Natural proteome diversity links aneuploidy tolerance to protein turnover.


Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
22 May 2024
Historique:
received: 07 04 2022
accepted: 19 04 2024
medline: 23 5 2024
pubmed: 23 5 2024
entrez: 22 5 2024
Statut: aheadofprint

Résumé

Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy-an imbalance in chromosome copy numbers-is frequent

Identifiants

pubmed: 38778096
doi: 10.1038/s41586-024-07442-9
pii: 10.1038/s41586-024-07442-9
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. The Author(s).

Références

Peter, J. et al. Genome evolution across 1,011 Saccharomyces cerevisiae isolates. Nature 556, 339–344 (2018).
pubmed: 29643504 pmcid: 6784862 doi: 10.1038/s41586-018-0030-5
Gallone, B. et al. Domestication and divergence of Saccharomyces cerevisiae beer yeasts. Cell 166, 1397–1410 (2016).
pubmed: 27610566 pmcid: 5018251 doi: 10.1016/j.cell.2016.08.020
Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007).
pubmed: 17702937 doi: 10.1126/science.1142210
Hose, J. et al. Dosage compensation can buffer copy-number variation in wild yeast. eLife 4, e05462 (2015).
pubmed: 25955966 pmcid: 4448642 doi: 10.7554/eLife.05462
Pavelka, N. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468, 321–325 (2010).
pubmed: 20962780 pmcid: 2978756 doi: 10.1038/nature09529
Caudal, E. et al. Pan-transcriptome reveals a large accessory genome contribution to gene expression variation in yeast. Preprint at bioRxiv https://doi.org/10.1101/2023.05.17.541122 (2023).
Legras, J.-L. et al. Adaptation of S. cerevisiae to fermented food environments reveals remarkable genome plasticity and the footprints of domestication. Mol. Biol. Evol. 35, 1712–1727 (2018).
pubmed: 29746697 pmcid: 5995190 doi: 10.1093/molbev/msy066
Bergström, A. et al. A high-definition view of functional genetic variation from natural yeast genomes. Mol. Biol. Evol. 31, 872–888 (2014).
pubmed: 24425782 pmcid: 3969562 doi: 10.1093/molbev/msu037
Zhu, Y. O., Sherlock, G. & Petrov, D. A. Whole genome analysis of 132 clinical Saccharomyces cerevisiae strains reveals extensive ploidy variation. G3 6, 2421–2434 (2016).
pubmed: 27317778 pmcid: 4978896 doi: 10.1534/g3.116.029397
Dephoure, N. et al. Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3, e03023 (2014).
pubmed: 25073701 pmcid: 4129440 doi: 10.7554/eLife.03023
Selmecki, A., Forche, A. & Berman, J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313, 367–370 (2006).
pubmed: 16857942 pmcid: 1717021 doi: 10.1126/science.1128242
Yona, A. H. et al. Chromosomal duplication is a transient evolutionary solution to stress. Proc. Natl Acad. Sci. USA 109, 21010–21015 (2012).
pubmed: 23197825 pmcid: 3529009 doi: 10.1073/pnas.1211150109
Yang, F. et al. Adaptation to fluconazole via aneuploidy enables cross-adaptation to amphotericin B and flucytosine in Cryptococcus neoformans. Microbiol. Spectr. 9, e0072321 (2021).
pubmed: 34585947 doi: 10.1128/Spectrum.00723-21
Beaupere, C. et al. Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast. Proc. Natl Acad. Sci. USA 115, 9586–9591 (2018).
pubmed: 30185560 pmcid: 6156608 doi: 10.1073/pnas.1804264115
Anderson, M. Z., Saha, A., Haseeb, A. & Bennett, R. J. A chromosome 4 trisomy contributes to increased fluconazole resistance in a clinical isolate of Candida albicans. Microbiology 163, 856–865 (2017).
pubmed: 28640746 pmcid: 5737213 doi: 10.1099/mic.0.000478
Berman, J. & Krysan, D. J. Drug resistance and tolerance in fungi. Nat. Rev. Microbiol. 18, 319–331 (2020).
pubmed: 32047294 pmcid: 7231573 doi: 10.1038/s41579-019-0322-2
Zhu, J., Tsai, H.-J., Gordon, M. R. & Li, R. Cellular stress associated with aneuploidy. Dev. Cell 44, 420–431 (2018).
pubmed: 29486194 pmcid: 6529225 doi: 10.1016/j.devcel.2018.02.002
Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13, 189–203 (2012).
pubmed: 22269907 doi: 10.1038/nrg3123
