camplisson, C.K., Nwizugbo, D.Z., Hsu, C., Avanessian, S.C., Tsue, A.F., Kania, E.E., Shechner, D.M., Beliveau, B.J.†, Schweppe, D.K.† DNA O-MAP uncovers the molecular neighborhoods associated with specific genomic loci. eLife https://elifesciences.org/reviewed-preprints/102489 (2024). [*Co-first authors] [†Co-corresponding authors]

Attar, S., Browning, V.E.*, Krebs, M.*, Liu, Y., Nichols, E.K., Tsue, A.F., Shechner, D.M., Shendure, J., Lieberman, J.A., Schweppe, D.K., Akilesh, S.†, Beliveau, B.J.† Efficient and highly amplified imaging of nucleic acid targets in cellular and histopathological samples with pSABER. Nature Methods https://doi.org/10.1038/s41592-024-02512-2 (2024). [*Equal author contribution] [†Co-corresponding authors]

Aguilar, R., Camplisson, C.K., Lin, Q., Miga, K.H., Noble, W.S.†, Beliveau, B.J.† Tigerfish designs oligonucleotide-based in situ hybridization probes targeting intervals of highly repetitive DNA at the scale of genomes. Nature Communications 15, 1027 (2024). [†Co-corresponding authors]

Hershberg, E.A.*, Camplisson, C.K.*, Close, J.L., Attar, S., Chern, R., Liu, Y., Akilesh, S., Nicovich, P.R., Beliveau, B.J. PaintSHOP enables the interactive design of transcriptome- and genome-scale oligonucleotide FISH experiments. Nature Methods 18, 937–944 (2021). [*Equal author contribution]

Kishi, J.Y.*, Lapan, S.W.*, Beliveau, B.J.*,†, West, E.R.*, Zhu, A., Sasaki, H.M., Saka, S.K., Wang, Y., Cepko, C.L.†, Yin, P.† SABER amplifies FISH: enhanced multiplexed imaging of RNA and DNA in cells and tissues. Nature Methods 16, 533–544 (2019). [*Equal author contribution] [†Co-corresponding authors]

additional publications

Research:

Our research focuses on the development of machine learning techniques for application to problems in molecular biology. We approach these problems using Bayesian techniques such as hidden Markov models, as well as support vector machines and related, non-Bayesian methods. Much of our work addresses two core problems in machine learning: incorporating domain-specific prior knowledge and learning from heterogeneous data. We apply our techniques to problems such as automatic gene finding, microarray expression analysis, gene functional classification, and protein remote homology detection.

Selected Publications:

J Liu, JT Halloran, JA Bilmes, RM Daza, C Lee, EM Mahen, D Prunkard, C Song, S Blau, MO Dorschner, VK Gadi, J Shendure, CA Blau, and WS Noble. “Comprehensive statistical inference of the clonal structure of cancer from multiple biopsies.” Scientific Reports. 7(1):16943, 2017.

MW Libbrecht, JA Bilmes and WS Noble. “Choosing non-redundant representative subsets of protein sequence data sets using submodular optimization.” Proteins. 86(4):454–466, 2018.

J Liu, D Lin, G Yardımcı, and WS Noble. “Unsupervised embedding of single-cell Hi-C data.” Bioinformatics (Proceedings of the ISMB). 34(13):i96–i104, 2018.

W Bai, J Bilmes and WS Noble. “Submodular generalized matching for peptide identification in tandem mass spectrometry.” IEEE Transactions in Computational Biology and Bioinformatics. 16(4):1168–1181, 2019.

A Bertero, PA Fields, V Ramani, G Bonora, G Yardımcı, H Reinecke, L Pabon, WS Noble, J Shendure, CE Murry. “Dynamics of genome reorganization during human cardiogenesis reveal an RBM20- dependent splicing factory.” Nature Communications. 10(1):1538, 2019.

