Genomics, Proteomics, and Bioinformatics

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Genomics, Proteomics, and Bioinformatics

• Biology 224
• Instructor Tom Peavy
• August 31, 2009

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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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On bioinformatics
Science is about building causal relations
between natural phenomena (for instance, between
a mutation in a gene and a disease). The
development of instruments to increase our
capacity to observe natural phenomena has,
therefore, played a crucial role in the
development of science - the microscope being the
paradigmatic example in biology. With the human
genome, the natural world takes an unprecedented
turn it is better described as a sequence of
symbols. Besides high-throughput machines such as
sequencers and DNA chip readers, the computer and
the associated software becomes the instrument to
observe it, and the discipline of bioinformatics
flourishes. Martin Reese and Roderic Guigó,
Genome Biology 2006 7(Suppl I)S1, introducing
EGASP, the Encyclopedia of DNA Elements (ENCODE)
Genome Annotation Assessment Project
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What do you want out of this course?
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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 Microarrays
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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Growth of GenBank Whole Genome
Shotgun (1982-November 2008)
250
200
150
Number of sequences in GenBank (millions)
Base pairs of DNA in GenBank (billions) Base
pairs in GenBank WGS (billions)
100
50
0
1982
1987
1992
1997
2002
2007
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Taxonomy at NCBI 200,000 species are
represented in GenBank
http//www.ncbi.nlm.nih.gov/Taxonomy/txstat.cgi
11/08
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The most sequenced organisms in GenBank
Homo sapiens 13.1 billion bases Mus musculus
8.4b Rattus norvegicus 6.1b Bos
taurus 5.2b Zea mays 4.6b Sus
scrofa 3.6b Danio rerio 3.0b Oryza sativa
(japonica) 1.5b Strongylocentrotus
purpurata 1.4b Nicotiana tabacum 1.1b
Updated 11-6-08 GenBank release 168.0 Excluding
WGS, organelles, metagenomics
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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 that is 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
a
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