Ben-David, U. & Amon, A. Context is everything: aneuploidy in cancer. Nat. Rev. Genet. 21, 44–62 (2020).
pubmed: 31548659 doi: 10.1038/s41576-019-0171-x
Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689 (2018).
pubmed: 29622463 pmcid: 6028190 doi: 10.1016/j.ccell.2018.03.007
Chunduri, N. K. & Storchová, Z. The diverse consequences of aneuploidy. Nat. Cell Biol. 21, 54–62 (2019).
pubmed: 30602769 doi: 10.1038/s41556-018-0243-8
Holland, A. J. & Cleveland, D. W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10, 478–487 (2009).
pubmed: 19546858 pmcid: 3154738 doi: 10.1038/nrm2718
Brennan, C. M. et al. Protein aggregation mediates stoichiometry of protein complexes in aneuploid cells. Genes Dev. 33, 1031–1047 (2019).
pubmed: 31196865 pmcid: 6672052 doi: 10.1101/gad.327494.119
Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8, 608 (2012).
pubmed: 22968442 pmcid: 3472693 doi: 10.1038/msb.2012.40
McShane, E. et al. Kinetic analysis of protein stability reveals age-dependent degradation. Cell 167, 803–815 (2016).
pubmed: 27720452 doi: 10.1016/j.cell.2016.09.015
Schukken, K. M. & Sheltzer, J. M. Extensive protein dosage compensation in aneuploid human cancers. Genome Res. 32, 1254–1270 (2022).
pubmed: 35701073 pmcid: 9341510 doi: 10.1101/gr.276378.121
Chunduri, N. K. et al. Systems approaches identify the consequences of monosomy in somatic human cells. Nat. Commun. 12, 5576 (2021).
pubmed: 34552071 pmcid: 8458293 doi: 10.1038/s41467-021-25288-x
Cuypers, B. et al. Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania. PLoS Pathog. 18, e1010848 (2022).
pubmed: 36149920 pmcid: 9534393 doi: 10.1371/journal.ppat.1010848
Senger, G., Santaguida, S. & Schaefer, M. H. Regulation of protein complex partners as a compensatory mechanism in aneuploid tumors. eLife 11, e75526 (2022).
pubmed: 35575458 pmcid: 9135399 doi: 10.7554/eLife.75526
Ippolito, M. R. et al. Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells. Preprint at bioRxiv https://doi.org/10.1101/2023.01.27.525826 (2023).
Liu, Y. et al. Systematic proteome and proteostasis profiling in human trisomy 21 fibroblast cells. Nat. Commun. 8, 1212 (2017).
pubmed: 29089484 pmcid: 5663699 doi: 10.1038/s41467-017-01422-6
Berman, J. Evolutionary genomics: when abnormality is beneficial. Nature 468, 183–184 (2010).
pubmed: 21068824 doi: 10.1038/468183a
Hose, J. et al. The genetic basis of aneuploidy tolerance in wild yeast. eLife 9, e52063 (2020).
pubmed: 31909711 pmcid: 6970514 doi: 10.7554/eLife.52063
Tsai, H. J. et al. Hypo-osmotic-like stress underlies general cellular defects of aneuploidy. Nature 570, 117–121 (2019).
pubmed: 31068692 pmcid: 6583789 doi: 10.1038/s41586-019-1187-2
Terhorst, A. et al. The environmental stress response causes ribosome loss in aneuploid yeast cells. Proc. Natl Acad. Sci. USA 117, 17031–17040 (2020).
pubmed: 32632008 pmcid: 7382292 doi: 10.1073/pnas.2005648117
Scopel, E. F. C., Hose, J., Bensasson, D. & Gasch, A. P. Genetic variation in aneuploidy prevalence and tolerance across Saccharomyces cerevisiae lineages. Genetics 217, iyab015 (2021).
pubmed: 33734361 pmcid: 8049548 doi: 10.1093/genetics/iyab015
Gasch, A. P. et al. Further support for aneuploidy tolerance in wild yeast and effects of dosage compensation on gene copy-number evolution. eLife 5, e14409 (2016).
pubmed: 26949252 pmcid: 4798956 doi: 10.7554/eLife.14409
Torres, E. M., Springer, M. & Amon, A. No current evidence for widespread dosage compensation in S. cerevisiae. eLife 5, e10996 (2016).
pubmed: 26949255 pmcid: 4798953 doi: 10.7554/eLife.10996
Steger, M. et al. Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale. Nat. Commun. 12, 5399 (2021).
pubmed: 34518535 pmcid: 8438043 doi: 10.1038/s41467-021-25454-1
Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
pubmed: 21593866 doi: 10.1038/nature10098
Messner, C. B. et al. Ultra-fast proteomics with Scanning SWATH. Nat. Biotechnol. 39, 846–854 (2021).
