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MODELLING OF BIOLOGICAL NETWORKS

Giuseppe Damiani

 

The development of biotechnology has produced an impressive amount of information but the meaning of the mass of accumulated data is only beginning to be unravelled. For example, the Human Genome Project was completed in 2003. More than 1000 genes that cause simple Mendelian disorders have been identified but  these diseases are rare and account for less than 2% of the total diseases in the economically advanced world. Complex diseases like most cancer and cardiovascular diseases that account for over 70% of premature morbidity and mortality are not genetic in the strict Mendelian sense and are mainly due to epigenetic processes driven by environmental factors. The reductionist approach of traditional genetic and the linear mathematical modelling are often unable to predict the non-linear behaviour of complex systems, such as the biological ones. A possible universal dynamics of complex systems was proposed in the “Binary Theory”: the same basic mechanism, named metabolic hypercycle, could determine the power-law correlation and fractal patterns displayed by the self-organised criticality of complex systems. The metabolic hypercycle is an auto-regulatory feedback loop between opposite autocatalitic activities of catabolic and anabolic type, described by the Lotka-Volterra prey-predator equation. Spatial and temporal developmental pathways of living organisms might be the results of maps and clocks based on metabolic hypercycles organized in scale-free networks. According to this hypothesis, it is possible the development of a functional classification of metabolic processes, genes and proteins in the catabolic and anabolic type. This classification is based on the interdisciplinary analysis of physiological, structural and sequence data. An important step in this project is the identification of conserved functional sequences motifs that can be used to derive diagnostic signatures of gene and protein families. A simple similarity searching using the available bioinformatics tools is often not enough to provide functional clues. To get the most from sequence data we need to take account of the interrelated network of signalling cascades, gene expression, and metabolic pathways. Therefore, a useful method for the functional classification of regulative molecules and processes is the analysis of their differential and alternative presence in quiescent and activated phases both at cell and organism level. The genetic apparatus evolved for the conservation and reproduction of biological macromolecules in the anabolic phase, while the epigenetic apparatus is responsible for the adaptation to variable environmental stresses in the catabolic phase. Using database searches, mRNAs fingerprinting, and quantitative RT-PCR we have identified several repetition of highly conserved sequences motifs in the 3’ untranslated regions of several mRNAs differentially expressed in different cell types. The presence of these conserved motifs in retroelements suggests a role for mobile elements in the spreading of regulative motifs in genes that need to be co-regulated. In human, the functional classification of regulative molecules at organism level might be based on their circadian variations in biological fluids. For example, the dehydroepiandrosterone, glucocorticoids, serotonin, adrenalin, glutamate, and glucagon peak during the diurnal catabolic phase, while the dehydroepiandrosteronesulfate, sexual steroids, melatonin, dopamin, gamma-aminobutyrate, and insulin increase in the nocturnal anabolic phase. Several conserved motifs are present in the amminoacidic sequences of the proteins that regulate the activity of these molecules as the steroid 21-hydroxylase (CYP21), the acetylcholine receptor, the glutamate decarboxylase, and the preproinsulin. These sequences interact with the heat shock proteins and the MHC (Major Histocompatibility Complex) proteins and are the main autoantigens involved in the progression of a wide range of autoimmune diseases as myasthenia gravis, insulin-dependent diabetes mellitus, and Addison’s disease. The MHC mediated immunization against peptides of regulative proteins might be the cause of a positive selection of the maternal immune system for the embryos with immunoreactive MHC alleles. These alleles are linked with variants of important regulative genes, as the CYP21 and the some Hsp70, and therefore a physiological adaptation might be transformed into adaptive changes of the genetic population structure in only one generation. This mechanism counteracts the negative aspects of natural selection and maintains the biodiversity of animal populations. Moreover heat shock and MHC proteins are involved in the regulation of epigenetic processes (as phosphorylation, acetylation and methylation) and of endogenous mutagenic processes due to mRNAs retrotranscription and their Chi-dependent micro-recombination with the genomic sequences. The hypothesised scenario is confirmed by many experimental data about differences in gene expression during the processes of cellular activation and differentiation, association between MHC alleles and metabolic or immune pathologies, functional classification of DRB1 alleles, convergent evolution of the region binding to antigenic peptides of MHC genes, fractal distribution of MHC polymorphism in different populations, non-mendelian segregation of MHC haplotypes, sex-dependent effects of MHC alleles on survival and longevity, and distribution of regulative sequence motifs and retroelements in “catabolic” genes. An objective of the project is the development of a unitary theoretical framework for a rational interpretation of complex diseases as many metabolic, neuropsychiatric, and autoimmune disorders, which are still misunderstood.


