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行政院國家科學委員會專題研究計畫 成果報告

利用「行為資料採礦」探索生物系統的網路基序

計畫類別: 個別型計畫

計畫編號: NSC93-2213-E-110-029-

執行期間: 93 年 08 月 01 日至 94 年 07 月 31 日

執行單位: 國立中山大學資訊管理學系(所)

計畫主持人: 鄭炳強

共同主持人: 鄒文雄

計畫參與人員: 王修齊、侯雍聰

報告類型: 精簡報告

處理方式: 本計畫可公開查詢

中 華 民 國 94 年 10 月 26 日

(2)

Discovering network motifs by behavior data mining

NSC 93-2213-E-110-029

93

8

1

94

7

31

Email: [email protected]

(motif)

Abstract

In the era of post-genome, scientists are

aware that the study of biological systems has

to be upgraded from molecular level to

network level. Past research shows that there

are some highly re-occurrence subnets exist in

the biological networks of Saccharomyces

Cerevisiae and E. Coli, which are called

network motifs. It is guessed that they are

reserved in the evolution because of their

specific functions which are useful to a system.

Current approaches to discover network motifs

all assume prior knowledge of links between

molecular nodes, and justify the existence by

some statistic techniques. Since a motif has its

dynamics behavior model, it will be interesting

if one could discover it from the existing

experimental behavior data by some data

mining techniques. We made this attempt in

this project and discussed what we found and

encountered problems.

Keywords: Network Motif, Behavior

Datamining, Sequence Alignment

(network motif)

[3]

(randomized network)

[3, 5] Milo

Lee[4]

6

1.Autoregulatory 2. Feed-forward loop 3.

Multi-component loop 4.Single input module 5.

Multi-input module 6.Regulator cascade (

1)

1. Feed-forward

loop(FFL)

(3)

module

(threshold)

FFL

[3]

(

)

1. Examples of network motifs in the yeast

regulatory network

Lee, T., et.al.,2002[4]

Alon

FFL [13 14]

(model)

Alon

DNA

Microarray[12]

mRNA

Microarray

[10

11]

-

[2

13

14]

[6

7

8

9]

g

1

3

7

mRNA

g

2

4

8

g

1

g

2

time series

[16]

T

={X

1

,X

2

, K,

n

}

(real number)

X

i

i

T

j

j

mRNA

10

n = 10

T

1

= {X

1

,X

2

, K,

n

} T

2

= {Y

1

,Y

2

, K,

n

}

f(T

1

,T

2

)

= [

X

1

-Y

1 2

+(X

2

-Y

2

)

2

+

K+X

n

-Y

n

)]

1/2

f(T

1

,T

2

)

(

)

T

1

, T

2

f(T

1

,T

2

)

Euclidean Distance

Microarray

mRNA

[1]

metric

(4)

Microarray

X

i

Y

i 1

Liping Ji

[11]

- 1(

) -1(

)

0(

)

m

n

m n

T

ij

T

ij

i

j

mRNA(

)

1 <= i <= m

0 <= j <= n

T

ij

T

i(j+1)

T

ij

(1)

T

ij

0

T

ij

= (T

i(j+1)

- T

ij

) /

T

ij

(2)

T

ij

= 0

T

i(j+1)

> 0

T

ij

= 1

(3)

T

ij

= 0

T

i(j+1)

< 0

T

ij

= -1

(4)

T

ij

= 0

T

i(j+1)

= 0

T

ij

= 0

Normalization Threshold(t) (

1)

T

ij

T

ij

(1)

T

ij

t

T

ij

= 1

(2)

T

ij

-t

T

ij

= -1

(3)

T

ij

= 0

2

(pattern)

metric

Hamming Distance:

s t |s| = |t| s

t

Hamming Distance

H(s t) =

1

( , )

n i i i

mismatch s t

s

i

t

i

( , )

i i

mismatch s t =1

mismatch s t =0

( , )

i i

H

____________________________________ 1 2 : ababcc

global

H(s

1

s

2

)

(local)

H

abababaaaabababa

bcbcbcaaaababab

n

T

p

w; w < n 1 <= p <= n-w+1

C

p

=

{X

p

,X

p+1

, K

p+w-1

}

p

w-1

T

aabb bbcc

aabbcc

3

T

i

:{-1,0,1}

q

3

q

q-cluster[11]

:(0 0)

(0 1)

(1 0)

(1 1)

