An Introduction to Bioinformatics Algorithms www.bioalgorithms.
info
Graph Algorithms
in Bioinformatics
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
The Bridge Problem
Find a tour crossing every bridge just once
Leonhard Euler, 1735
Bridges of Königsberg
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
Eulerian Cycle Problem
• Find a cycle that
visits every edge
exactly once
• Linear time
More complicated Königsberg
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
Hamiltonian Cycle Problem
• Find a cycle that
visits every vertex
exactly once
• NP – complete
Game invented by Sir
William Hamilton in 1857
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Mapping Problems to Graphs
• Arthur Cayley studied
chemical structures
of hydrocarbons in
the mid-1800s
• He used trees
(acyclic connected
graphs) to enumerate
structural isomers
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Beginning of Graph Theory in Biology
Benzer’s work
• Developed deletion
mapping
• “Proved” linearity of
the gene
• Demonstrated
internal structure of
the gene
Seymour Benzer, 1950s
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Viruses Attack Bacteria
• Normally bacteriophage T4 kills bacteria
• However if T4 is mutated (e.g., an important gene is
deleted) it gets disable and looses an ability to kill
bacteria
• Suppose the bacteria is infected with two different
mutants each of which is disabled – would the
bacteria still survive?
• Amazingly, a pair of disable viruses can kill a
bacteria even if each of them is disabled.
• How can it be explained?
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Benzer’s Experiment
• Idea: infect bacteria with pairs of mutant T4
bacteriophage (virus)
• Each T4 mutant has an unknown interval
deleted from its genome
• If the two intervals overlap: T4 pair is missing
part of its genome and is disabled – bacteria
survive
• If the two intervals do not overlap: T4 pair
has its entire genome and is enabled –
bacteria die
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Complementation between pairs of
mutant T4 bacteriophages
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Benzer’s Experiment and Graphs
• Construct an interval graph: each T4
mutant is a vertex, place an edge between
mutant pairs where bacteria survived (i.e., the
deleted intervals in the pair of mutants
overlap)
• Interval graph structure reveals whether DNA
is linear or branched DNA
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Interval Graph: Linear Genes
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Interval Graph: Branched Genes
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Interval Graph: Comparison
Linear genome Branched genome
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
DNA Sequencing: History
Sanger method (1977): Gilbert method (1977):
labeled ddNTPs chemical method to
terminate DNA cleave DNA at specific
copying at random points (G, G+A, T+C, C).
points.
Both methods generate
labeled fragments of
varying lengths that are
further electrophoresed.
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Sanger Method: Generating Read
1. Start at primer
(restriction site)
2. Grow DNA chain
3. Include ddNTPs
4. Stops reaction at all
possible points
5. Separate products
by length, using gel
electrophoresis
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DNA Sequencing
• Shear DNA into
millions of small
fragments
• Read 500 – 700
nucleotides at a time
from the small
fragments (Sanger
method)
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Fragment Assembly
• Computational Challenge: assemble
individual short fragments (reads) into a
single genomic sequence (“superstring”)
• Until late 1990s the shotgun fragment
assembly of human genome was viewed as
intractable problem
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Shortest Superstring Problem
• Problem: Given a set of strings, find a
shortest string that contains all of them
• Input: Strings s1, s2,…., sn
• Output: A string s that contains all strings
s1, s2,…., sn as substrings, such that the
length of s is minimized
• Complexity: NP – complete
• Note: this formulation does not take into
account sequencing errors
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Shortest Superstring Problem: Example
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Reducing SSP to TSP
• Define overlap ( si, sj ) as the length of the longest prefix of
sj that matches a suffix of si.
aaaggcatcaaatctaaaggcatcaaa
aaaggcatcaaatctaaaggcatcaaa
What is overlap ( si, sj ) for these strings?
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Reducing SSP to TSP
• Define overlap ( si, sj ) as the length of the longest prefix of
sj that matches a suffix of si.
aaaggcatcaaatctaaaggcatcaaa
aaaggcatcaaatctaaaggcatcaaa
aaaggcatcaaatctaaaggcatcaaa
overlap=12
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Reducing SSP to TSP
• Define overlap ( si, sj ) as the length of the longest prefix of
sj that matches a suffix of si.
aaaggcatcaaatctaaaggcatcaaa
aaaggcatcaaatctaaaggcatcaaa
aaaggcatcaaatctaaaggcatcaaa
• Construct a graph with n vertices representing the n strings
s1, s2,…., sn.
