生命科學(xué)引論：Towards-the-Complex-Simplicity

1、Towards the Complex Simplicity Omics, Math and EvolutionBiology used to be elegant and simple;Omics and the resulting complexity;Math the ultimate solution!?Evolution, evolution, and evolutionWhere are we?Biology used to be elegant and simpleGregor Mendel (1822-1884)9:3:3:1Part IOne gene/one enzymeB

2、eadle and Tatum at 1958Neurospora crassa as the model organismThe Ultimate Simplicity - Double HelixWatson and Cricklac Operon the Classical Elegance Jacob at 1965Their work was initially considered unworthy of publication, and so they established their own new journal - the Journal of Molecular Bio

3、logy, and their article on the Lac-Operon fills about 80 pages in the first issue! The Holy CodeHolleyKhoranaNirenbergEngineering BiologyArberSmithNathansThe Magical CycleHartwell at 2001It Smells!Richar AxelLinda BuckOmics and the resulting complexityPart IIUncharacterized GenesKnown Genes a quarte

4、r of genes are still uncharacterized even in yeast S.cerevisiae, the best studied organismThe human genome is pervasively transcribed (The ENCODE Project Consortium, 2007)Divergence time (My)Human; Chimpanzee; Orangutan; Rhesus macaqueExpression change in brain among primates as a function of diverg

5、ence timeThe trans-cis binding differs significantly human and mouse(Odom et. al., 2007)2/3 yeast genes can be deleted without significant consequenceGrowth rate(Giaever et. al., 2002)7% of genes with increased expression are also required for optimal growth in the conditions (Giaever et. al., 2002)

6、The Mediator complex(Collins et. al., 2007)Guilt by association(The Wellcome Trust Case Control Consortium, 2007)Math a solution!?E.coli flagella gene regulatory network(Kalir and Alon, 2004)Part IIIThe function of each promoter was dertermined(Kalir and Alon, 2004)(Kalir and Alon, 2004)Yeast protei

7、n-protein interaction network(Jeong et. al., 2001)hubnon-hubCentrality and lethality in protein network(Jeong et. al., 2001)Hypothesis:A protein is essential is because it involves inessential protein-protein interactions (ePPI)The two proteins linked by an essential PPI must be essential. ePPIEssen

8、tial proteinNon-essential protein(He and Zhang, 2006)A simple formula predicts PE quite wellPE = 1-(1-)(1-)k, the probability that a gene is essential, but due to factors other than ePPIs;, the proportion of ePPI in the network;k, the number of interaction a protein has.(He and Zhang, 2006)The E.col

9、i metabolic network(Almaas et al., 2004)Maximizevalue:R_BiomassEcoliSubject TomM_10fthf_c: - 1 R_AICART - 1 R_FTHFD - 1 R_GARFT + 1 R_MTHFC = 0mM_12dgr_EC_c: - 0.02 R_DAGK_EC + 0.02 R_PAPA_EC + 0.02 R_PEPT_EC = 0mM_12ppd_S_c: + 1 R_12PPDt + 1 R_LCARS = 0mM_12ppd_S_e: - 1 R_12PPDt - 1 R_EX_12ppd_S_e_

10、 = 0mM_13dpg_c: + 1 R_GAPD + 1 R_PGK = 0mM_15dap_c: - 1 R_CADVt + 1 R_LYSDC = 0mM_15dap_e: + 1 R_CADVt - 1 R_EX_15dap_e_ = 0mM_1pyr5c_c: + 1 R_G5SADs - 1 R_P5CD - 1 R_P5CR + 1 R_PROD2 = 0mM_23ddhb_c: - 1 R_DHBD + 1 R_ICHORT = 0mM_23dhb_c: + 1 R_DHBD - 1 R_DHBSr = 0mM_23dhba_c: + 1 R_DHBSr - 3 R_ENTC

11、S = 0mM_23dhdp_c: - 1 R_DHDPRy + 1 R_DHDPS = 0mM_23dhmb_c: - 1 R_DHAD1 + 1 R_KARA1i = 0mM_23dhmp_c: - 1 R_DHAD2 + 1 R_KARA2i = 0mM_23doguln_c: - 1 R_DOGULNR = 0mM_25aics_c: - 1 R_ADSL2r + 1 R_PRASCS = 0mM_25dkglcn_c: - 1 R_DKGLCNR1 - 1 R_DKGLCNR2x - 1 R_DKGLCNR2y = 0mM_25drapp_c: - 1 R_DHPPDA2 + 1 R

12、_GTPCII2 = 0mM_26dap_LL_c: - 1 R_DAPE + 1 R_SDPDS = 0mM_26dap_M_c: - 1 R_DAPDC + 1 R_DAPE + 1 R_DAPabc - 1 R_UAAGDS = 0mM_26dap_M_e: - 1 R_DAPabc - 1 R_EX_26dap_M_e_ = 0mM_2ahbut_c: + 1 R_ACHBS - 1 R_KARA2i = 0mM_2aobut_c: - 1 R_GLYATi + 1 R_THRD = 0mM_2cpr5p_c: - 1 R_IGPS + 1 R_PRAIi = 0Reduce the

13、metabolic network into linear functionsFlux balance analysis:S . v = 0;ai = vi = biLinear programming to find the optimal solutionComparison of E.coli growth rate between in silico prediction and adaptive evolution on glucose(Ibarra et. al., 2002)Evolution, evolution, and evolutionMolecular BiologyU

14、ndertand genesUnderstand processesPart IV“Nothing in biology makes sense except in the light of evolution”Dobzhansky (1900 1975)To be simple, or to be complexUneven environmentgainlosebenefitrisksave energynew nichesdisfunctionenergy-wastingFor a single generation, in a given environment, most of genes are not necessaryGrowth rateImportant knowledge was discovered earlier(He and Zhang, 2009)The value of the inc