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    Preliminaries: What Is Life?

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    Fadhili Dunga
    This document provides an introduction and overview of computational biology and genomics. It discusses the current state of genomic projects including completed microbial genomes like H. influenzae and E. coli. Ongoing projects on more complex genomes like C. elegans, S. cerevisiae, Arabidopsis, rice and the human genome are mentioned. A list of potential topics for the computational biology course is given covering areas like the human genome project, gene finding, linkage analysis, functional genomics, proteonomics, rational drug design and DNA computing. Computational tools and technologies for cloning, mapping, sequencing and probing are also summarized.

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    Preliminaries: What Is Life?

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    Fadhili Dunga
    27 views8 pages
    This document provides an introduction and overview of computational biology and genomics. It discusses the current state of genomic projects including completed microbial genomes like H. influenzae and E. coli. Ongoing projects on more complex genomes like C. elegans, S. cerevisiae, Arabidopsis, rice and the human genome are mentioned. A list of potential topics for the computational biology course is given covering areas like the human genome project, gene finding, linkage analysis, functional genomics, proteonomics, rational drug design and DNA computing. Computational tools and technologies for cloning, mapping, sequencing and probing are also summarized.

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    This document provides an introduction and overview of computational biology and genomics. It discusses the current state of genomic projects including completed microbial genomes like H. influenzae and E. coli. Ongoing projects on more complex genomes like C. elegans, S. cerevisiae, Arabidopsis, rice and the human genome are mentioned. A list of potential topics for the computational biology course is given covering areas like the human genome project, gene finding, linkage analysis, functional genomics, proteonomics, rational drug design and DNA computing. Computational tools and technologies for cloning, mapping, sequencing and probing are also summarized.

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    © All Rights Reserved
    Download as PS, PDF, TXT or read online from Scribd
    Download as ps, pdf, or txt
    27 views8 pages

    Preliminaries: What Is Life?

    Uploaded by

    Fadhili Dunga
    This document provides an introduction and overview of computational biology and genomics. It discusses the current state of genomic projects including completed microbial genomes like H. influenzae and E. coli. Ongoing projects on more complex genomes like C. elegans, S. cerevisiae, Arabidopsis, rice and the human genome are mentioned. A list of potential topics for the computational biology course is given covering areas like the human genome project, gene finding, linkage analysis, functional genomics, proteonomics, rational drug design and DNA computing. Computational tools and technologies for cloning, mapping, sequencing and probing are also summarized.

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    of 8

    Chapter 1

    Introduction

    Preliminaries
    \The spread, both in width and depth, of the mul-
    tifarious branches of knowledge during the last hun-
    dred odd years has confronted us with a queer dilemma.
    We feel clearly that we are only now beginning to ac-
    quire reliable material for welding together the sum
    total of all that is known into a whole; but, on the
    other hand, it has become next to impossible for a
    single mind fully to command more than a small spe-
    cialized portion of it.
    \I can see no further escape from this dilemma (lest
    our true aim be lost for ever) than that some of
    us should venture to embark on a synthesis of facts
    and theories, albeit with second-hand and incomplete
    knowledge of some of them { and at the risk of mak-
    ing fools of ourselves.
    \So much for my apology. "

    |Erwin Schrodinger, What is Life?


    1
    2 Introduction Chapter 1

    1.1 Information
    Bud Mishra
    Room 801, Warren Weaver Hall
    Courant Institute
    Tel #: 212.998.3464
    e-mail: [email protected]
    URL:http://cs.nyu.edu/cs/faculty/~mishra/index.html

    1.2 Computational Biology X


    The goal of the rst lecture was to design a syllabus for the course
    in accordance with the interest and aptitude of the students of
    the class. Since it was unclear what the composition of the
    class would be, the syllabus that we will come up with remains
    somewhat of a mystery. Only to the extent that I can in uence
    this class in designing a meaningful syllabus, I oer a big picture
    of the subject and a set of topics currently of active research.
    Here are my choice of topics:
    Human Genome Project: Read 3 billion base pairs in 46 hu-
    man chromosomes.
    Single Nucleotide Polymorphisms: Catalog the single base
    pair variations occurring about 1 in 800 base pairs of hu-
    man genome over the entire population.
    Gene Hunting: Identify all (about 100,000) the genes in hu-
    man genome.
    Particularly interesting are the ones involved in cancer|
    about 100 oncogenes .
    Linkage Analysis: Relate genes to phenotypes (externally ob-
    servable traits) by analyzing genomes in a family or over
    a population.
    Functional Genomics: Understand how an interactive network
    of genes aect a chain of metabolic pathways to ultimately
    determine the phenotypes.