• Insert edges of length overlap ( si, sj ) between vertices si
and sj.
• Find the shortest path which visits every vertex exactly
once. This is the Traveling Salesman Problem (TSP),
which is also NP – complete.
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Reducing SSP to TSP (cont’d)
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SSP to TSP: An Example
S = { ATC, CCA, CAG, TCC, AGT }
SSP TSP ATC
AGT
0 2 1
CCA 1
AGT 1 CCA
ATC
1
ATCCAGT 2 2 2
TCC
CAG 1 TCC
CAG
ATCCAGT
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Sequencing by Hybridization (SBH): History
• 1988: SBH suggested as an First microarray
prototype (1989)
an alternative sequencing
method. Nobody believed it
will ever work
First commercial
DNA microarray
prototype w/16,000
• 1991: Light directed polymer features (1994)
synthesis developed by Steve
Fodor and colleagues.
500,000 features
per chip (2002)
• 1994: Affymetrix develops
first 64-kb DNA microarray
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How SBH Works
• Attach all possible DNA probes of length l to a
flat surface, each probe at a distinct and known
location. This set of probes is called the DNA
array.
• Apply a solution containing fluorescently labeled
DNA fragment to the array.
• The DNA fragment hybridizes with those probes
that are complementary to substrings of length l
of the fragment.
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How SBH Works (cont’d)
• Using a spectroscopic detector, determine
which probes hybridize to the DNA fragment
to obtain the l–mer composition of the target
DNA fragment.
• Apply the combinatorial algorithm (below) to
reconstruct the sequence of the target DNA
fragment from the l – mer composition.
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Hybridization on DNA Array
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l-mer composition
• Spectrum ( s, l ) - unordered multiset of all
possible (n – l + 1) l-mers in a string s of length n
• The order of individual elements in Spectrum ( s, l )
does not matter
• For s = TATGGTGC all of the following are
equivalent representations of Spectrum ( s, 3 ):
{TAT, ATG, TGG, GGT, GTG, TGC}
{ATG, GGT, GTG, TAT, TGC, TGG}
{TGG, TGC, TAT, GTG, GGT, ATG}
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
l-mer composition
• Spectrum ( s, l ) - unordered multiset of all
possible (n – l + 1) l-mers in a string s of length n
• The order of individual elements in Spectrum ( s, l )
does not matter
• For s = TATGGTGC all of the following are
equivalent representations of Spectrum ( s, 3 ):
{TAT, ATG, TGG, GGT, GTG, TGC}
{ATG, GGT, GTG, TAT, TGC, TGG}
{TGG, TGC, TAT, GTG, GGT, ATG}
• We usually choose the lexicographically maximal
representation as the canonical one.
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Different sequences – the same spectrum
• Different sequences may have the same
spectrum:
Spectrum(GTATCT,2)=
Spectrum(GTCTAT,2)=
{AT, CT, GT, TA, TC}
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The SBH Problem
• Goal: Reconstruct a string from its l-mer
composition
• Input: A set S, representing all l-mers from an
(unknown) string s
• Output: String s such that Spectrum ( s,l ) = S
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SBH: Hamiltonian Path Approach
S = { ATG AGG TGC TCC GTC GGT GCA CAG }
H ATG AGG TGC TCC GTC GGT GCA CAG
ATGCAGG TC C
Path visited every VERTEX once
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SBH: Hamiltonian Path Approach
A more complicated graph:
S = { ATG TGG TGC GTG GGC GCA GCG CGT }
H
An Introduction to Bioinformatics Algorithms www.bioalgorithms.info
SBH: Hamiltonian Path Approach
S = { ATG TGG TGC GTG GGC GCA GCG CGT }
Path 1:
H
ATGCGTGGCA
Path 2:
ATGGCGTGCA
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SBH: Eulerian Path Approach
S = { ATG, TGC, GTG, GGC, GCA, GCG, CGT }
Vertices correspond to ( l – 1 ) – mers : { AT, TG, GC, GG, GT, CA, CG }
Edges correspond to l – mers from S
GT CG
AT TG GC CA
Path visited every EDGE once
GG
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SBH: Eulerian Path Approach
S = { AT, TG, GC, GG, GT, CA, CG } corresponds to two different
paths:
GT CG GT CG
AT TG GC AT TG GC
CA CA
GG GG
ATGGCGTGCA ATGCGTGGCA
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Euler Theorem
• A graph is balanced if for every vertex the
number of incoming edges equals to the
number of outgoing edges:
in(v)=out(v)
• Theorem: A connected graph is Eulerian if
and only if each of its vertices is balanced.