pubmed: 33767396 pmcid: 7611254 doi: 10.1038/s41587-021-00860-4
Demichev, V., Messner, C. B., Vernardis, S. I., Lilley, K. S. & Ralser, M. DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods 17, 41–44 (2020).
pubmed: 31768060 doi: 10.1038/s41592-019-0638-x
Larrimore, K. E., Barattin-Voynova, N. S., Reid, D. W. & Ng, D. T. W. Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations, or stress responses. BMC Biol. 18, 117 (2020).
pubmed: 32900371 pmcid: 7487686 doi: 10.1186/s12915-020-00852-x
Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).
pubmed: 11102521 pmcid: 15070 doi: 10.1091/mbc.11.12.4241
Messner, C. B. et al. The proteomic landscape of genome-wide genetic perturbations. Cell 186, 2018–2034 (2023).
pubmed: 37080200 pmcid: 7615649 doi: 10.1016/j.cell.2023.03.026
Martin-Perez, M. & Villén, J. Determinants and regulation of protein turnover in yeast. Cell Syst. 5, 283–294 (2017).
pubmed: 28918244 pmcid: 5935796 doi: 10.1016/j.cels.2017.08.008
Olin-Sandoval, V. et al. Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism. Nature 572, 249–253 (2019).
pubmed: 31367038 pmcid: 6774798 doi: 10.1038/s41586-019-1442-6
Gasch, A. P., Payseur, B. A. & Pool, J. E. The power of natural variation for model organism biology. Trends Genet. 32, 147–154 (2016).
pubmed: 26777596 pmcid: 4769656 doi: 10.1016/j.tig.2015.12.003
She, R. & Jarosz, D. F. Mapping causal variants with single-nucleotide resolution reveals biochemical drivers of phenotypic change. Cell 172, 478–490 (2018).
pubmed: 29373829 pmcid: 5788306 doi: 10.1016/j.cell.2017.12.015
McQueary, H. C. et al. No evidence for whole-chromosome dosage compensation or global transcriptomic expression differences in spontaneously-aneuploid mutation accumulation lines of Saccharomyces cerevisiae. Preprint at bioRxiv https://doi.org/10.1101/2020.12.01.404830 (2020).
Donnelly, N., Passerini, V., Dürrbaum, M., Stingele, S. & Storchová, Z. HSF1 deficiency and impaired HSP 90‐dependent protein folding are hallmarks of aneuploid human cells. EMBO J. 33, 2374–2387 (2014).
pubmed: 25205676 pmcid: 4253526 doi: 10.15252/embj.201488648
Oromendia, A. B., Dodgson, S. E. & Amon, A. Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 26, 2696–2708 (2012).
pubmed: 23222101 pmcid: 3533075 doi: 10.1101/gad.207407.112
Torres, E. M. et al. Identification of aneuploidy-tolerating mutations. Cell 143, 71–83 (2010).
pubmed: 20850176 pmcid: 2993244 doi: 10.1016/j.cell.2010.08.038
Drysdale, J. W. & Munro, H. N. Regulation of synthesis and turnover of ferritin in rat liver. J. Biol. Chem. 241, 3630–3637 (1966).
pubmed: 5919688 doi: 10.1016/S0021-9258(18)99877-7
Kustatscher, G., Grabowski, P. & Rappsilber, J. Pervasive coexpression of spatially proximal genes is buffered at the protein level. Mol. Syst. Biol. 13, 937 (2017).
pubmed: 28835372 pmcid: 5572396 doi: 10.15252/msb.20177548
Marsit, S. & Dequin, S. Diversity and adaptive evolution of Saccharomyces wine yeast: a review. FEMS Yeast Res. 15, fov067 (2015).
pubmed: 26205244 pmcid: 4629790 doi: 10.1093/femsyr/fov067
Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010).
pubmed: 20196867 pmcid: 2864565 doi: 10.1186/gb-2010-11-3-r25
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
pubmed: 19910308 doi: 10.1093/bioinformatics/btp616
McCarthy, D. J., Chen, Y. & Smyth, G. K. Differential expression analysis of multifactor RNA-seq experiments with respect to biological variation. Nucleic Acids Res. 40, 4288–4297 (2012).
pubmed: 22287627 pmcid: 3378882 doi: 10.1093/nar/gks042
Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).
pubmed: 11752295 pmcid: 99122 doi: 10.1093/nar/30.1.207
Messner, C. B. et al. Ultra-high-throughput clinical proteomics reveals classifiers of COVID-19 infection. Cell Syst. 11, 11–24 (2020).
pubmed: 32619549 pmcid: 7264033 doi: 10.1016/j.cels.2020.05.012
