Design Flow Enhancements for DNA Arrays

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Design Flow Enhancements for DNA Arrays
Andrew B. Kahng1 Ion I. Mandoiu2 Sherief Reda1
Xu Xu1 Alex Zelikovsky3
(1) CSE Department, University of California at
San Diego
(2) CSE Department, University of Connecticut
(3) CS Department, Georgia State University
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Introduction to DNA microarrays and manufacturing
challenges
DNA microarray design flow
DNA microarray design flow enhancements
Integration of Probe Placement and Embedding
Integration of Probe Selection and Physical Design
Conclusions and future research directions
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Uses of DNA arrays
Practical experiment using DNA arrays
DNA manufacturing process
Problems and challenges in DNA manufacturing
process
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Introduction to DNA Probe Arrays
DNA Arrays (Gene Chips) used in wide range of
genomic analyses gene expression detection drug
discovery mutation detection Diverse fields from
health care to environmental sciences
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DNA Array Hybridization Experiment
Tagged RNA fragments flushed over array
Images courtesy of Affymetrix.
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DNA Array Manufacturing Process
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A 33 array
CG
AC
G
AC
ACG
AG
AG
C
CG
Nucleotide Deposition Sequence ACG
array probes
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A 33 array
CG
AC
G
AC
ACG
AG
AG
C
CG
Nucleotide Deposition Sequence ACG
array probes
9
A 33 array
CG
AC
G
AC
ACG
AG
AG
C
CG
Nucleotide Deposition Sequence ACG
array probes
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A 33 array
CG
AC
G
AC
ACG
AG
AG
C
CG
Nucleotide Deposition Sequence ACG
array probes
12
Introduction to DNA arrays manufacturing
challenges
DNA array design flow
DNA array design flow enhancements
Integration of Probe Placement and Embedding
Integration of Probe Selection and Physical Design
Conclusions
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Border minimization was first introduced by
Feldman and Pevzner. Gray Code masks for
sequencing by hybridization, Genomics, 1994, pp.
233-235
Work by Hannenhalli et al. gave heuristics for
the placement problem by using a TSP formulation.
Kahng et al. Border length minimization in DNA
Array Design, WABI02, suggested constructive
methods for placement and embedding
Kahng et al. Engineering a Scalable Placement
Heuristic for DNA Probe Arrays , RECOMB03,
suggested scalable placement improvement and
embedding techniques
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Probe Selection
Logic Synthesis
Probe Selection
Logic Synthesis
BIST and DFT
Analogy
Placement
Physical Design
Routing
DNA Array
VLSI Chip
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Physical Design
Probe Embedding
? Degrees of freedom (DOF) in probe embedding
? DOF exploitation for border conflict reduction
Probe Placement
? Similar probes should be placed close together
? Constructive placement
? Placement improvement operators
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G
Group
T
C
Deposition Sequence
Hypothetical Probe
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Embedding Determines Border Conflicts
G
T
C
A
G
T
C
Deposition Sequence
A
G
T
Probes
C
A
A
A
G
G
T
T
T
G
C
G
A
A
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Problem Optimally embedding a probe with respect
to its neighbors
T
A
T
G
G
A
A
A
A
A
A
A
C
A
Before optimal re-embedding
Kahng et al. Border Length Minimization in DNA
Array Design, WABI02
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Use optimal re-embedding algorithm to re-embed
each probe with respect to its neighbors
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Radix-sorting the probes order reduces
discrepancies between adjacent probes
1
2
3
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Probe 1
Probe 2
Probe 3
Probe 5
Probe 4
Radix-sort the probes in lexicographical order
Problem How to place the 1-D ordering of probes
onto the 2-D chip?
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1
2
3
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2
3
Probe 1
Probe 2
5
4
1
Probe 3
Probe 4
Probe 5
Thread on the chip
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For each site position (i, j)
From within the next k rows, find the best probe
to place in (i, j)
Move the best probe to (i, j) and lock it in this
position
Array of size 4 4
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Introduction to DNA arrays manufacturing
challenges
DNA array design flow
DNA array design flow enhancements
Integration of Probe Placement and Embedding
Integration of Probe Selection and Physical Design
Conclusions
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Integration of Probe Placement and Embedding
Probe Selection
? Initial embeddings influence the placement
results
? Propose and implement two flows
Integration of Probe Selection and Physical Design
? Probe pools add additional degrees of freedom
Physical Design
? Integrate probe selection into physical design
? Propose and implement two flows incorporating
probe pools
DNA Array
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Probe Selection
DNA Array
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Row Epitaxial
Re-embedding
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Probe Pool Pool Size 4
Probe Selection
Probe 1
Probe 2
Probe 3
Probe 4
Gene Target Sequence
Physical Design
DNA Array
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Chip size 100
Chip size 200
Conflicts
Conflicts
Pool Size
Pool Size
Chip size 300
Chip size 500
Conflicts
Conflicts
Pool Size
Pool Size
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Chip size 100
Chip size 200
CPU (1000s)
CPU (1000s)
Pool Size
Pool Size
Chip size 300
Chip size 500
CPU (1000s)
CPU (1000s)
Pool Size
Pool Size
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Initial ASAP embeddings produce a decent
reduction in border conflicts.
Integration of placement and embedding yield up
to 6 improvement
Probe pools add an extra 12-13 improvement
Probe pools offer an extra degree of freedom
exploited to further reduce border conflicts
Total improvement up to 18 compared to results
published in the literature
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Probe selection should incorporate ability to
uniquely detect target sequences present in
sample. This should be done with no ambiguity.
Methods similar to Boolean covering and test
diagnosis can be used.
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Insertion of probe test can benefit from test and
diagnosis topics for VLSI circuits.
Stronger placement operators leading to further
reduction in the border cost.
Future work also covers next generation chips 10k
10k
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We presented a DNA design flow benefiting from
experiences of the VLSI design flow
We introduced feedback loops and integrated a
number of steps for further reduction in the
border cost and hence unwanted illumination
We examined the embedding options and placement
on the total border cost
We examined the effects of probe selection on
both placement and embedding
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