Genetic Basis of Metabolome Variation in Yeast
Many traits, from human height to E. coli growth rate, quantitatively vary across members of a species. Among the most medically and agriculturally important traits are levels of cellular metabolites, such as cholesterol levels in humans or starch in food crops. Metabolic variation in yeast also holds practical importance with some Saccharomyces strains better suited to making ethanol for biofuel and others tailored to making flavorful wine. This metabolic heterogeneity can be used to gain insight into general principles of metabolic regulation which effect metabolite abundance in eukaryotes. To this end, we examined inter-strain differences in metabolism in over 100 closely related S. cerevisiae strains. We identified over 50 genetic loci that control the levels of specific metabolites, including not only loci that encode metabolic enzymes, but also those that encode global cellular regulators. For example, differences in the sequence of ira2, an inhibitor of Ras, lead to differences in central carbon metabolite levels, and polymorphisms in slt2, a poorly characterized MAP kinase, alter levels of sulfur-containing metabolites. These findings provide insights into the mechanisms cells use to control metabolite concentrations.
Vyšlo v časopise:
Genetic Basis of Metabolome Variation in Yeast. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004142
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1004142
Souhrn
Many traits, from human height to E. coli growth rate, quantitatively vary across members of a species. Among the most medically and agriculturally important traits are levels of cellular metabolites, such as cholesterol levels in humans or starch in food crops. Metabolic variation in yeast also holds practical importance with some Saccharomyces strains better suited to making ethanol for biofuel and others tailored to making flavorful wine. This metabolic heterogeneity can be used to gain insight into general principles of metabolic regulation which effect metabolite abundance in eukaryotes. To this end, we examined inter-strain differences in metabolism in over 100 closely related S. cerevisiae strains. We identified over 50 genetic loci that control the levels of specific metabolites, including not only loci that encode metabolic enzymes, but also those that encode global cellular regulators. For example, differences in the sequence of ira2, an inhibitor of Ras, lead to differences in central carbon metabolite levels, and polymorphisms in slt2, a poorly characterized MAP kinase, alter levels of sulfur-containing metabolites. These findings provide insights into the mechanisms cells use to control metabolite concentrations.
Zdroje
1. BijlsmaS, BobeldijkI, VerheijER, RamakerR (2006) Large-scale human metabolomics studies: a strategy for data (pre-) processing and validation. Analytical Chemistry 78: 567–574.
2. SladekR, RocheleauG, RungJ, DinaC, ShenL, et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445: 881–885.
3. MarchesiJR, HolmesE, KhanF, KochharS, ScanlanP, et al. (2007) Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. Journal of proteome research 6: 546–551.
4. Swiegers JH, Pretorius IS (2005) Yeast Modulation of Wine Flavor. In: Advances in applied microbiology, Elsevier. pp. 131–175.
5. KeaslingJD, ChouH (2008) Metabolic engineering delivers next-generation biofuels. Nature Publishing Group 26: 298–299.
6. WahlbomCF, Cordero OteroRR, van ZylWH, Hahn-HägerdalB, JönssonLJ (2003) Molecular analysis of a Saccharomyces cerevisiae mutant with improved ability to utilize xylose shows enhanced expression of proteins involved in transport, initial xylose metabolism, and the pentose phosphate pathway. Applied and environmental microbiology 69: 740–746.
7. FiehnO (2002) Metabolomics–the link between genotypes and phenotypes. Plant molecular biology 48: 155–171.
8. GoodacreR, VaidyanathanS, DunnWB, HarriganGG, KellDB (2004) Metabolomics by numbers: acquiring and understanding global metabolite data. Trends in biotechnology 22: 245–252.
9. HallRD (2006) Plant metabolomics: from holistic hope, to hype, to hot topic. The New phytologist 169: 453–468.
10. SchauerN, FernieAR (2006) Plant metabolomics: towards biological function and mechanism. Trends in plant science 11: 508–516.
11. AllenJ, DaveyHM, BroadhurstD, HealdJK, RowlandJJ, et al. (2003) High-throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nature Biotechnology 21: 692–696.
12. BenfeyPN, Mitchell-OldsT (2008) From genotype to phenotype: systems biology meets natural variation. Science 320: 495–497.