Vowinckel, J. et al. Cost-effective generation of precise label-free quantitative proteomes in high-throughput by microLC and data-independent acquisition. Sci. Rep. 8, 4346 (2018).
pubmed: 29531254 pmcid: 5847575 doi: 10.1038/s41598-018-22610-4
UniProt Consortium. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 49, D480–D489 (2021).
doi: 10.1093/nar/gkaa1100
Cox, J. et al. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol. Cell. Proteomics 13, 2513–2526 (2014).
pubmed: 24942700 pmcid: 4159666 doi: 10.1074/mcp.M113.031591
Troyanskaya, O. et al. Missing value estimation methods for DNA microarrays. Bioinformatics 17, 520–525 (2001).
pubmed: 11395428 doi: 10.1093/bioinformatics/17.6.520
Rappsilber, J., Ishihama, Y. & Mann, M. Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. Anal. Chem. 75, 663–670 (2003).
pubmed: 12585499 doi: 10.1021/ac026117i
Mülleder, M., Campbell, K., Matsarskaia, O., Eckerstorfer, F. & Ralser, M. Saccharomyces cerevisiae single-copy plasmids for auxotrophy compensation, multiple marker selection, and for designing metabolically cooperating communities. F1000Res. 5, 2351 (2016).
pubmed: 27830062 pmcid: 5081161 doi: 10.12688/f1000research.9606.1
Mülleder, M. et al. Functional metabolomics describes the yeast biosynthetic regulome. Cell 167, 553–565 (2016).
pubmed: 27693354 pmcid: 5055083 doi: 10.1016/j.cell.2016.09.007
Kanehisa, M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28, 1947–1951 (2019).
pubmed: 31441146 pmcid: 6798127 doi: 10.1002/pro.3715
Carlson, M. org.Sc.sgd.db: Genome wide annotation for yeast. R v.2 (Bioconductor, 2014).
Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32, 2847–2849 (2016).
pubmed: 27207943 doi: 10.1093/bioinformatics/btw313
Yahya, G. et al. Sublinear scaling of the cellular proteome with ploidy. Nat. Commun. 13, 6182 (2022).
pubmed: 36261409 pmcid: 9581932 doi: 10.1038/s41467-022-33904-7
Meldal, B. H. M. et al. Complex Portal 2018: extended content and enhanced visualization tools for macromolecular complexes. Nucleic Acids Res. 47, D550–D558 (2019).
pubmed: 30357405 doi: 10.1093/nar/gky1001
Szklarczyk, D. et al. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015).
pubmed: 25352553 doi: 10.1093/nar/gku1003
Piovesan, D. et al. MobiDB: 10 years of intrinsically disordered proteins. Nucleic Acids Res. 51, D438–D444 (2023).
pubmed: 36416266 doi: 10.1093/nar/gkac1065
Steenwyk, J. L. et al. BioKIT: a versatile toolkit for processing and analyzing diverse types of sequence data. Genetics 221, iyac079 (2022).
pubmed: 35536198 pmcid: 9252278 doi: 10.1093/genetics/iyac079
McManus, C. J., May, G. E., Spealman, P. & Shteyman, A. Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast. Genome Res. 24, 422–430 (2014).
pubmed: 24318730 pmcid: 3941107 doi: 10.1101/gr.164996.113
Chen, Y. & Nielsen, J. Yeast has evolved to minimize protein resource cost for synthesizing amino acids. Proc. Natl Acad. Sci. USA 119, e2114622119 (2022).
pubmed: 35042799 pmcid: 8795554 doi: 10.1073/pnas.2114622119
Ghaemmaghami, S. et al. Global analysis of protein expression in yeast. Nature 425, 737–741 (2003).
pubmed: 14562106 doi: 10.1038/nature02046
Robin, X. et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12, 77 (2011).
pubmed: 21414208 pmcid: 3068975 doi: 10.1186/1471-2105-12-77
Cherry, J. M. et al. Saccharomyces Genome Database: the genomics resource of budding yeast. Nucleic Acids Res. 40, D700–5 (2012).
pubmed: 22110037 doi: 10.1093/nar/gkr1029
Liao, Y., Wang, J., Jaehnig, E. J., Shi, Z. & Zhang, B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 47, W199–W205 (2019).
pubmed: 31114916 pmcid: 6602449 doi: 10.1093/nar/gkz401
Kassambara, A. rstatix: Pipe-friendly framework for basic statistical tests. R v.0.6.0 (CRAN, 2020).
Finley, D., Ulrich, H. D., Sommer, T. & Kaiser, P. The ubiquitin–proteasome system of Saccharomyces cerevisiae. Genetics 192, 319–360 (2012).
pubmed: 23028185 pmcid: 3454868 doi: 10.1534/genetics.112.140467