DF Read, K Cook, YY Lu, K Le Roch, and WS Noble. “Predicting gene expression in the human malaria parasite Plasmodium falciparum.” PLOS Computational Biology. 15(9):e1007329, 2019.

J Schreiber, TJ Durham, J Bilmes, WS Noble. “Multi-scale deep tensor factorization learns a latent representation of the human epigenome.” Genome Biology. 21:81, 2020.

additional publication listings available via PubMed

Research

I have been in love with DNA for as long as I can remember.  I chose to study replication because it is central to the biological role of DNA as the molecule of inheritance, and I found in Baker’s yeast the perfect organism to investigate this fundamental process. 

Research is conducted in collaboration with Professor M. K. Raghuraman (Raghu).  We are studying the regulation of replication that ensures that each chromosome is duplicated in a timely and precise way, and are characterizing the consequences for chromosomes when these processes go awry.  Although the chromosomes of the budding yeast are orders of magnitude smaller than those of plants and animals, they are organized for replication in much the same way: replication occurs from multiple, closely-spaced origins and different parts of a chromosome are replicated at different times during the S phase of the cell cycle, using machinery that is conserved from yeast to humans.  Thus, studying how this small organism replicates and maintains its chromosomes gives us insights into how the same processes occur—or go awry—in our own cells.

Nearly 50 years ago, we pioneered the use of 2-dimensional gel electrophoresis techniques to map specific replication origins and to determine the efficiency with which they are activated.  In the early days of DNA microarrays we developed methods and algorithms to study replication on a genome wide scale.  While we now also use DNA sequencing to answer some questions about genome structure and replication, we find gels and Southern hybridization are often still the best tools to answer the questions that interest us. 

While this work continues, in collaborations with Maitreya Dunham’s lab, we are also exploring the changes to chromosomes that occur during laboratory evolution and replicative aging and find they are often the consequence of an error in replication.  Growing yeast cells continuously for many weeks in chemostats limiting for sulfur invariably results in the amplification of the gene that encodes the primary sulfate transporter, SUL1.  While that outcome itself isn’t that surprising, the mechanisms that cells use to bring about the amplification are novel.  The primary form of amplicon of the SUL1 gene and its adjacent origin of replication is a triplicated chromosomal fragment with the center copy in an inverted orientation.  We proposed that an error in replication fork progressions explains  how this particular structure is generated.  When we interfere with this mechanism by mutating different genes involved in DNA replication or chromosome maintenance, we uncovered other mechanisms that cells use to achieve the selective benefits from SUL1 amplification.  Structures similar to the yeast SUL1 amplicons have been found in humans where they are often associated with genetic disorders.  We have also used chemostats to explore genomic changes that occur during aging of yeast cells.  We propose that aberrant repair of broken replication forks generates branched chromosomes that cannot be properly segregated at division—thereby limiting yeast’s life span.  Might these errors also be contributing to human aging?  Stay tuned!

Selected Publications

Brewer, B. J. and W. L. Fangman (1987). “The localization of replication origins on ARS plasmids in S. cerevisiae.” Cell 51(3): 463-471; https://doi.org/10.1016/0092-8674(87)90642-8.

Raghuraman, M. K., E. A. Winzeler, D. Collingwood, S. Hunt, L. Wodicka, A. Conway, D. J. Lockhart, R. W. Davis, B. J. Brewer and W. L. Fangman (2001). “Replication dynamics of the yeast genome.” Science 294(5540): 115-121; https://doi.org/10.1126/science.294.5540.115.

Brewer, B. J., C. Payen, M. K. Raghuraman and M. J. Dunham (2011). “Origin-dependent inverted-repeat amplification: a replication-based model for generating palindromic amplicons.” PLoS Genet 7(3): e1002016; https://pmc.ncbi.nlm.nih.gov/articles/PMC3060070.