13. Villas-BôasSG, MoxleyJF, AkessonM, StephanopoulosG, NielsenJ (2005) Highthroughput metabolic state analysis: the missing link in integrated functional genomics of yeasts. The Biochemical journal 388: 669–677.
14. SmedsgaardJ, NielsenJ (2005) Metabolite profiling of fungi and yeast: from phenotype to metabolome by MS and informatics. Journal of experimental botany 56: 273–286.
15. ClasquinMF, MelamudE, SingerA, GoodingJR, XuX, et al. (2011) Riboneogenesis in yeast. Cell 145: 969–980.
16. DellaPennaD, LastRL (2008) Genome-enabled approaches shed new light on plant metabolism. Science 320: 479–481.
17. McMullenMD, ByrnePF, SnookME, WisemanBR, LeeEA, et al. (1998) Quantitative trait loci and metabolic pathways. Proceedings of the National Academy of Sciences of the United States of America 95: 1996–2000.
18. BostB, DillmannC, de VienneD (1999) Fluxes and metabolic pools as model traits for quantitative genetics. I. The L-shaped distribution of gene effects. Genetics 153: 2001–2012.
19. Mitchell-OldsT, PedersenD (1998) The molecular basis of quantitative genetic variation in central and secondary metabolism in Arabidopsis. Genetics 149: 739–747.
20. KeurentjesJJB, FuJ, de VosCHR, LommenA, HallRD, et al. (2006) The genetics of plant metabolism. Nature Genetics 38: 842–849.
21. LisecJ, MeyerRC, SteinfathM, RedestigH, BecherM, et al. (2008) Identification of metabolic and biomass QTL in Arabidopsis thaliana in a parallel analysis of RIL and IL populations. The Plant journal: for cell and molecular biology 53: 960–972.
22. BentsinkL, Alonso-BlancoC, VreugdenhilD, TesnierK, GrootSP, et al. (2000) Genetic analysis of seed-soluble oligosaccharides in relation to seed storability of Arabidopsis. Plant physiology 124: 1595–1604.
23. HobbsDH, FlinthamJE, HillsMJ (2004) Genetic control of storage oil synthesis in seeds of Arabidopsis. Plant physiology 136: 3341–3349.
24. KliebensteinDJ, GershenzonJ, Mitchell-OldsT (2001) Comparative quantitative trait loci mapping of aliphatic, indolic and benzylic glucosinolate production in Arabidopsis thaliana leaves and seeds. Genetics 159: 359–370.
25. WentzellAM, RoweHC, HansenBG, TicconiC, HalkierBA, et al. (2007) Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways. PLoS Genetics 3: 1687–1701.
26. DumasME, WilderSP, BihoreauMT, BartonRH, FearnsideJF, et al. (2007) Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models. Nature Genetics 39: 666–672.
27. RoweHC, HansenBG, HalkierBA (2008) Biochemical networks and epistasis shape the Arabidopsis thaliana metabolome. Plant Cell 20: 1199–1216.
28. ZhuJ, SovaP, XuQ, DombekKM, XuEY, et al. (2012) Stitching together Multiple Data Dimensions Reveals Interacting Metabolomic and Transcriptomic Networks That Modulate Cell Regulation. PLoS Biology 10: e1001301.
29. SmithEN, KruglyakL (2008) Gene–Environment Interaction in Yeast Gene Expression. PLoS Biology 6: 810–824.
30. FossEJ, RadulovicD, ShafferSA, RuderferDM, BedalovA, et al. (2007) Genetic basis of proteome variation in yeast. Nature Genetics 39: 1369–1375.
31. BremRB, StoreyJD, WhittleJ, KruglyakL (2005) Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436: 701–703.
32. BremRB, KruglyakL (2005) The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proceedings of the National Academy of Sciences of the United States of America 102: 1572–1577.
33. PerlsteinEO, RuderferDM, RobertsDC, SchreiberSL, KruglyakL (2007) Genetic basis of individual differences in the response to small-molecule drugs in yeast. Nature Genetics 39: 496–502.
34. PerlsteinEO, RuderferDM, RamachandranG, HaggartySJ, KruglyakL, et al. (2006) Revealing complex traits with small molecules and naturally recombinant yeast strains. Chemistry & biology 13: 319–327.
