Cross-Species Multi-Scalar Resolution of the Developing Lung Transcriptome

Alvin. T. Kho1*, Soumyaroop Bhattacharya3*, Vincent J. Carey3, Kelan G. Tantisira3,

Roger Gaedigk2, Scott T. Weiss3, J. Steven Leeder2 and Thomas J. Mariani3.

1Children’s Hospital Informatics Program, Children’s Hospital Boston, Boston, MA, 2Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, and

3Department of Medicine and the Channing Laboratory, Brigham and Women’s Hospital, Boston, MA.

Supported by NIH Grants: HL71885 (TJ Mariani); HL65899 (ST Weiss)

Introduction

• Regulatory mechanisms of human lung development are poorly defined

• Animal models complement human studies

• Can we resolve human developmental gene expression patterns using mouse data?

PCA of Mouse Samples

• 12 fetal (3 time points) and • 12 neonatal (3 time points)

mouse lung samples run on Affymetrix MG-U74Av2 arrays (Bonner et al. 2003)

PMT =

PCKM

Gene 1 Gene NPC1

*

Gene 1

M =

Gene N

Sample1 SampleKM

(Kho et al., 2004)Mouse PCA Co-ordinates => PM

T * M

PC1 vs PC2 all 12,488 probe sets (age labelled)

E & P, 45

PC1 vs PC2 all 54,675 probe sets (age labelled)

PCA of Human Samples

• 34 fetal and 11 neonatal human lung samples run on

Affymetrix HG-U133 Plus2.0 arrays

E, 34

Human PCA Co-ordinates => PHT * H

Projection of Human Samples in Mouse SpaceE & P 45

Rank Correl with

Age

E & P: 45

54,675 probe sets

E: 34

54,675 probe sets

E & P: 45

7,683 probe sets

E: 34

7,683 probe sets

PC1 0.930 0.675 0.966 0.933

40.51% 40.51%

10

.29

%

10

.29

%

E 34

10.2

9%

40.51%

New PCA Co-ordinates => PMT * H

Gene Ontology (GO) Enrichment

21

Human Lung Development

6

Mouse Lung Development

6

Mouse Cerebellum Development

6

Significant GO classes (EASE) @ Bonferroni corrected p<0.05for Genes with highest PC1, PC2 & PC3 loadings

GO Id Gene CategoryRank in Human

Rank in Mouse

GO:0009607 response to biotic stimulus 1 5

GO:0006952 defense response 2 2

GO:0006955 immune response 3 1

GO:0009613response to pest/pathogen/parasite 4 10

GO:0005576 extracellular 9 4

GO:0005615 extracellular space 13 3

Control Data set

Conclusions

• We observed large-scale concordance between human and murine developing lung transcriptome.

• PCA-based change-of-coordinates approach is applicable for general cross-systems multi-scalar model assessment.