Genomics, Proteomics, and Bioinformatics

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Genomics, Proteomics, and Bioinformatics

• Biology 224
• Instructor Tom Peavy
• January 29, 2008

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What is bioinformatics?

• Interface of biology and computers
• Analysis of genomes, genes, mRNA and proteins
  using computer algorithms and computer databases

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What is Genomics?
What is Proteomics?
What is the Transcriptome?
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What do you want out of this course?
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Top ten challenges for bioinformatics
1 Precise models of where and when
transcription will occur in a genome
(initiation and termination) 2 Precise,
predictive models of alternative RNA
splicing 3 Precise models of biological
pathways ability to predict cellular
responses to external stimuli 4 Determining
proteinDNA, proteinRNA, proteinprotein
recognition codes 5 Accurate ab initio protein
structure prediction
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Top ten challenges for bioinformatics
6 Rational design of small molecule inhibitors
of proteins 7 Mechanistic understanding of
protein evolution 8 Mechanistic understanding
of speciation 9 Development of effective gene
ontologies systematic ways to describe
gene and protein function 10 Education
development of bioinformatics curricula
Source Ewan Birney, Chris Burge, Jim Fickett
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Themes throughout the course gene/protein
families

• Retinol-binding protein 4 (RBP4)
• member of the lipocalin family
• small, abundant carrier protein
• We will study it in a variety of contexts
  including
• --homologs in various species
• --sequence alignment
• --gene expression
• --protein structure
• --phylogeny

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Tool-users
Tool-makers
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DNA
RNA
phenotype
protein
protein sequence databases
cDNA ESTs UniGene
genomic DNA databases
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There are three major public DNA databases
GenBank
EMBL
DDBJ
Housed at EBI European Bioinformatics Institute
Housed at NCBI National Center
for Biotechnology Information
Housed in Japan
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Growth of GenBank
Base pairs of DNA (billions)
Sequences (millions)
1982
1986
1990
1994
1998
2002
Updated 8-12-04 gt40b base pairs
Year
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• Press Release (August 22, 2005)
• 100 gigabases of sequence data
• (NCBI, EMBL, DDBJ)
• over 165,000 organisms

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The growth of GenBank. The blue area shows the
total number of bases including those from whole
genome shotgun sequencing projects (WGS). The
checkered area shows only the non-WGS portion.
With release 149, the number of WGS bases
exceeded the number of bases in the traditional
GenBank divisions.
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Go to NCBI website http//www.ncbi.nlm.nih.gov/
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• PubMed is
• National Library of Medicine's search service
• 12 million citations in MEDLINE
• links to participating online journals
• PubMed tutorial (via Education on side bar)

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• Entrez integrates
• the scientific literature
• DNA and protein sequence databases
• 3D protein structure data
• population study data sets
• assemblies of complete genomes

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Entrez is a search and retrieval system that
integrates NCBI databases
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• BLAST is
• Basic Local Alignment Search Tool
• NCBI's sequence similarity search tool
• supports analysis of DNA and protein databases
• 80,000 searches per day

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• OMIM is
• Online Mendelian Inheritance in Man
• catalog of human genes and genetic disorders
• edited by Dr. Victor McKusick, others at JHU

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• Books is
• searchable resource of on-line books

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• TaxBrowser is
• browser for the major divisions of living
  organisms
• (archaea, bacteria, eukaryota, viruses)
• taxonomy information such as genetic codes
• molecular data on extinct organisms

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• Structure site includes
• Molecular Modelling Database (MMDB)
• biopolymer structures obtained from
• the Protein Data Bank (PDB)
• Cn3D (a 3D-structure viewer)
• vector alignment search tool (VAST)

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Review ofGenetics, Biochemistry Evolution
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Human Genome Project
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What is a typical Genomic structure for a
Eukaryotic gene?
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Synonymous vs. nonsynonymous changes
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Synonymous Substitution
Non-synonymous Substitution
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Central Dogma

• DNA ? RNA ? protein
• sequence ? structure ? function ? evolution

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What kind of modifications Are made to Eukaryotic
mRNAs?
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RNA Modifications
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What are cDNAs?
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Protein structures

• X-ray crystallography and Nuclear magnetic
  resonance (NMR)
• Primary structure
• linear AA
• Secondary structure-
• alpha helix and beta sheet
• Tertiary structures-
• 3-d that exposes binding domains etc

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Linkage maps

• YAC Yeast artificial chromosome
• BAC Bacterial artificial chromosome
• -used to clone large pieces of DNA
• -overlapping clones
• Are genes linked?

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Organization of genomes

• Groups of genes within a species
• -Comparative Genomics
• plastid genomes and mt genomes

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How do we determine functions of genes?
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How do we determine functions of genes?

• Expression patterns
• Northerns
• RT-PCR
• SAGE
• Microarrays
• Transgenics
• insert genes what results?
• Mutants
• classical genetics
• molecular genetics

• And Functional Protein Assays

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Charles Darwin

• Descent with modification
• species change through time and are related to a
  common ancestor
• Natural Selection is the process by which this
  change occurs

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Understanding Natural selection

• acts on individuals though consequences occur in
  populations
• Individuals phenotype reason survived and
  reproduced
• after a time this will change the distribution in
  the population,
• what ultimately changes?
• Gene pool

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New alleles

• Point change is all needed
• not always a "big deal"
• neutral change
• can be in Sickle cell anemia

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Gene duplication

• creates an additional copy of a gene
• unequal cross-over
• X-rays
• Are these duplicates maintained in populations?
• Psuedogenes

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Polyploidy

• additional set of chromosomes
• Found in plants
• Amphibians, invertebrates
• Through a type of parthenogenesis
• Triploid
• Poor fertility
• Hybridization or meiosis malfunction

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Homology

• study of likeness (literal)
• Similarity between species (or genes) that
  results from inheritance of traits from a common
  ancestor
• Unless know of a common ancestor have to be
  careful when using this word.

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Orthologous vs Paralogous Genes
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Gene Duplication
Speciation
Species 1
Species 2
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Species

• All organisms alive today can trace their
  ancestry back to the origin of life some 3.8
  billion years ago
• Since then millions if not billions of branching
  events have occurred
• Mechanisms have to be in place for change to
  occur
• genetic drift and natural selection