Overview of Bioinformatics and Molecular Biology June 13, 2005 History of Genome Sequencing Project...
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Overview of Bioinformatics and Molecular Biology
June 13, 2005 History of Genome Sequencing Project Learning objectives-
What is sickle cell anemia? Increased knowledge of the structure of atoms, molecules, and biomolecules Central Dogma How DNA mutations result in abnormal proteins Protein structure classifications How to perform comparisons of protein sequences
Workshop-Import cytochrome C protein sequences from different species. Perform Clustal W comparison Homework-Use the internet or written text sources
Definition of Bioinformatics Many definitions at the moment:
Use of computers to catalog and organize biological information into meaningful entities.
Conceptualization of biology in terms of molecules and the application of “informatics” techniques (from disciplines such as applied math, computer science and statistics) to understand and organize the information associated with these molecules
Bioinformatics is Multidisciplinary
ComputerScience
Math
Statistics
StructuralBiology
Phylogenetics
Drug Design
Genomics
MolecularLife Sciences
Textbook
Bioinformatics and FunctionalGenomicsby Jonathan PevsnerISBN: 0471210048
• Genome sequence acquisition and analysis. • Basic and applied research with DNA microarrays. • Proteomics.
History of the Human Genome Project
1953
Watson,CrickDNAstructure
1972
Berg,1st recombinantDNA
1977
Maxam,Gilbert,SangersequenceDNA
1980
Botstein,Davis,SkolnickWhitepropose to map humangenome withRFLPs
1982
Wadaproposes tobuild automated sequencingrobots
1984
MRCpublishesfirst largegenomeEpstein-Barrvirus (170 kb)
1985
Sinsheimer hosts meeting to discuss HGP at UCSantaCruz;Kary Mullis develops PCR
1986
DOE begins genome studies with $5.3 million
1987
Gilbert announces plans to start company to sequence and copyright DNA; Burke, Olson, Carle develop YACs; Donis-Keller publish first map (403 markers)
History of the Human Genome Project (continued)
1987 (cont)
Hood producesfirst automated sequencer;Dupont devolops fluorescent dideoxy-nucleotides
1988
NIH supports the HGP;Watson heads the project and allocates part of the budget to study social and ethical issues
1989
Hood, Olson, Botstein Cantor propose using STS’s to map the human genome
1990
Proposal to sequence20 Mb in model organism by 2005;Lipman, Myers publish the BLAST algorithm
1991
Venter announces strategy to sequence ESTs. He plans to patentpartial cDNAs;Uberbacher develops GRAIL, a gene finding program
1992
Simon develops BACs; US and French teams publish first physical maps of chromosomes; first genetic maps of mouse and human genome published
1993
Collins is named director of NCHGR; revise plan to complete seq of human genome by 2005
1995
Venter publishes first sequence of free-living organism:H. influenzae (1.8 Mb);Brown publishes on DNA arrays
1996
Yeast genome is sequenced (S. cerevisiae)
History of the Human Genome Project (continued)
1997
Blattner, Plunket complete E. coli sequence; a capillary sequencing machine is introduced.
1998
SNP project is initiated; rice genome project is started; Venter creates new company called Celera and proposes to sequence HG within 3 years; C. elegans genome completed
1999
NIH proposes to sequence mouse genome in 3 years; first sequence of chromosome 22 is announced
2000
Celera and others publish Drosphila sequence (180 Mb); human chromosome 21 is completely sequenced; proposal to sequence puffer fish; Arabadopsis sequence is completed
2001
Celera publishes human sequence in Science; the HGP consortium publishes the human sequence in Nature
2003
Completed genomes:112 Microbial18 Eukaryotes1275 Viruses
Basis of molecular biology Hierarchy of relationships (some exceptions):
Genome
Gene 1 Gene 3Gene 2 Gene X
Protein 1 Protein 2 Protein 3 Protein X
Function 1 Function 2 Function 3 Function X
How can one use bioinformatics to link diseases to genes?
Positional cloning of genes1. Find genetic markers
associated with disease
2. Sequence DNA next to the markers
3. Compare DNA from afflicted individuals to DNA of normal individuals (database)
4. Find abnormality5. Predict gene function
from sequence information
Disease
Map
Gene
Function
Unknown Function
How much of the genome is defined?
How is Bioinformatics Used?
Experimental proof is still the “Gold Standard”.
Bioinformatics isn’t going to replace lab work anytime soon
Bioinformatics is often used to help “focus”the experiments of the benchtop scientist
Symptoms of Sickle Cell Anemia
pain episodes strokes increased
infections leg ulcers bone damage yellow eyes or
jaundice early gallstones lung blockage
kidney damage and loss of body water in urine
painful erections in men (priapism)
blood blockage in the spleen or liver (sequestration)
eye damage low red blood cell
counts (anemia) delayed growth
Amino acid characteristics
Website for Amino acid interactive Workshop Amino acids
1 2
DNA sequenceWrite the primary sequence of the DNA displayed in 3Bhttp://www.blc.arizona.edu/Molecular_Graphics/DNA_Structure/DNA_Tutorial.HTML
http://www.rothamsted.bbsrc.ac.uk/notebook/courses/guide/dnast.htm
Website for interactive workshop for DNA analysis
Interactive display of amino acids and codons
Translation exercise
Translate the following sequence using the codontable:
ATGGUGCACCUGACUCCUGAGGAGAAG
Perform same procedure using a software program:
http://us.expasy.org/tools/dna.html
Central Dogma
DNA
RNA
Protein
DNA
RNA (with ribosomes)
*
>gi|1244762|gb|AAA98563.1| p53 tumor suppressor homolog
MSQGTSPNSQETFNLLWDSLEQVTANEYTQIHERGVGYEYHEAEPDQTSLEISAYRIAQPDPYGRSESYD
LLNPIINQIPAPMPIADTQNNPLVNHCPYEDMPVSSTPYSPHDHVQSPQPSVPSNIKYPGEYVFEMSFAQ
PSKETKSTTWTYSEKLDKLYVRMATTCPVRFKTARPPPSGCQIRAMPIYMKPEHVQEVVKRCPNHATAKE
HNEKHPAPLHIVRCEHKLAKYHEDKYSGRQSVLIPHEMPQAGSEWVVNLYQFMCLGSCVGGPNRRPIQLV
FTLEKDNQVLGRRAVEVRICACPGRDRKADEKASLVSKPPSPKKNGFPQRSLVLTNDITKITPKKRKIDD
ECFTLKVRGRENYEILCKLRDIMELAARIPEAERLLYKQERQAPIGRLTSLPSSSSNGSQDGSRSSTAFS
TSDSSQVNSSQNNTQMVNGQVPHEEETPVTKCEPTENTIAQWLTKLGLQAYIDNFQQKGLHNMFQLDEFT
LEDLQSMRIGTGHRNKIWKSLLDYRRLLSSGTESQALQHAASNASTLSVGSQNSYCPGFYEVTRYTYKHT
ISYL
FASTA format
Multiple sequence alignment Human-locus number AAA35732 Dog-locus number CCDG Yeast-locus number from structure
database 1YCC
CLUSTAL PROGRAM
Workshop due on Tuesday Find out the chromosomal location of the gene
that causes sickle cell anemia. Give the name of the gene. Find out the nucleotide change and amino
acid change that leads to sickle cell anemia (there may be more than one change that gives rise to the disease)
If sickle cell anemia is so devastating, why has it lasted in the population for such a long time? Give a molecular explanation (you may have to do a little research to get this)