Sanchez, J. C., A. Ollodart, C. R. L. Large, C. Clough, G. M. Alvino, M. Tsuchiya, M. Crane, E. X. Kwan, M. Kaeberlein, M. J. Dunham, M. K. Raghuraman and B. J. Brewer (2019). “Phenotypic and Genotypic Consequences of CRISPR/Cas9 Editing of the Replication Origins in the rDNA of Saccharomyces cerevisiae.” Genetics 213(1): 229-249; https://pmc.ncbi.nlm.nih.gov/articles/PMC6727806.

Kwan, E. X., G. M. Alvino, K. L. Lynch, P. F. Levan, H. M. Amemiya, X. S. Wang, S. A. Johnson, J. C. Sanchez, M. A. Miller, M. Croy, S. B. Lee, M. Naushab, A. Bedalov, J. T. Cuperus, B. J. Brewer, C. Queitsch and M. K. Raghuraman (2023). “Ribosomal DNA replication time coordinates completion of genome replication and anaphase in yeast.” Cell Rep 42(3): 112161; https://pmc.ncbi.nlm.nih.gov/articles/PMC10142053.

Brewer, B. J., M. J. Dunham and M. K. Raghuraman (2024). “A unifying model that explains the origins of human inverted copy number variants.” PLoS Genet 20(1): e1011091; https://pmc.ncbi.nlm.nih.gov/articles/PMC10766186.

Brewer, B.J., R. Martin, E. Ramage, C. Payen, S. C. Di Rienzi, Y. Zhao, K. Van Sickle, J. I. Verhey, M. Zalusky, D. E. Miller, D., G. T. Ong, J. L.  McKee, G. M. Alvino, M. J. Dunham and M. K. Raghuraman (2026). “Telomeric amplicons of SUL1 and Y’ in yeast are generated by microhomology-mediated break induced replication occurring in cis.” PLoS Genetics, in minor revision. https://doi.org/10.64898/2026.04.07.716220.  Submitted April 17, 2026

Armstrong, J. O., E. X. Kwan, G. M. Alvino, M. K. Raghuraman, M. J. Dunham and B. J. Brewer. (2026) “Beyond ERCs: exploring catastrophic forms of rDNA instability in aging yeast.” PLoS Genetics, under review. https://doi.org/10.64898/2026.04.21.719800.  Submitted April 18, 2026

additional publication listings available via PubMed | CV

Research:

My laboratory uses the fruit fly Drosophila melanogaster as a genetic model system to understand the mechanisms underlying neurodegenerative disorders, such as Parkinson’s disease. Flies are a terrific system for this work because of the many powerful genetic tools that have been developed over the long history of their use as a model organism, and because recent work has established that neurodegenerative disorders can be successfully modeled using flies. At present, we are pursuing three different projects in the lab.

Mitochondrial quality control: The accumulation of damaged mitochondria is linked to aging and common neurodegenerative diseases. Previous work has shown that damaged mitochondria can be selectively degraded in the lysosome through a process termed mitophagy, but the underlying mechanisms were completely unknown until recently. Our work on the Parkinson’s disease-related factors PINK1 and Parkin helped establish that they play crucial roles in mitophagy. A major focus of our laboratory is now aimed at understanding how PINK1 and Parkin promote mitophagy, and to identify other components of this mitochondrial quality control apparatus.

Functional analysis of the glucocerebrosidase (GBA) gene: Mutations in the GBA gene are by far the most common genetic association with Parkinson’s disease. GBA encodes a lysosomal enzyme required for the breakdown of the sphingolipid glucocylceramide, suggesting that the accumulation of glucocylceramide and related sphingolipids upon mutational inactivation of GBA triggers the onset of Parkinson’s disease. We have created a fly model of GBAdeficiency and are using it to explore the mechanisms underlying this frequent cause of Parkinson’s disease.

Traumatic brain injury: Over the past several years it has become increasingly clear that traumatic brain injuries significantly increase the risk for developing neurodegenerative diseases years or even decades after the injury. We have recently created a fly model of traumatic brain injury and are using this model to explore the underlying mechanisms.

Selected Publications:

full list of lab publications available via PubMed