Molecular Genetics, Biology And Informatics

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Molecular Genetics, Biology And Informatics

• Norie de la Cruz, PhD

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Biology at the Movies

• Ian was right Life did find a way
• -- Michael Creighton (movie adaptation of
  Jurassic Park)

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Biology at the Extremes

• Life is very creative
• archeans able to live at 120 degrees Celcius
• organisms able to transduce solar energy to
  chemicals
• creatures able to recycle its own waste products
  to amino acids
• creatures able to lift 50x their weight
• creatures able to contemplate themselvesCogito
  ergo sum

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So where are the threads of commonality?

• Evolution
• Molecular Level genetic material

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Genetic Materials exert their influence far and
wide

• Cell function
• Metabolism and homeostasis
• Development
• Apoptosis
• Reproduction
• Etc.

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Natures creativity variations on variations

• Motifs
• Gene structures
• Sequence similarities
• Functional adaptation
• Alleles
• Etc.

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Bioinformatics tries to make sense of natures
methodology

• Underlying themes gene structure
• Clustering of particular biological activities
  microarray analyses, proteomics, physionomics
• Defining motifs structure predictions
• Understanding the direction of change --
  phylogenetics
• Understanding the influence of molecular
  phenomena QTLs and diseases

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Overview

• DNA and RNA and Proteins
• The Central Dogma of Molecular Biology
• Components of the gene
• Transcription and RNA processing
• Translation and post translational modifications
• Organization of DNA into chromosomes
• Genomes

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DNA

• Deoxyribonucleic acid
• Double stranded backbone is made of sugar
  phosphate moieties
• Strands connected by nitrogen containing
  nucleotide bases

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DNA
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DNA
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DNA and complementarity
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DNA is capable of self-replication information
is copied
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Organisms pass on information via DNA
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Information in DNA can change evolution and
phylogeny
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Information in DNA can be read gene expression
and RNA
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RNA

• Ribonucleic acid
• Thymine -gt Uracil
• Types
• mRNA
• tRNA
• rRNA
• miRNA

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RNA

• Single stranded
• Less stable than DNA
• Folds into complex structures
• Older than DNA
• Some RNAs posses catalytic activities to perform
  self-splicing

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Proteins

• Chains of amino acids

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Protein Secondary Structures

• Alpha Helices
• Beta Sheets

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Protein Tertiary Structures
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Protein Quaternary Structures
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Information Flow the Central Dogma of Molecular
Biology

• The transfer of information from DNA to make a
  protein
• Transcription of DNA into mRNA
• Translation convert information encoded by mRNA
  into amino acid sequence

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Central Dogma, cont.

• Tremendous number of enzymes needed to
• Uncoil DNA
• Transcribe
• Repair mismatches
• Splice exons together
• Transfer protect unstable mRNA
• Assemble amino acids
• Fold protein
• Etc, etc.

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DNA

• Sequence data

sense
GGTCTTCTTGGGTGAGAATAACTTTAA
5
3
5
3
anti-sense
CCAGAAGAACCCACTCTTATTGAAATT
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Transcription
sense
GGTCTTCTTGGGTGAGAATAACTTTAA
5
3
5
3
anti-sense
CCAGAAGAACCCACTCTTATTGAAATT
Transcription of anti-sense strand RNA polymerase
GGUCUUCUUGGGUGAGAAUAACUUUAA
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RNA
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Transcription

• Precisely controlled process
• Signals that control process part of the DNA
  sequence Genes
• Signals interact with various molecules to effect
  trascription

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Gene Structure
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Existence of Genes

• Want to identify potentially new genes
• Typical coding gene structure
• Non-coding genes vary more

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Gene Elements

• Promoters/Repressors
• Enhancers
• Terminators
• Splice sites
• Removal of introns
• Exonic Splice Enhancers/Repressors
• Binding sites
• Gene-Gene, Gene-RNA, Gene-Protein interactions

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Splicing Alternative Splicing

• Each exon is translated into mRNA sequence
• These are trimmed and spliced together
• The order of the splicing is crucial
• The same gene can be spliced in more than one
  way, producing multiple transcriptional units
  (TUs)
• Some researchers have proposed counting TUs
  rather than genes or loci to determine the number
  of genes in a given genome (this is why there is
  much controversy about counting genes)

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Translating mRNA to proteins

• Occurs in the ribosome
• tRNA carries amino acids from cytoplasm to
  ribosome
• mRNA is the template for translation

codon
stop
mRNA
GGUCUUCUUGGGUGAGAAUAACUUUAA
5
G L L G
amino acid sequence
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(No Transcript)
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Translation

• Tightly controlled process involving plenty of
  control proteins and rRNAs
• Precisely defined starting position
  Shine-Dalgarno sequence in prokaryotes.
• Precisely defined ending points

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Post translational processing

• Protein folds into a precise configuration
• Protein maybe chemically modified to control
  activity
• Protein interacts with other molecules to control
  activity, supply active ingredients
• Activity may also be controlled by degradation or
  compartmentalization

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Information is in the sequence the secondary,
tertiary and quaternary structure heavily
dependent on the primary structure or the sequence

• Amino acids determine secondary structure due to
  propensities to form helixes and sheets
• Tertiary structure dependent on the interactions
  of helices and sheets, forces for interaction
  dependent on the nature and composition of the
  amino acids making up the secondary structures
• Ditto for quarternary structures and features
  that signal for post translational modifications

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Genomes and Chromosomes

• Complete set of instructions for making an
  organism almost
• Prokaryotic genomes typically composed of one
  chromosome
• Human genome contains 3Bbp organized into 24
  distinct units called chromosomes
• Humans have 22 pairs of autosomes and 1 pair of
  sex chromosomes (XX in females, XY in males)
• Morphological examination of eukaryotic
  chromosomes possible
• Chromosomes contain roughly equal quantities DNA
  and protein
• Chromosomes contain DNA tightly wound around
  protein cores

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Chromosomes and Genomes

• Genetic information is passed along packaged in
  chromosomes
• Genes are arranged linearly along the chromosomes
• Arrangement of genes and other elements within
  the chromosome is critical to proper functioning
  of the organism
• Inheritance patterns and the resulting
  characteristics of the organism present another
  area for bioinformatic analysis -- QTLs

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Genomes are dynamic
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Genomes are dynamic
E.coli K-12
E.coli O157 sakai

• Rearrangements
• Inversions
• Duplications
• Deletions
• Recombinations
• Transposition

S.typhi CT18
S.typhimurium LT2
IS maps
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Genomes are dynamic
4.1 3.4
3.6-4.2
1.7 1.2
1.2 - 1.8
1.3 -1.8
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Recap biological sequences can yield a lot of
information to bioinformatic scrutiny

• Composition and structure of genomic sequences
• Sequence similarity and divergence recurring
  themes and phylogeny
• Structure of genes
• Coding (protein producing)
• Non-coding (functional RNA)
• Predict structure
• RNA secondary/tertiary structure
• Protein secondary/tertiary structure

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Is sequence everything? Dont bet on it, but
its a great place to start

• Proliferation of the omics
• Proteo
• Pheno
• Physio
• Pharamacogeno