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Euler Theorem: Proof
• Eulerian → balanced
for every edge entering v (incoming edge)
there exists an edge leaving v (outgoing
edge). Therefore
in(v)=out(v)
• Balanced → Eulerian
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Algorithm for Constructing an Eulerian Cycle
a. Start with an arbitrary
vertex v and form an
arbitrary cycle with unused
edges until a dead end is
reached. Since the graph is
Eulerian this dead end is
necessarily the starting
point, i.e., vertex v.
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Algorithm for Constructing an Eulerian Cycle (cont’d)
b. If cycle from (a) above is
not an Eulerian cycle, it
must contain a vertex w,
which has untraversed
edges. Perform step (a)
again, using vertex w as
the starting point. Once
again, we will end up in
the starting vertex w.
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Algorithm for Constructing an Eulerian Cycle (cont’d)
c. Combine the cycles
from (a) and (b) into
a single cycle and
iterate step (b).
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Euler Theorem: Extension
• Theorem: A connected graph has an
Eulerian path if and only if it contains at most
two semi-balanced vertices and all other
vertices are balanced.
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Some Difficulties with SBH
• Fidelity of Hybridization: difficult to detect
differences between probes hybridized with perfect
matches and 1 or 2 mismatches
• Array Size: Effect of low fidelity can be decreased
with longer l-mers, but array size increases
exponentially in l. Array size is limited with current
technology.
• Practicality: SBH is still impractical. As DNA
microarray technology improves, SBH may become
practical in the future
• Practicality again: Although SBH is still impractical,
it spearheaded expression analysis and SNP
analysis techniques
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Traditional DNA Sequencing
DNA
DNA fragments
Known
Vector location
Circular genome (restriction
(bacterium, plasmid) + = site)
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Different Types of Vectors
VECTOR Size of insert (bp)
Plasmid 2,000 - 10,000
Cosmid 40,000
BAC (Bacterial Artificial
70,000 - 300,000
Chromosome)
> 300,000
YAC (Yeast Artificial
Chromosome) Not used much
recently
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Shotgun Sequencing
genomic segment
cut many times at
random (Shotgun)
Get one or two
reads from each
segment
~500 bp ~500 bp
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Fragment Assembly
reads
Cover region with ~7-fold redundancy
Overlap reads and extend to reconstruct the
original genomic region
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Read Coverage
Length of genomic segment: L
Number of reads: n Coverage C=nl/L
Length of each read: l
How much coverage is enough?
Lander-Waterman model:
Assuming uniform distribution of reads, C=10 results in 1 gapped
region per 1,000,000 nucleotides
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Challenges in Fragment Assembly
• Repeats: A major problem for fragment assembly
• > 50% of human genome are repeats:
- over 1 million Alu repeats (about 300 bp)
- about 200,000 LINE repeats (1000 bp and longer)
Repeat Repeat Repeat
Green and blue fragments are interchangeable when
assembling repetitive DNA
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Triazzle: A Fun Example
The puzzle looks simple
BUT there are repeats!!!
The repeats make it
very difficult.