 
References

  1. Il gioco della vita - La teoria binaria dell'universo fisico (1984) G.Damiani. (Italiana Audiovisivi ed. - Roma).
  2. Genesi binaria (1997) G.Damiani (Centro culturale polivalente “G.B. Pergolesi e R. Piccinini” - Roma).
  3. Morphé and Evolution (1997) G.Damiani, P.Della Franca. Biology Forum, 90: 227-266 (Tilgher - Genova).
  4. Evolution of life in a fractal Universe (1998) G.Damiani. Fractals in biology and medicine Vol. 2, Editors G.A.Losa, D.Merlini, T.F.Nonnenmacher, E.R.Weibel, 169-187 (Birkhauser Verlag - Basel).
  5. Identification of mRNAs differentially expressed in lymphocytes following interleukin-2 activation (1998) G.Damiani, E.Capelli, S.Comincini, E.Mori, S.Panelli, M.Cuccia. Experimental Cell Research. 244: 11-17.
  6. Transizioni di fase e controllo del metabolismo negli organismi viventi (1999) G.Damiani, P.Della Franca. La matematizzazione della biologia: storia e problematiche attuali, P.Cerrai, P.Freguglia. 97-106 (Quattroventi - Urbino).
  7. Il sistema neuroendocrinoimmunitario e il controllo della biodiversità nelle popolazioni di animali superiori (2000) G.Damiani, M.Bardin, P.DellaFranca, S.Panelli, S.Pirovano, E.Capelli, M.Cuccia. Biodiversità, germoplasma locale e sua valorizzazione. M.Agabbio. 1125-1128 (Carlo Delfino ed. - Sassari).
  8. HLA ed evoluzione (2001) G.Damiani, M.Cuccia. HLA: Immunogenetica e applicazioni in Medicina. Ed. V.Misefari. 245-257 (SIMTI - Milano).
  9. Il ritmo della vita: l’iperciclo metabolico (2002) G.Damiani, S.Panelli, P.Della Franca. Systema Naturae 4, 279-320 (peQuod editor - Ancona).
  10. Metabolic Hypercycles, Universality and Fractals in Biological Evolution (2002) G.Damiani.  Fractals in biology and medicine Vol. 3, Editors G.A.Losa, D.Merlini, T.F.Nonnenmacher, E.R.Weibel 259-269 (Birkhauser Verlag - Basel).
  11. Evaluation of gene expression in human lymphocytes activated in the presence of melatonin (2002) E.Capelli, I.Campo, S.Panelli, G.Damiani, MG.Barbone, A.Lucchelli, M.Cuccia. Int. Immunopharmacol. 2:885-892.
  12. Recombinant DRB sequences produced by mismatch repair of heteroduplexes during cloning in Escherichia coli. (2002) M.Longeri, M.Zanotti, G.Damiani. Eur. J. Immunogenet. 29, 517-523.
  13. Evolution and regulation of metabolic networks (2005) G.Damiani.  Fractals in biology and medicine Vol. 4, Editors G.A.Losa, D.Merlini, T.F.Nonnenmacher, E.R.Weibel 257-268 (Birkhauser Verlag - Basel).
  14. Lo Yin e Yang dell’evoluzione biologica (2006) G.Damiani, P. Della Franca. La logica dell’evoluzione dei viventi: spunti di riflessione. A cura di Felicita Scapini. 61-85 (University Press - Firenze).




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