• The ICBSE (Systems Genetics)
    Systems Genetics - Medicine and Bioengineering 
    Analysis and Construction of Genomes

    Jie (Bangzhe) Zeng

    1. Evo-Devo of Bio-systems

    The systems genetics, by the views of system theory, is investigated at the aspects of dynamic analysis of genes group, signal transduction network and proliferation, differentiation and apoptosis of cytogenesis, and exploring of morphogenetic mechanism of cell lineages differentiation and cell lineages mapping. The study of genomic stability, genotype - phenotype complexity, is very useful for understanding of the pathogenesis, and for drug discovery of cancer, psychiatry, cardiovascular and ageing diseases etc.

    The systems genetics is the discipline to study the complex patterns relationship between phenotype and genotype, the genes expression network of genomic program, the bio-logic principles of bio-systems and organizing patterns of genomes, and the modules constructing to the pattern of in morphogenesis.

    The cells are organized in spatiotemporal pattern of developing which regulated by secretion rhythm of signals and genomic program expression of genes. The cell lineages occur as the result of a complex synergistic or competitive regulation among numerous factors inducing or inhibiting the expression of genes. There many transcription factors activate or repress their own expression and thus constitute the auto-regulatory feedback loops. The organogenesis of bio-systems, involves a series of metabolism, molecular signals and genes regulated expression in the cell division, differentiation and patterning of vascular, neural network and endocrine, immune systems.

    2. Cell, Molecular and Systems Genetics
    Structurity is included the aspects of structural integration ("O"), functional adaptation ("S") and organizational construction ("V") of systems. Same stratum systems interacting transfer to other level stratum. No-growth inner system is contraction of solidity, fluid alternation sphere structure, growth assimilate system is construction of fractal structure, and self-construction of body from subsystem to supra-system.

    The history of genetics can be divided into three periods of it's establish:

    (1). Cytogenetics - medical genetics, Mendelian genetics is investigated in the field of gene mapping and genotype - phenotype analysis.

    (2). Molecular biology of gene, molecular genetics is investigated in the field of gene expression, the central dogma theory.

    (3). Systems genetics - from gene to genome, which is investigated in the field of self-organization patterns of genome, genomic program expression, patterns of signaling network and cells lineage mapping patterns in morphogenesis. Systems genetics is investigating the fundamentals of bio-systems mechanism, genetic self-organization, bio-logic of genome, multiple signals, modules construction and genetic control of bio-system patterning organism developing and genomic evolution. And, synthetic biology is the engineering applications of genomic intelligence, artificial bio-systems for used as cell computer, bioreactor and cell factory etc.

    3. Principles of Systems Genetics

    The systems genetics includes the follow three main aspects:

    A) Genomic organization of genes
    Genomic organization of structure integration, coordinative organization of genome by structure stratum: elements of gene->gene groups organization->specie genomic pattern, evolutionary morphogenetic modules of bio-system pattern. The independent organism phenotype is controlled by synergic expression of gene group (multi-genes), and this phenotype forms a functional or morphogenesis unit (module). Each specie has it's unique structure of genomic organizing pattern among chromosomes by the constructing of genomic stability during evolution of genetic co-adaptation.

    The biochemical metabolism, enzyme groups systems include the essential systems in original cells, adaptation systems in cell species, and program induced expression systems in tissue cells such as the neuron, endocrine, immune and vascular cells etc.

    The homeostasis or dynamics of molecules synthesis between degradation, cells proliferation between apoptosis are involved the replication, fragmentation, recombination and expression of genes. The genomic stratification is the self-organization of gene families, gene groups and gene chains. To compare the genes organization in genome with the expression pattern of proteins, we can understand the genetic logic of genomic maps.

    B) Genomic regulation of genes expression pattern
    Genomic program expression by functional adaptation, program expression of organism phenotype in morphogenesis and adaptation development: signal transduction network, gene induced expression->cell cycle regulation and cell fate determination->signal pattern and cells mapping in morphogenesis.

    Regulation of gene expression and protein degradation includes several aspects: 1). gene expression cascade, 2). transcription, translation and degradation, 3). Clock Regulation of gene expression, 4). Gene expression profiles. The regulation of gene expression depends on the elements in the sequence of gene, the promotor for transcription regulation, the un-translated region of mRNA for regulation of mRNA stability and translation, the membrane domain for protein degradation. There are signal molecules for regulation of gene specifically expression and assemble of cell compartments at multiple levels.

    C) Signal transduction and controlling of cytogenesis

    On the cascades of interacting regulatory in gene expression, the commitment factors, transcription factors which mediate the phenotypic expression of different cell types, receptors, intercellular signals and cell-adhesion molecules, they act on some cells very early and during a limited period of time. The major groups of transcription factors have been classified according to the motif in the DNA-binding domains. Interestingly, many transcription factors activate or repress their own expression and thus constitute the auto-regulatory feedback loop which function as molecular clock. These factors regulate the cell cycle and cell specifically fate determination in morphogenesis of organism. In oocyte, cellular factors can reboot somatic nuclei genetic reprogram and maintain ES cell in totipotent.