    c Mishra, 1999
    Section 1.2 Introduction 3

    Cell Informatics: Interaction between proteins (membrane and


    soluble ones) to determine the dynamics of a cell.
    Interaction among a heterogenous population of cells.
    Rational Drug Design: Design of drugs and delivery systems
    to modify the dynamics of the cells.
    Phylogenomics: Relates genes within and across species to
    understand their evolutionary relationship.
    DNA Computers: Build highly parallel computers using DNA
    strands as data encoding elements.
    DNA Nanorobots: Build highly parallel and cooperative nanorobots
    with actuators and sensors (as well as distributed con-
    trollers) all built out of DNA and amino acid sequences.

    1.2.1 Biological Problems


    Pairwise and Multiple Sequence Alignment:
    (Dynamic programming, similarity matrices, competitive
    heuristics)
    Fragment and Map Assembly:
    (Interval Tree and Other Graph Theoretic Approaches,
    Bayesian Approaches)
    Sequence Feature Extraction:
    (Data Mining, Bioinformatics| Bayesian Inference, HMM
    (Hidden Markov Models), Neural Networks, Genetic Algo-
    rithms)
    Phylogenomics:
    (Phylogenetic Tree Construction)
    RNA Secondary Structure Prediction:
    (??)
    Proteonomics:

    c Mishra, 1999
    4 Introduction Chapter 1

    Protein Homology Modeling


    Protein Threading
    Protein Molecular Dynamics
    Protein ab initio Structure Prediction

    1.2.2 Computational Tools


    Bayesian Statistics:
    Hidden Markov Models (HMM)
    Expectation Maximization (EM)
    Monte Carlo Methods
    Neural Networks
    Genetic Algorithms
    Bounded/Constrained Search
    Simulated Annealing
    Combinatorial Approaches:
    Stringology
    Interval Graphs
    Tree Algorithms
    Dynamic Programming
    Information Theoretic Approaches:
    Entropy Maximization
    Competitive Methods (Universal Schemes)
    Stochastic Control

    c Mishra, 1999
    Section 1.3 Introduction 5

    1.2.3 Technology
    Cloning:
    In vivo methods
    PCR (Polymeric Chain Reaction)
    Mapping:
    Fingerprints
    Multiple Complete Digestion
    Optical Mapping
    Radiation Hybridization
    Sequencing:
    Sanger Sequencing
    Sequencing by Hybridization
    MALDI-TOF (Mass Spectrometry)
    Other Single molecule methods
    Probing:
    In situ Hybridization
    Gene Chips
    Southern Blotting

    1.3 State-of-the-Arts
    What can be accomplished in Genomics can be inferred by tak-
    ing a closer look at various completed and ongoing genomic
    projects. Many of the completed genomic projects deal with
    microbes (2{3 Mb genome size).
    These organisms had been selected for dierent reasons. Since
    E. coli is one of the best characterized organism both genetically