Try it – only $7.99 at
www.triazzle.com
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Repeat Types
• Low-Complexity DNA (e.g. ATATATATACATA…)
• Microsatellite repeats (a1…ak)N where k ~ 3-6
(e.g. CAGCAGTAGCAGCACCAG)
• Transposons/retrotransposons
• SINE Short Interspersed Nuclear Elements
(e.g., Alu: ~300 bp long, 106 copies)
• LINE Long Interspersed Nuclear Elements
~500 - 5,000 bp long, 200,000 copies
• LTR retroposons Long Terminal Repeats (~700 bp) at
each end
• Gene Families genes duplicate & then diverge
• Segmental duplications ~very long, very similar copies
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Overlap-Layout-Consensus
Assemblers: ARACHNE, PHRAP, CAP, TIGR, CELERA
Overlap: find potentially overlapping reads
Layout: merge reads into contigs and
contigs into supercontigs
..ACGATTACAATAGGTT..
Consensus: derive the DNA
sequence and correct read errors
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Overlap
• Find the best match between the suffix of one
read and the prefix of another
• Due to sequencing errors, need to use
dynamic programming to find the optimal
overlap alignment
• Apply a filtration method to filter out pairs of
fragments that do not share a significantly
long common substring
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Overlapping Reads
• Sort all k-mers in reads (k ~ 24)
• Find pairs of reads sharing a k-mer
• Extend to full alignment – throw away if not
>95% similar
TACA TAGATTACACAGATTAC T GA
|| ||||||||||||||||| | ||
TAGT TAGATTACACAGATTAC TAGA
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Overlapping Reads and Repeats
• A k-mer that appears N times, initiates N2
comparisons
• For an Alu that appears 106 times 1012
comparisons – too much
• Solution:
Discard all k-mers that appear more than
t × Coverage, (t ~ 10)
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Finding Overlapping Reads
Create local multiple alignments from the
overlapping reads
TAGATTACACAGATTACTGA
TAGATTACACAGATTACTGA
TAG TTACACAGATTATTGA
TAGATTACACAGATTACTGA
TAGATTACACAGATTACTGA
TAGATTACACAGATTACTGA
TAG TTACACAGATTATTGA
TAGATTACACAGATTACTGA
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Finding Overlapping Reads (cont’d)
• Correct errors using multiple alignment
C: 20 C: 20
C: 35 C: 35
T: 30 C: 0
TAGATTACACAGATTACTGA C: 35 C: 35
TAGATTACACAGATTACTGA C: 40 C: 40
TAG TTACACAGATTATTGA
TAGATTACACAGATTACTGA
TAGATTACACAGATTACTGA
A: 15 A: 15
A: 25 A: 25
- A: 0
A: 40 A: 40
A: 25 A: 25
• Score alignments
• Accept alignments with good scores
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Layout
• Repeats are a major challenge
• Do two aligned fragments really overlap, or
are they from two copies of a repeat?
• Solution: repeat masking – hide the
repeats!!!
• Masking results in high rate of misassembly
(up to 20%)
• Misassembly means alot more work at the
finishing step
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Merge Reads into Contigs
repeat region
Merge reads up to potential repeat boundaries
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Repeats, Errors, and Contig Lengths
• Repeats shorter than read length are OK
• Repeats with more base pair differencess
than sequencing error rate are OK
• To make a smaller portion of the genome
appear repetitive, try to:
• Increase read length
• Decrease sequencing error rate
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Error Correction
Role of error correction:
Discards ~90% of single-letter sequencing
errors
decreases error rate
⇒ decreases effective repeat content
⇒ increases contig length
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Merge Reads into Contigs (cont’d)
repeat region
• Ignore non-maximal reads
• Merge only maximal reads into contigs
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Merge Reads into Contigs (cont’d)
sequencing
repeat boundary??? error
b
a
• Ignore “hanging” reads, when detecting repeat boundaries
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Merge Reads into Contigs (cont’d)
?????
Unambiguous
• Insert non-maximal reads whenever unambiguous
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Link Contigs into Supercontigs
Normal density
Too dense:
Overcollapsed?
Inconsistent links:
Overcollapsed?
