The Van Leeuwen lab is located at the Center for Integrative Genomics in Lausanne.

Our main research interest is to use functional genomics tools to improve our understanding of how mutations can interact to produce unexpected phenotypes, and how this determines the severity of genetic traits, including human disease.

Research

The sequencing of thousands of humans has led to the identification of people that are healthy despite carrying mutations that have been directly associated with severe early-onset Mendelian diseases, such as cystic fibrosis. A plausible explanation is that these individuals carry secondary mutations elsewhere in the genome that can compensate for the deleterious effect of the disease-associated mutation, a phenomenon referred to as genetic suppression. However, we currently lack the expertise to identify these suppressor mutations among the millions of variants scattered across the genomes of these resilient individuals. Understanding the general mechanisms of suppression will aid the identification of the genes in which suppressing mutations can occur, which in turn will help define molecular mechanisms of disease and identify potential drug targets to guide the development of therapeutics.

Expanding the yeast suppression network

We recently mapped a global suppression network in the budding yeast, Saccharomyces cerevisiae, based on both literature-curated interaction data as well as novel spontaneous suppressor mutations that we identified through genetic mapping and whole-genome sequencing. These interaction networks highlighted general mechanisms of suppression, and allowed us to make detailed predictions of gene function that were not obvious from other genetic or physical interaction data. Although genetic suppression interactions can overlap with other types of interactions, they mostly define novel gene-gene relationships. Thus, expanding the global suppression network offers a new opportunity for exploring the functional wiring diagrams of a cell. We are currently generating thousands of suppressor mutations of partial loss-of-function alleles of all essential yeast genes, which provides insight on suppression mechanisms for partial loss-of-function alleles, and greatly expands the yeast suppression network. This large-scale analysis also identifies critical residues or domains within each protein and provides new insights into protein structure-function relationships.

Understanding drug resistance by chemical suppression analysis

Suppression strategies can also be applied to explore mechanisms of drug resistance, by identifying suppressors of the sensitivity of cells to a chemotherapeutic agent. Often the mutation of multiple genes can confer resistance to a drug. For instance, mutations in six genes are known to result in 6-thioguanine resistance, and dozens of genes have been related to cisplatin-resistance. To gain insight into the complex genetic interaction networks that underlie drug resistance, we are performing chemical suppression screens in a ‘wild-type’ cell line to identify genes that when mutated can confer resistance to a drug of interest. In subsequent CRISPR knockout screens, we use the resistant mutant cell lines to identify modifier genes that suppress drug resistance, and make the cells sensitive to the chemical agent again. This gains an understanding of the underlying mechanisms of chemo-resistance, and identifies potential new drug targets for combination therapies.

Suppression screens in human cell lines

The ongoing developments in CRISPR-technologies, together with the continued decline in sequencing costs, provide the opportunity to take the analysis of genetic suppression interactions to human cell lines. As most suppression interactions occur between genes that have a close functional connection, mapping suppression in human cells will gain valuable knowledge on gene and pathway function as well as on the functional wiring of a human cell. Furthermore, identifying suppressors of disease alleles may potentially yield new drug targets. We recently performed genome-wide CRISPR knockout screens in human haploid cell lines. This allowed us to identify a set of genes that are required for cell growth in all cell lines. These ‘essential’ genes are enriched for human disease genes, and are thus interesting targets for suppression analysis. As cells lacking one of these genes will have a severe fitness defect, making it difficult to perform standard genome-wide screens, we are developing new approaches to identify suppressor mutations for these genes.

Higher-order suppression interactions

Although the isolation of suppression interactions between two genes provides valuable information on functional connections between genes, multiple mutations are likely involved in affecting the penetrance of any given allele in natural populations. To be able to fully understand genotype to phenotype relationships, we thus need to map interactions involving more than two genes. We are initially harnessing the power of yeast genetics to study these complex interactions. Based on our previous suppression studies, we have defined a set of genes that when mutated cause a fitness defect which is likely to be suppressible by multiple mutations, and we are currently experimentally trying to isolate these. In addition, we are comparing the complete set of genetic interactions for a mutant allele both in presence and absence of a suppressor mutation, which allows us to identify positive or negative modifiers of the suppression interaction. These projects gain further insight into mechanisms of suppression, and increase our understanding of how multiple mutations can combine to yield phenotypes.

