Using evolutionary conserved modules in gene networks as a strategy to leverage high throughput gene expression queries.
BACKGROUND
Large-scale gene expression studies have not yielded the expected insight into genetic networks that control complex processes. These anticipated discoveries have been limited not by technology, but by a lack of effective strategies to investigate the data in a manageable and meaningful way. Previous work suggests that using a pre-determined seed-network of gene relationships to query large-scale expression datasets is an effective way to generate candidate genes for further study and network expansion or enrichment. Based on the evolutionary conservation of gene relationships, we test the hypothesis that a seed network derived from studies of retinal cell determination in the fly, Drosophila melanogaster, will be an effective way to identify novel candidate genes for their role in mouse retinal development.


RESULTS
Our results demonstrate that a number of gene relationships regulating retinal cell differentiation in the fly are identifiable as pairwise correlations between genes from developing mouse retina. In addition, we demonstrate that our extracted seed-network of correlated mouse genes is an effective tool for querying datasets and provides a context to generate hypotheses. Our query identified 46 genes correlated with our extracted seed-network members. Approximately 54% of these candidates had been previously linked to the developing brain and 33% had been previously linked to the developing retina. Five of six candidate genes investigated further were validated by experiments examining spatial and temporal protein expression in the developing retina.


CONCLUSIONS
We present an effective strategy for pursuing a systems biology approach that utilizes an evolutionary comparative framework between two model organisms, fly and mouse. Future implementation of this strategy will be useful to determine the extent of network conservation, not just gene conservation, between species and will facilitate the use of prior biological knowledge to develop rational systems-based hypotheses.
Serb
Jeanne M
JM
Department of Ecology, Evolution and Organismal Biology, Iowa State University, Ames, Iowa, United States of America. serb@iastate.edu
Orr
Megan C
MC
West Greenlee
M Heather
MH
D000465:Algorithms; D000818:Animals; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D015870:Gene Expression; D053263:Gene Regulatory Networks; D051379:Mice / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000254:growth & development / Q000378:metabolism
D011506:Proteins
Neuron. 2002 Jan 31;33(3):411-24
11832228
Bioinform Biol Insights. 2008 Feb 01;2:401-12
19812791
PLoS One. 2008 Sep 15;3(9):e3210
18791639
Arch Biochem Biophys. 1988 Nov 1;266(2):416-26
3190236
Genome Res. 2004 Jun;14(6):1085-94
15173114
Mech Dev. 2000 Apr;92(2):263-71
10727864
J Comp Neurol. 2001 Jan 22;429(4):601-14
11135238
Am J Hum Genet. 2007 Sep;81(3):507-18
17701896
Brain Res. 2006 Dec 18;1126(1):102-8
16938280
J Neurosci Methods. 2008 Sep 15;174(1):10-7
18640154
Bioinformatics. 2006 Jul 1;22(13):1616-22
16595558
Genes Cells. 2006 Dec;11(12):1337-52
17121542
J Neurosci Res. 2001 Nov 1;66(3):396-405
11746357
Invest Ophthalmol Vis Sci. 2004 Mar;45(3):1009-19
14985324
J Biol Chem. 2001 Mar 9;276(10):6889-92
11238441
FASEB J. 2009 May;23(5):1347-57
19126596
Cell Motil Cytoskeleton. 2001 Aug;49(4):229-40
11746667
Biochem Biophys Res Commun. 2006 Mar 3;341(1):1-5
16406235
Nature. 2002 Dec 5;420(6915):563-73
12466851
Nature. 2005 Aug 11;436(7052):861-5
16094371
Int J Dev Biol. 2004;48(8-9):913-24
15558482
Nucleic Acids Res. 2008 Jan;36(Database issue):D724-8