    c Mishra, 1999
    6 Introduction Chapter 1

    and biochemically, it was a natural choice. B. subtilis was cho-


    sen because it is Gram positive, as opposed to E. coli , which
    is Gram negative. Also, B. subtilis goes through dierentiation
    during the sporulation process. S. cerevisae is eukaryotic, but
    can be handled much the same way as any other microorganism.
    Since, it has chromosomes in a nucleus and undergoes meiotic
    and mitotic processes, its genome is likely to tell us a lot about
    other eukaryotes. The nematode worm, C. elegans , is a simple
    multicellular organism with about 2000 cells, and biologists have
    already mapped the line of descent from zygote for each of these
    cells. So the genome sequence of this organism is of considerable
    interest to developmental biologists. It will then be possible to
    see how and which genes are expressed and when and where the
    dierent cell lineages branch o during the dierentiation.
    1. Haemophilus in uenzae : First organism to have its genome
    completely sequenced. (Fleischmann, TIGR, 1995). A
    genome of 1.8Mb encoding 1743 genes.
    2. Escherichia coli : A gram negative bacterium. K12 is
    the common strain and not virulent. However, the strain
    0157 has been implicated in serious virulent outbreaks.
    (Blattner, Wisconsin). A genome of 4.6Mb encoding 4300
    genes.
    3. Bacillus subtilis : A gram positive bacterium. (Kunst, 46
    laboratories involving 160 people). A genome of 4.2 Mb
    encoding 4100 genes.
    4. Synechocystis PCC6803 : A cyanobacterium. (Kaneko)
    5. Mycobacterium tuberculosis : The causative agent of tuber-
    culosis.
    6. Treponema pallidum : The spirocehete causing syphillis.
    7. Borrelia burgodorferi : The spirocehete causing Lyme dis-
    ease.

    c Mishra, 1999
    Section 1.3 Introduction 7

    8. Deinococcus radiodurans : An organism capable of with-


    standing unusually high degree of UV radiation.
    9. Aquifex aeolicus : A marine hypothermophile capable of
    growth at 95 C. It represents the deepest lineage within
    the bacterial domain and may hold clues to primitive proky-
    rotic life-forms.
    10. Caenorhabdeitis elegans : The nematode worm|rst ani-
    mal genome to be completely sequenced.
    11. Saccharomyces cervisiae : The brewer's yeast, an eukary-
    ote. A genome of 12 Mb with 5900 genes. (96 labs with
    640 people in 6 years).
    12. Arabidopsis : A plant|ongoing.
    13. Oryza sativa : Rice|ongoing.
    14. Homo sapiens : About 3% completed.
    The information gleaned from these genome projects have
    already elucidated several biochemical processes of fundamental
    importance in understanding life itself. Here are some examples:
    1. The genome of D. radiodurans indicated that it is the rst
    non-photosynthetic organism to possess the light-sensing
    protein phytochrome, which regulates synthesis of pig-
    ments against radiation. It also has a new type of RecA
    protein that helps it in DNA-repair. The related metabolic
    pathway repairs DNA breakages (more than 150 break-
    ages at a time), caused by UV radiation. It was previ-
    ously known that this octaploid organism has enough re-
    dundancy to provide sucient information to assist the
    repair.
    2. Study of E. coli and B. Subtilis genomes shed more light
    on bacterial DNA restriction-modication systems (enzyme
    systems that protect bacteria from viral DNA by cutting
    it up to small pieces while leaving its own DNA unharmed

    c Mishra, 1999
    8 Bio... Chapter 1

    by a methylation process). These bacteria seemed to have


    3 to 4 such restriction-modication systems, while more
    pathogenic variety seem to have even many more. (H. in-
    uenza , 7, N. gonorrhoeae , 18, H. pylori , 23).
    3. New metabolic pathway in E. coli for sugar acid idonate
    was discovered.
    4. Comparison of pathogenic E. coli (0157) strain with the
    non-pathogenic strain (K12) showed that 0157 has a much
    bigger genome (about 1.2 Mb more, representing a 20%
    increase). In the extra genetic material the organism seem
    to code for virulence factor-bearing prophage. Also, there
    seem to be \pathogenicity island" in that region that allows
    the bacteria to secrete toxic protein into the host cells.
    More surprisingly, the extra DNA in 0157 (the pathogenic
    strain) is shared by Y. pestis , the agent involved in plague !
    5. Many bacteria were found to have metabolic pathways for
    the inter-conversion of ve- and six-carbon sugars. Previ-
    ously, it was thought that this was only possible in methanogenic
    bacteria.
    6. Many new protein paralogs of unknown function have been
    discovered.
    7. One can now estimate metabolic capability of an organ-
    ism easily. For instance, one can estimate the nutrients
    that can be taken up by a cell. This knowledge is rather
    important in choosing bacteria for bioremediation.
    8. Comparative genomics allows the researchers to infer hori-
    zontal gene-transfer between related gram-negative bacte-
    ria.
    9. It helps the biotechnologists to construct expression vec-
    tors, gene knockouts, reporter-gene, etc.


    c Mishra, 1999

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