35. BrauerMJ, YuanJ, BennettBD, LuW, KimballE, et al. (2006) Conservation of the metabolomic response to starvation across two divergent microbes. Proceedings of the National Academy of Sciences of the United States of America 103: 19302–19307.
36. LuW, BennettBD, RabinowitzJD (2008) Analytical strategies for LC-MS-based targeted metabolomics. Journal of chromatography B, Analytical technologies in the biomedical and life sciences 871: 236–242.
37. StoreyJD, TibshiraniR (2003) Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America 100: 9440–9445.
38. BromanKW, WuH, SenŚ, ChurchillGA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19: 889–890.
39. KampferAJ, BalogEM (2010) S-adenosyl-L-methionine regulation of the cardiac ryanodine receptor involves multiple mechanisms. Biochemistry 49: 7600–7614.
40. FetrowCW, AvilaJR (2001) Efficacy of the dietary supplement S-adenosyl-Lmethionine. The Annals of pharmacotherapy 35: 1414–1425.
41. MoML, PalssonBØ, HerrgardMJ (2009) Connecting extracellular metabolomic measurements to intracellular flux states in yeast. BMC Systems Biology 3: 37.
42. de LlanosR, Herńandez-HaroC, BarrioE, QuerolA, Ferńandez-EspinarMT, et al. (2010) Differences in activation of MAP kinases and variability in the polyglutamine tract of Slt2 in clinical and non-clinical isolates of Saccharomyces cerevisiae. Yeast (Chichester, England) 27: 549–561.
43. ChoiES, ParkBS, LeeSW, OhMK (2009) Increased production of S-adenosyl-Lmethionine using recombinant Saccharomyces cerevisiae sake K6. Korean Journal of Chemical Engineering 26: 156–159.
44. LeeSW, ParkBS, ChoiES, OhMK (2010) Overexpression of ethionine resistance gene for maximized production of S-adenosylmethionine in Saccharomyces cerevisiae sake kyokai No. 6. Korean Journal of Chemical Engineering 27: 587–589.
45. ShiomiN, FukudaH, FukudaY, MurataK (1991) Nucleotide sequence and characterization of a Gene conferring resistance to ethionine in yeast Saccharomyces cerevisiae. Journal of Fermentation and Bioengineering 71: 211–215.
46. TanakaK, LinBK, WoodDR, TamanoiF (1991) IRA2, an upstream negative regulator of RAS in yeast, is a RAS GTPase-activating protein. Proceedings of the National Academy of Sciences of the United States of America 88: 468–472.
47. KimJw, DangCV (2006) Cancer's molecular sweet tooth and the Warburg effect. Cancer research 66: 8927–8930.
48. StoreyJD, AkeyJM, KruglyakL (2005) Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biology 3: e267.
49. ParriniMC, JacquetE, BernardiA, JacquetM, ParmeggianiA (1995) Properties and regulation of the catalytic domain of Ira2p, a Saccharomyces cerevisiae GTPase-activating protein of Ras2p. Biochemistry 34: 13776–13783.
50. BroachJR (1991) RAS genes in Saccharomyces cerevisiae: signal transduction in search of a pathway. Trends in genetics: TIG 7: 28–33.
51. Lynch M, Walsh B (1998) Genetics and analysis of quantitative traits. Sinauer Associates, 1 edition.
52. WestMAL, KimK, KliebensteinDJ, van LeeuwenH, MichelmoreRW, et al. (2006) Global eQTL Mapping Reveals the Complex Genetic Architecture of Transcript-Level Variation in Arabidopsis. Genetics 175: 1441–1450.
53. BloomJS, EhrenreichIM, LooWT, LiteTLV, KruglyakL (2013) Finding the sources of missing heritability in a yeast cross. Nature 494: 234–237.
54. MatoJM, CorralesFJ, LuSC (2002) AvilaMA (2002) S-Adenosylmethionine: a control switch that regulates liver function. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 16: 15–26.
55. MischoulonD, FavaM (2002) Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. The American journal of clinical nutrition 76: 1158S–61S.