Auteurs

Julia Muenzner (J)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Pauline Trébulle (P)

Molecular Biology of Metabolism Laboratory, Francis Crick Institute, London, UK.
Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Federica Agostini (F)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Henrik Zauber (H)

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Christoph B Messner (CB)

Molecular Biology of Metabolism Laboratory, Francis Crick Institute, London, UK.
Precision Proteomics Center, Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Martin Steger (M)

Evotec (München), Martinsried, Germany.
NEOsphere Biotechnologies, Martinsried, Germany.

Christiane Kilian (C)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Kate Lau (K)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Natalie Barthel (N)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Andrea Lehmann (A)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.

Kathrin Textoris-Taube (K)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.
Core Facility High-Throughput Mass Spectrometry, Charité Universitätsmedizin, Berlin, Germany.

Elodie Caudal (E)

Université de Strasbourg, CNRS GMGM UMR 7156, Strasbourg, France.

Anna-Sophia Egger (AS)

Molecular Biology of Metabolism Laboratory, Francis Crick Institute, London, UK.

Fatma Amari (F)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.
Core Facility High-Throughput Mass Spectrometry, Charité Universitätsmedizin, Berlin, Germany.

Matteo De Chiara (M)

Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.

Vadim Demichev (V)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany.
Molecular Biology of Metabolism Laboratory, Francis Crick Institute, London, UK.

Toni I Gossmann (TI)

Computational Systems Biology, Faculty of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany.

Michael Mülleder (M)

Core Facility High-Throughput Mass Spectrometry, Charité Universitätsmedizin, Berlin, Germany.

Gianni Liti (G)

Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.

Joseph Schacherer (J)

Université de Strasbourg, CNRS GMGM UMR 7156, Strasbourg, France.
Institut Universitaire de France (IUF), Paris, France.

Matthias Selbach (M)

Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Judith Berman (J)

Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel. jberman@tauex.tau.ac.il.

Markus Ralser (M)

Department of Biochemistry, Charité Universitätsmedizin, Berlin, Germany. markus.ralser@charite.de.
Molecular Biology of Metabolism Laboratory, Francis Crick Institute, London, UK. markus.ralser@charite.de.
Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. markus.ralser@charite.de.
Max Planck Institute for Molecular Genetics, Berlin, Germany. markus.ralser@charite.de.

Classifications MeSH