Publications

Peer-reviewed papers


  • Global Genetic Networks and the Genotype to Phenotype Relationship

    Michael Costanzo, Elena Kuzmin, Jolanda van Leeuwen, Barbara Mair, Jason Moffat, Charles Boone, and Brenda J. Andrews

    Cell (2019), 177, 85-100

    PDF / Pubmed
  • Genetic Network Complexity Shapes Background-Dependent Phenotypic Expression

    Jing Hou, Jolanda van Leeuwen, Brenda J. Andrews, and Charles Boone

    Trends Genet (2018), 34, 578-586

    PDF / Pubmed
  • Yeast Aim21/Tda2 both regulates free actin by reducing barbed end assembly and forms a complex with Cap1/Cap2 to balance actin assembly between patches and cables

    Myungjoo Shin, Jolanda van Leeuwen, Charles Boone, and Anthony Bretscher

    Mol Biol Cell (2018), 29, 923-936

    Pubmed
  • Systematic analysis of complex genetic interactions

    Elena Kuzmin, Benjamin VanderSluis, Wen Wang, Guihong Tan, Raamesh Deshpande, Yiqun Chen, Matej Usaj, Attila Balint, Mojca Mattiazzi Usaj, Jolanda van Leeuwen, Elizabeth N. Koch, Carles Pons, Andrius J. Dagilis, Michael Pryszlak, Zi Wang, Julia Hanchard, Margot Riggi, Kaicong Xu, Hamed Heydari, Bryan-Joseph San Luis, Ermira Shuteriqi, Hongwei Zhu, Nydia Van Dyk, Sara Sharifpoor, Michael Costanzo, Robbie Loewith, Amy Caudy, Daniel Bolnick, Grant W. Brown, Brenda J. Andrews, Charles Boone, and Chad L. Myers

    Science (2018), 360, eaa01729

    PDF / Pubmed
  • Mapping a diversity of genetic interactions in yeast

    Jolanda van Leeuwen, Charles Boone, and Brenda J. Andrews

    Curt Opin Syst Biol (2017), 6, 14-21

    PDF
  • Evaluation and design of genome-wide CRISPR/Cas9 knockout screens

    Traver Hart, Amy Tong, Katie Chan, Jolanda van Leeuwen, Ashwin Seetharaman, Michael Aregger, Megha Chandrashekhar, Nicole Hustedt, Sahil Seth, Avery Noonan, Andrea Habsid, Olga Sizova, Lyudmilla Nedyalkova, Ryan Climie, Leanne Tworzyanski, Keith Lawson, Maria Augusta Sartori, Sabriyeh Alibeh, David Tieu, Sanna Masud, Patricia Mero, Alexander Weiss, Kevin R. Brown, Matej Ušaj, Maximilian Billmann, Mahfuzur Rahman, Michael Costanzo, Chad L. Myers, Brenda Andrews, Charles Boone, Daniel Durocher, and Jason Moffat

    G3 (Bethesda) (2017), 7, 2719-2727

    PDF / Pubmed
  • Functional annotation of chemical libraries across diverse biological processes

    Jeff S. Piotrowski*, Sheena C. Li*, Raamesh Deshpande*, Scott W. Simpkins*, Justin Nelson, Yoko Yashiroda, Jacqueline M. Barber, Hamid Safizadeh, Erin Wilson, Hiroki Okada, Abraham A. Gebre, Karen Kubo, Nikko Torres, Marissa A. LeBlanc, Kerry Andrusiak, Reika Okamoto, Mami Yoshimura, Eva DeRango-Adem, Jolanda van Leeuwen, Katsuhiko Shirahige, Anastasia Baryshnikova, Grant W. Brown, Hiroyuki Hirano, Michael Costanzo, Brenda Andrews, Yoshikazu Ohya, Hiroyuki Osada, Minoru Yoshida, Chad L. Myers, and Charles Boone

    Nat Chem Biol (2017), 13, 982-993

    PDF / Pubmed
  • Mechanisms of suppression: the wiring of genetic resilience

    Jolanda van Leeuwen, Carles Pons, Charles Boone, and Brenda J. Andrews

    BioEssays (2017), 39, 1700042

    PDF / Pubmed
  • The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

    Angelina Huseinovic, Jolanda S. van Leeuwen, Tibor van Welsem, Fred van Leeuwen, Nico. P.E. Vermeulen, Jan M. Kooter and J. Chris Vos

    PLoS One (2017), 12, e017357

    PDF / Pubmed
  • Exploring genetic suppression interactions on a global scale

    Jolanda van Leeuwen*, Carles Pons*, Joseph C. Mellor, Takafumi N. Yamaguchi, Helena Friesen, John Koschwanez, Mojca Mattiazzi Ušaj, Maria Pechlaner, Mehmet Takar, Matej Ušaj, Benjamin VanderSluis, Kerry Andrusiak, Pritpal Bansal, Anastasia Baryshnikova, Claire Boone, Jessica Cao, Atina Cote, Marinella Gebbia, Gene Horecka, Ira Horecka, Elena Kuzmin, Nicole Legro, Wendy Liang, Natascha van Lieshout, Margaret McNee, Bryan-Joseph San Luis, Fatemeh Shaeri, Ermira Shuteriqi, Song Sun, Lu Yang, Ji-Young Youn, Michael Yuen, Michael Costanzo, Anne-Claude Gingras, Patrick Aloy, Chris Oostenbrink, Andrew Murray, Todd R. Graham, Chad L. Myers, Brenda J. Andrews, Frederick P. Roth, and Charles Boone

    Science (2016), 354, 599

    PDF / Pubmed
  • A global genetic interaction network maps a wiring diagram of cellular function

