UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

Bioinformatics Tutorials

BIOINFORMATICS
AND
GENE DISCOVERY

Iosif Vaisman

1998
From genes to proteins
 From genes to proteins
DNA

PROMOTER
ELEMENTS
TRANSCRIPTION
RNA

SPLICE
SITES
SPLICING
mRNA
START STOP
CODON CODON

TRANSLATION

PROTEI
From genes to proteins
 Comparative Sequence Sizes
• Yeast chromosome 3 350,000
• Escherichia coli (bacterium) genome 4,600,000
• Largest yeast chromosome now mapped 5,800,000
• Entire yeast genome 15,000,000
• Smallest human chromosome (Y) 50,000,000
• Largest human chromosome (1) 250,000,000
• Entire human genome 3,000,000,000
Low-resolution physical map
of chromosome 19
Chromosome 19 gene map
 Computational Gene Prediction

• Where the genes are unlikely to be located?

• How do transcription factors know where to bind a region of DNA?
• Where are the transcription, splicing, and translation start and stop
signals?
• What does coding region do (and non-coding regions do not) ?
• Can we learn from examples?
• Does this sequence look familiar?
Artificial Intelligence in Biosciences

Neural Networks (NN)

Genetic Algorithms (GA)
Hidden Markov Models (HMM)
Stochastic context-free grammars (CFG)
Information Theory

0 1

1 bit
Information Theory

00 01

1 bit

10 11

1 bit
Information Theory

1 bit

1 bit
 Scientific Models
Physical models -- Mathematical models

Mechanistic models Stochastic models

Mechanism Black box
Predictive power
Elegance Predictive power
Consistency

Hidden Markov models

Stochastic mechanism
 Neural Networks
•interconnected assembly of simple processing elements (units or nodes)
•nodes functionality is similar to that of the animal neuron
•processing ability is stored in the inter-unit connection strengths (weights)
•weights are obtained by a process of adaptation to, or learning from, a set
of training patterns
 Genetic Algorithms
Search or optimization methods using simulated evolution.
Population of potential solutions is subjected to
natural selection, crossover, and mutation

choose initial population

evaluate each individual's fitness
repeat
select individuals to reproduce
mate pairs at random
apply crossover operator
apply mutation operator
evaluate each individual's fitness
until terminating condition
 Crossover
Parent A

Parent B

crossover point
Child AB

Child BA

Mutation
 Markov Model (or Markov Chain)
A T C T A G

Probability for each character based only on several

preceding characters in the sequence

# of preceding characters = order of the Markov Model

Probability of a sequence

P(s) = P[A] P[A,T] P[A,T,C] P[T,C,T] P[C,T,A] P[T,A,G]

 Hidden Markov Models
States -- well defined conditions
Edges -- transitions between the states
ATGAC
T G
ATTAC
A A C
ACGAC
C T ACTAC

Each transition asigned a probability.

Probability of the sequence:

single path with the highest probability --- Viterbi path
sum of the probabilities over all paths -- Baum-Welch method
 Hidden Markov Model of Biased Coin Tosses

• States (Si): Two Biased Coins {C1, C2}

• Outputs (Oj): Two Possible Outputs {H, T}

• p(OutputsOij): p(C1, H), p(C1, T), p(C2, H) p(C2, T)

• Transitions: From State X to Y {A11, A22, A12, A21}
• p(Initial Si): p(I, C1), p(I, C2)

• p(End Si): p(C1, E), p(C2, E)

Hidden Markov Model for Exon and Stop Codon
(VEIL Algorithm)
 GRAIL gene identification program
REFINED EXON FINAL EXON
POSSIBLE EXONS POSITIONS CANDIDATES
Suboptimal Solutions for the Human Growth
Hormone Gene (GeneParser)
 Measures of Prediction Accuracy
Nucleotide Level
TN FN TP FP TN FN TP FN TN
REALITY

PREDICTION

REALITY
Sensitivity
c nc
PREDICTION

Sn = TP / (TP + FN)
TP FP
c

Specificity
FN TN
nc

Sp = TP / (TP + FP)
 Measures of Prediction Accuracy
Exon Level
WRONG CORRECT MISSING
EXON EXON EXON

REALITY

PREDICTION

number of correct exons

Sensitivity Sn = number of actual exons

number of correct exons

Specificity Sp = number of predicted exons
GeneMark Accuracy Evaluation
 Bibliography
http://linkage.rockefeller.edu/wli/gene/list.html
and
http://www-hto.usc.edu/software/procrustes/fans_ref/

Gene Discovery Exercise

http://metalab.unc.edu/pharmacy/Bioinfo/Gene