56. RèmeCA, DramardV, KernL, HofmansJ, HalsbergheC, et al. (2008) Effect of Sadenosylmethionine tablets on the reduction of age-related mental decline in dogs: a double-blinded, placebo-controlled trial. Veterinary therapeutics: research in applied veterinary medicine 9: 69–82.
57. FusoA, SeminaraL, CavallaroRA, D'AnselmiF (2005) Sadenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Molecular and Cellular Neuroscience 28: 154–204.
58. Martin-YkenH, DagkessamanskaiaA, BasmajiF, LagorceA, FrancoisJ (2003) The interaction of Slt2 MAP kinase with Knr4 is necessary for signalling through the cell wall integrity pathway in Saccharomyces cerevisiae. Molecular microbiology 49: 23–35.
59. ChenY, FeldmanDE, DengC, BrownJA, De GiacomoAF, et al. (2005) Identification of mitogen-activated protein kinase signaling pathways that confer resistance to endoplasmic reticulum stress in Saccharomyces cerevisiae. Molecular cancer research: MCR 3: 669–677.
60. LesageG, BusseyH (2006) Cell wall assembly in Saccharomyces cerevisiae. Microbiology and molecular biology reviews: MMBR 70: 317–343.
61. BoerVM, de WindeJH, PronkJT, PiperMDW (2003) The Genome-wide Transcriptional Responses of Saccharomyces cerevisiae Grown on Glucose in Aerobic Chemostat Cultures Limited for Carbon, Nitrogen, Phosphorus, or Sulfur. The Journal of biological chemistry 278: 3265–3274.
62. CavalieriD, TownsendJP, HartlDL (2000) Manifold anomalies in gene expression in a vineyard isolate of Saccharomyces cerevisiae revealed by DNA microarray analysis. Proceedings of the National Academy of Sciences of the United States of America 97: 12369–12374.
63. MaddenK, SheuYJ, BaetzK, AndrewsB, SnyderM (1997) SBF Cell Cycle Regulator as a Target of the Yeast PKC-MAP Kinase Pathway. Science 275: 1781–1784.
64. BlankHM, GajjarS, BelyaninA, PolymenisM (2009) Sulfur metabolism actively promotes initiation of cell division in yeast. PloS one 4: e8018.
65. TuBP, KudlickiA, RowickaM, McKnightSL (2005) Logic of the Yeast Metabolic Cycle: Temporal Compartmentalization of Cellular Processes. Science 310: 1152–1158.
66. TuBP, McKnightSL (2006) Metabolic cycles as an underlying basis of biological oscillations. Nature reviews Molecular cell biology 7: 696–701.
67. TuBP, MohlerRE, LiuJC, DombekKM, YoungET, et al. (2007) Cyclic changes in metabolic state during the life of a yeast cell. Proceedings of the National Academy of Sciences of the United States of America 104: 16886–16891.
68. KruglyakL, LanderES (1995) A nonparametric approach for mapping quantitative trait loci. Genetics 139: 1421–1428.
69. BajadSU, LuW, KimballEH, YuanJ, PetersonC, et al. (2006) Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatographytandem mass spectrometry. Journal of chromatography A 1125: 76–88.
70. LuoB, GroenkeK, TakorsR, WandreyC, OldigesM (2007) Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. Journal of chromatography A 1147: 153–164.
71. MelamudE, VastagL, RabinowitzJD (2010) Metabolomic Analysis and Visualization Engine for LC-MS Data. Analytical Chemistry 82: 9818–9826.
72. GrayM, PiccirilloS, HonigbergSM (2005) Two-step method for constructing unmarked insertions, deletions and allele substitutions in the yeast genome. FEMS microbiology letters 248: 31–36.
73. Davison AC, Hinkley DV (1997) Bootstrap Methods and their Application. Cambridge University Press.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2014 Číslo 3
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Worldwide Patterns of Ancestry, Divergence, and Admixture in Domesticated Cattle
- Genome-Wide DNA Methylation Analysis of Human Pancreatic Islets from Type 2 Diabetic and Non-Diabetic Donors Identifies Candidate Genes That Influence Insulin Secretion
- Genetic Dissection of Photoreceptor Subtype Specification by the Zinc Finger Proteins Elbow and No ocelli
- GC-Rich DNA Elements Enable Replication Origin Activity in the Methylotrophic Yeast