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Link Contigs into Supercontigs
(cont’d)
Find all links between unique contigs
Connect contigs incrementally, if ≥ 2 links
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Link Contigs into Supercontigs
(cont’d)
Fill gaps in supercontigs with paths of
overcollapsed contigs
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Link Contigs into Supercontigs
(cont’d) d ( A, B )
Contig A
Contig B
Define G = ( V, E )
V := contigs
E := ( A, B ) such that d( A, B ) < C
so Efficiency; full shortest paths cannot be computed
Reason to do so:
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Link Contigs into Supercontigs
(cont’d)
Contig A
Contig B
Define T: contigs linked to either A or B
Fill gap between A and B if there is a path in
G passing only from contigs in T
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Consensus
• A consensus sequence is derived from a
profile of the assembled fragments
• A sufficient number of reads is required to
ensure a statistically significant consensus
• Reading errors are corrected
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Derive Consensus Sequence
TAGATTACACAGATTACTGA TTGATGGCGTAA CTA
TAGATTACACAGATTACTGACTTGATGGCGTAAACTA
TAG TTACACAGATTATTGACTTCATGGCGTAA CTA
TAGATTACACAGATTACTGACTTGATGGCGTAA CTA
TAGATTACACAGATTACTGACTTGATGGGGTAA CTA
TAGATTACACAGATTACTGACTTGATGGCGTAA CTA
Derive multiple alignment from pairwise read
alignments
Derive each consensus base by weighted
voting
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EULER - A New Approach to
Fragment Assembly
• Traditional “overlap-layout-consensus” technique
has a high rate of mis-assembly
• EULER uses the Eulerian Path approach borrowed
from the SBH problem
• Fragment assembly without repeat masking can be
done in linear time with greater accuracy
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Overlap Graph: Hamiltonian
Approach
Each vertex represents a read from the original sequence.
Vertices from repeats are connected to many others.
Repeat Repeat Repeat
Find a path visiting every VERTEX exactly once: Hamiltonian path problem
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Overlap Graph: Eulerian Approach
Repeat Repeat Repeat
Placing each repeat edge
together gives a clear
progression of the path
through the entire sequence.
Find a path visiting every EDGE
exactly once:
Eulerian path problem
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Multiple Repeats
Repeat1 Repeat2 Repeat1 Repeat2
Can be easily
constructed with any
number of repeats
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Construction of Repeat Graph
• Construction of repeat graph from k – mers:
emulates an SBH experiment with a huge
(virtual) DNA chip.
• Breaking reads into k – mers: Transform
sequencing data into virtual DNA chip data.
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Construction of Repeat Graph (cont’d)
• Error correction in reads: “consensus first”
approach to fragment assembly. Makes
reads (almost) error-free BEFORE the
assembly even starts.
• Using reads and mate-pairs to simplify the
repeat graph (Eulerian Superpath Problem).
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Approaches to Fragment Assembly
Find a path visiting every VERTEX exactly
once in the OVERLAP graph:
Hamiltonian path problem
NP-complete: algorithms unknown
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Approaches to Fragment Assembly
(cont’d)
Find a path visiting every EDGE exactly once
in the REPEAT graph:
Eulerian path problem
Linear time algorithms are known
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Making Repeat Graph Without DNA
• Problem: Construct the repeat graph from a
collection of reads.
• Solution: Break the reads into smaller pieces.
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Repeat Sequences: Emulating a
DNA Chip
• Virtual DNA chip allows the biological
problem to be solved within the technological
constraints.
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Repeat Sequences: Emulating a
DNA Chip (cont’d)
• Reads are constructed from an original
sequence in lengths that allow biologists a
high level of certainty.
• They are then broken again to allow the
technology to sequence each within a
reasonable array.
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Minimizing Errors
• If an error exists in one of the 20-mer reads,
the error will be perpetuated among all of the
smaller pieces broken from that read.
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Minimizing Errors (cont’d)
• However, that error will not be present in the
other instances of the 20-mer read.
• So it is possible to eliminate most point
mutation errors before reconstructing the
original sequence.
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Conclusions
• Graph theory is a vital tool for solving
biological problems
• Wide range of applications, including
sequencing, motif finding, protein networks,
and many more
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References
• Simons, Robert W. Advanced Molecular Genetics Course,
UCLA (2002).
http://www.mimg.ucla.edu/bobs/C159/Presentations/Benzer.pdf
• Batzoglou, S. Computational Genomics Course, Stanford
University (2004).
http://www.stanford.edu/class/cs262/handouts.html