    Michael Costanzo*, Benjamin VanderSluis*, Elizabeth N. Koch*, Anastasia Baryshnikova*, Carles Pons*, Guihong Tan*, Wen Wang, Matej Usaj, Julia Hanchard, Susan D. Lee, Vicent Pelechano, Erin B. Styles, Maximilian Billmann, Jolanda van Leeuwen, Nydia van Dyk, Zhen-Yuan Lin, Elena Kuzmin, Justin Nelson, Jeff S. Piotrowski, Tharan Srikumar, Sondra Bahr, Yiqun Chen, Raamesh Deshpande, Christoph F. Kurat, Sheena C. Li, Zhijian Li, Mojca Mattiazzi Usaj, Hiroki Okada, Natasha Pascoe, Bryan-Joseph San Luis, Sara Sharifpoor, Emira Shuteriqi, Scott W. Simpkins, Jamie Snider, Harsha Garadi Suresh, Yizhao Tan, Hongwei Zhu, Noel Malod-Dognin, Vuk Janjic, Natasa Przulj, Olga G. Troyanskaya, Igor Stagljar, Tian Xia, Yoshikazu Ohya, Anne-Claude Gingras, Brian Raught, Michael Boutros, Lars M. Steinmetz, Claire L. Moore, Adam P. Rosebrock, Amy A. Caudy, Chad L. Myers, Brenda Andrews, and Charles Boone

    Science (2016), 353, 1381

    PDF / Pubmed
  • Yeast as a humanized model organism for biotransformation-related toxicity

    Jolanda S. van Leeuwen, Nico P.E. Vermeulen, and J. Chris Vos

    Curr Drug Metab (2012), 13, 1464-1475

    PDF / Pubmed
  • Differential involvement of mitochondrial dysfunction, cytochrome P450 activity and active transport in the toxicity of structurally related NSAIDs

    Jolanda S. van Leeuwen, Betül Ünlü, Nico P.E. Vermeulen, and J. Chris Vos

    Tox In Vitro (2012), 26, 197-205

    PDF / Pubmed
  • Involvement of the pleiotropic drug resistance response, protein kinase C signaling, and altered zinc homeostasis in resistance of Saccharomyces cerevisiae to diclofenac.

    Jolanda S. van Leeuwen, Nico P.E. Vermeulen, and J. Chris Vos

    Curr Drug Metab (2011), 13, 1464-1475

    PDF / Pubmed
  • Efficient screening of P450 BM3 mutants for their metabolic activity and diversity towards a wide set of drug-like molecules in chemical space

    Jelle Reinen, Jolanda S. van Leeuwen, Yongmin Li, Lifang Sun, Peter D.J. Grootenhuis, Caroline J. Decker, John Saunders, Nico P.E. Vermeulen, and Jan N.M. Commandeur

    Drug Metab Dispos (2011), 39, 1568-1576

    PDF / Pubmed
  • Metabolism related toxicity of diclofenac in yeast as model system

    Jolanda S. van Leeuwen, Galvin Vredenburg, Sanja Dragovic, T.F. Jennifer Tjong, J. Chris Vos, and Nico P.E. Vermeulen

    Toxicol Lett (2011), 200, 162-168

    PDF / Pubmed
  • Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

    Jolanda S. van Leeuwen, Rick Orij, Marijke Luttik, Gertien J. Smits, Nico P.E. Vermeulen, and J. Chris Vos

    Microbiology (2011), 157, 685-694

    PDF / Pubmed

Other publications


  • Construction of multi-fragment plasmids by homologous recombination in yeast (topic introduction)

    Jolanda van Leeuwen, Brenda Andrews, Charles Boone, and Guihong Tan

    Cold Spring Harb Protoc (2015), 9, pdb.top084111

    PDF / Pubmed
  • Rapid and efficient plasmid construction by homologous recombination in yeast (protocol)

    Jolanda van Leeuwen, Brenda Andrews, Charles Boone, and Guihong Tan

    Cold Spring Harb Protoc (2015), 9, pdb.prot085100

    PDF / Pubmed
  • Yeast as a model eukaryote in drug safety studies: New insights on diclofenac-induced toxicity (thesis)

    Jolanda S. van Leeuwen

    (2011)

    PDF
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People

Jolanda van Leeuwen

Jolanda van Leeuwen

Principal Investigator

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Lab manager

Maykel Lopes

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Postdoctoral Fellow

Amandine Batté

Postdoctoral Fellow

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Postdoctoral Fellow

Betül Ünlü

Postdoctoral Fellow

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PhD student

Dinis Barros

PhD student

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PhD student

Linh Ho

PhD student

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PhD Student

Andreia Lopes

Technician

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Address

  • University of Lausanne

  • Center for Integrative Genomics (CIG), FBM
  • Quartier Unil Sorge
  • Bâtiment Génopode
  • Office: Room 4005
  • Lab: Room 4012 & 4013
  • CH-1015 Lausanne
  • Switzerland

  • jolanda.vanleeuwen [at] unil.ch
  • Phone: +41 21 692 3926 (Lab 4013) or +41 21 692 3938 (Lab 4012)
UNIL Genopode, Suisse