2

H = 0

q

q-clusters

FFL

[14]

FFL

X

Y

Y

Z

X

)

Y

Z

X

Y Z

q-cluster :

0 1 1 1 1

(3

2) (5

3) (7

4)

0 -1 -1 -1 -1

(3

7) (5

8) (7

8)

3

5

7

____________________________________ 3 sliding window

(5)

FFL

5

false-

positive

Microarray array

[13

14]

Microarray mRNA

[12]

(

FFL-Motif)

[13

14]

Microarray

(

mRNA

false- positive

[12]

Microarray

10

[12]

mRNA

(post-translational modification)

Microarray mRNA

[13

14]

[15]

Microarray

(

:

-DNA

-knockout

)

Microarray

[1] Patrick O. Brown and David Botstein, § Expl ori ng new world genome with DNA microarray. Nature Genet. 21, 33-37 (1999).

[2] Ptashne M., § Regul ati on of tr anscri pti on: fr o m lambda to eukaryotes. ¨Trends Biochem. Sci. 30, 275-279 (2005).

[3] Milo R. et al., § Net wor k Motifs: Si mpl e Buil di ng Blocks of Complex Networks. ¨ Science 298, 824-827 (2002).

[4] Tong Ihn Lee, Nicola J. Rinaldi, Francois Robert, Duncan T. Odom, Ziv Bar-Joseph, Georg K. Gerber, Nancy M. Hannett, Christopher T. Harbison, Craig M. Thompson, Itamar Simon, Julia Zeitlinger, Ezra G. Jennings, Heather L. Murray, D. Benjamin Gordon, Bing Ren, John J. Wyrick, Jean-Bosco Tagne, Thomas L. Volkert, Ernest Fraenkel, David K. Gifford, and Richard A. Young, Transcriptional Regulatory Networks in Saccharomyces cerevisiae. ¨Science 298, 799-804 (2002).

[5] Shen-Orr S.S., Milo R., Mangan S. & Alon U., Network motifs in the transcriptional regulation network of Escherichia coli. Nature Genet. 31, 64-68 (2002).

[6] Pilpel Y, Sudarsanam P, Church GM.,

Identifying regulatory networks by combinatorial analysis of promoter elements. Nature Genet. 29, 153-159 (2001).

[7] Bailey, Timothy L. and Noble, William Stafford, Searching for statistically significant regulatory modules. Bioinformatics 19, 16-25 (2003). [8] Butte AJ, Tamayo P, Slonim D, Golub TR,

Kohane IS, Discovering functional relationships between RNA Expression and chemotherapeutic susceptibility using relevance networks.

Proc. Natl. Acad. Sci. 22, 12182 6 (2000).

[9] Eisen, M.B., Spellman, P.T., Brown, P.O. and Botstein, D., Cluster Analysis and Display of Genome-wide expression patterns. Proc. Natl. Acad. Sci. 16, 707-726 (1998).

[10] Kwon, Andrew T., Hoos, Holger H., and Ng, Raymond, Inference of transcriptional regulation relationships from gene expression data. Bioinformatics 19, 905-912 (2003).

[11] Ji Liping and Tan Kian-Lee, Identifying Time-Lagged Gene Clusters on Gene Expression Data. ¨Bioinformatics 21, 509 - 516 (2005). [12] Spellman,P., Sherlock,G., Zhang,M., Iyer,V.,

Anders,K., Eisen,M., Brown,P., Botstein,D. and Futcher,B., § Co mpr ehensi v identification of cell cycle-regulated genes of the yeast Saccharomyces

(6)

cerevisiae microarray hybridization. ¨ Mol. Biol. Cell 9, 3273 3297 (1998).

[13] Mangan S. and Alon U., §Str uct ur e and f uncti on of the feed-forward loop network motif. Proc. Natl. Acad. Sci. USA 100, 11980 11985 (2003). [14] Mangan S., Zaslaver A. & Alon U., ¨ The

Coherent Feedforward Loop Serves as a Sign sensitive Delay Element in Transcription Networks. J. Mol. Biol. 334, 197 204 (2003). [15] Bar-Joseph, Z. § Anal yzi ng ti me seri es gene

expression data , Bioinformatics 20, 2493 2503 (2004)

[16] Antunes C.M. & Oliveira A.L., Temporal data mining: An overview. ¨KDD Workshop on Temporal Data Mining (2001)

參考文獻

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