18158299
Development. 2001 Jul;128(13):2497-508
11493566
J Neurosci. 1996 Aug 15;16(16):5082-94
8756438
J Neurochem. 2008 Sep;106(5):2015-29
18513372
Int J Dev Biol. 2004;48(8-9):743-53
15558467
Hum Mol Genet. 2002 May 15;11(10):1161-7
12015275
PLoS Biol. 2004 Sep;2(9):E247
15226823
J Comput Biol. 2000;7(3-4):601-20
11108481
J Neurosci Res. 2008 Aug 1;86(10):2134-46
18338816
Hum Mol Genet. 2000 Apr 12;9(6):917-25
10767315
Invest Ophthalmol Vis Sci. 2007 Jan;48(1):40-51
17197514
Curr Eye Res. 2007 Mar;32(3):259-69
17453946
J Comp Neurol. 2007 Jun 20;502(6):1047-65
17444492
Hum Mol Genet. 2009 Jan 15;18(2):248-60
18930956
Neuroscience. 2004;123(4):951-65
14751288
Mol Cell Biol. 2007 May;27(9):3327-36
17325045
Development. 2000 Mar;127(6):1231-41
10683176
Surv Ophthalmol. 2008 Mar-Apr;53(2):150-63
18348880
FASEB J. 2008 Feb;22(2):401-9
17785607
J Neurobiol. 2003 Feb 5;54(2):358-69
12500311
J Neurosci Res. 2008 Jun;86(8):1823-35
18214992
Cell. 2007 Feb 9;128(3):547-60
17289573
Nat Rev Genet. 2002 Feb;3(2):103-13
11836504
Development. 2008 Nov;135(21):3531-41
18832395
Cell Tissue Res. 2005 Dec;322(3):365-78
16082520
Development. 2000 May;127(9):1879-86
10751176
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9037-42
12070347
Brain Res. 1999 Dec 11;850(1-2):1-13
10629743
Yonsei Med J. 2003 Dec 30;44(6):1059-68
14703617
Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5469-75
17122138
Development. 1998 Dec;125(23):4821-33
9806930
Gene. 2000 Jan 25;242(1-2):175-82
10721710
Genes Dev. 2001 Jan 1;15(1):24-9
11156601
EMBO Rep. 2005 Jun;6(6):563-9
15891769
Neuroscience. 2005;131(4):935-43
15749346
Brain Res Dev Brain Res. 2001 Jul 23;129(1):47-56
11454412
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D572-80
16381935
Pac Symp Biocomput. 2002;:437-49
11928497
Trends Genet. 1999 Sep;15(9):371-7
10461206
Nat Rev Neurosci. 2001 Feb;2(2):109-18
11252990
J Neurosci. 2004 Feb 25;24(8):1976-86
14985440
PLoS Genet. 2009 Mar;5(3):e1000414
19293945
Nucleic Acids Res. 2008 Jan;36(Database issue):D735-40
18056084
Brain Res Mol Brain Res. 1999 Jun 18;70(1):141-6
10381552
J Neurosci. 2001 Jun 15;21(12):4259-71
11404411
Exp Eye Res. 1998 Dec;67(6):699-707
9990334
Am J Hum Genet. 2007 Sep;81(3):552-8
17701900
Mol Vis. 2007 Jul 13;13:1144-53
17653061
Neuron. 2006 Dec 7;52(5):803-16
17145502
Nat Neurosci. 2005 Apr;8(4):435-42
15768038
J Neurochem. 2001 Dec;79(6):1129-35
11752054
Development. 2004 Mar;131(5):1065-73
14973285
Brain Res. 2000 Apr 10;861(2):399-407
10760501
Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3535-43
18441302
Mol Cell Biol Res Commun. 2000 Jul;4(1):20-5
11152623
Protein Sci. 2004 Feb;13(2):545-8
14718656
Brain Res. 1995 Feb 20;672(1-2):29-41
7749751
Dev Cell. 2009 Feb;16(2):280-91
19217429
Nat Med. 2003 Sep;9(9):1166-72
12910263
BMC Dev Biol. 2006 Oct 17;6:48
17044933
BMC Bioinformatics. 2007 Sep 27;8 Suppl 6:S5
17903286
J Neurosci. 2001 Aug 15;21(16):5973-83
11487620
Brain Res. 2006 Jul 7;1098(1):113-25
16777074
Genomics. 2005 Oct;86(4):476-88
16098712
Science. 1994 Aug 5;265(5173):785-9
7914031
J Neurosci. 2007 Dec 26;27(52):14459-69
18160654
Anat Embryol (Berl). 2001 Feb;203(2):77-87
11218061
Dev Biol. 1976 Oct 15;53(2):217-40
825400
J Neurosci. 2006 Feb 22;26(8):2241-9
16495451
J Neurochem. 1993 Dec;61(6):2104-14
8245965
BMC Dev Biol. 2005 Jul 20;5:14
16033648
J Neurosci. 2008 Jun 4;28(23):5910-9
18524895
Neuron. 2008 Sep 11;59(5):746-58
18786358
Genome Biol. 2004;5(12):R100
15575966
Novartis Found Symp. 2002;244:102-11; discussion 111-4, 203-6, 253-7
11990786
EMBO J. 2006 Jan 25;25(2):420-31
16407979
Development. 1999 Feb;126(5):935-43
9927595
Development. 1997 Jan;124(1):219-31
9006082