    D). Cell cycle and cell fate determination
    Cell dynamics and cytogenesis included: 1). cell dynamics, cycle regulation, 2). cell mitotic, differentiation, proliferation and apoptosis, 3). cell morphogenesis, 4). cell mutagenesis and evolution (genetic mutation).

    Signaling regulation of cells division, differentiation and apoptosis in organism patterning, which involves signal molecules intracellular asymmetry, structure duplication (amplify) of cell genome and tissue specifically expression of genes by genomic program, specific induce expression and differentiation. The sequential expression of genes chain in genomic program involves the interaction among locus of genes in chromosome, molecules network within cell and signal communication between cells.

    E). Vascular, neuro-endocrine and morphogenesis pattern
    The stable rhythm patterns of secretary molecules regulate gene expression in bio-molecules synthesis, degradation and cells differentiation, proliferation and apoptosis, includes: 1). signaling dynamics and pattern formation, 2). cell lineage mapping and organogenesis pattern, 3). oscillation, morphogenesis and psychosomatic regulation etc.
    In mammalian embryo, the notochord which developed from grey crescent of organizer, the double gradient of head and trunk signals, coordinative movement of embryo cells groups, the stem cell producing center and the neuro-endocrine, immune system play roles in the control of morphogenesis at multiple levels. The connection of neural networks occurs as the result of cell recognition and specific protein biosynthesis. The cell phenotypes expression and mapping of cells fate determination in organogenesis involves a series of genes spatially and temporally expression by genomic program.

    The tissue cells are constructed in patterning of coherent body, and cell cycle and fate determination be controlled by secretary (neuro- hormonal) rhythms of signals. The neuron, endocrine, immune and vascular cell types which develop from ectoderm, endoderm and mesoderm of embryo, these cells have specific receptors and signal molecules for cell bidirectional communication. The stimulation pattern of learning experience strengthens specific connections among neurons, specific protein bio-synthesis. Morphogenesis of organs depends on the mapping of cell fate determination, and cell proliferation, differentiation or apoptosis by the patterns of secretary signals and signal transduction pathways.

    F). Genomic stratified (mutation) construction

    Genomic stratified (mutation) construction C self-organization of genomic evolution, cellular mutation pattern and co-evolution of organisms.

    1). Replication and homologous recombination: Genetic crossover, genes re-arrangement in duplication, mutation and repair of DNA, the mobile elements of virus and cancer gene transposon cause cellular gene mutation, gene target and homologous recombination within genome. The homologous recombination, genes rearrangement in the genetic crossover, transpose of mobile elements recombinant of genes at same level of genomic structure. Gene families originated from a series of mutations during gene duplication. The artificial evolution is engineering of genome by using the mechanism of natural evolution (amplification, rearrangement and transposon) of genes.

    2). Multify stratum construction in genome: The main evolution pathway of organisms is the evolution from prokaryocyte, eukaryocyte to multi-cells organism. Genes group, genes chain and genes family are organized in the multify stratum construction of genomes.

    3). Genomics and pan-evolution: The origin of biological species involves the multiple stratum structure of gene groups at different levels, interacting among genes in host genome and the genetic co-adaptation. DNA recombination, mutagenesis and transgenesis: transposon->genetic crossover-> gene group duplication and genomic self-organization. The genes replication, transgensis, transcription, fragmentation, mutagenesis and bio-molecules interacting is the dynamics of genomic information system. Between genes in allele or among linear locus, there are mutation patterns of genomic evolution and expression patterns of development.

    4. Structure Theory of Systems Genetics

    The genetics and bio-logic of the molecular, cellular and organism patterning involved in the structure (organization), function (development) and mutant (evolution, self-organization) of genomes.

    Laws of genetic structurity: 1).structure integration, coordinative organization of genes in genome, the independent phenotype is controlled by genes group (multi-genes); 2).function adaptation, duplication (amplify) of cell genome, tissue-specific expression of genes and molecular modules, the expression of genes chain depends on the self-adaptation in signals field of the cell micro-environment; 3).construct stratification, recombination, multify stratum structure of genome, the mutation in genes family of gene transpose, recombination and amplification.

    Ref.

    1. BJ.Zeng, On the concept of systems biological engineering (biotechnology), Communication on Transgenic animals, CAS, June, 1994.

    2. BJ.Zeng, Transgenic animal expression systems - transgenic egg plan (systems genetics), Communication on Transgenic animals, CAS, Nov., 1994.

    3. BJ.Zeng, From positive to synthetic medical science (systems medicine and pharmacology), Communication on Transgenic animals, CAS, Nov., 1995.

    4. BJ.Zeng, The structure theory of self-organization systems, Communication on Transgenic animals, CAS, Aug.-Oct., 1996.


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